Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [ClH:1].[NH:2]1[C:6]2=[N:7][CH:8]=[CH:9][C:10]([O:11][C:12]3[CH:17]=[CH:16][C:15]([NH:18]C4C(C(NC5C=CC(F)=CC=5F)=O)=CN=CC=4)=[CH:14][C:13]=3[F:36])=[C:5]2[CH:4]=[CH:3]1.[CH2:37]([NH:44][C:45](=[O:53])[C:46]1[CH:51]=[CH:50][CH:49]=[N:48][C:47]=1[Cl:52])[C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1>>[ClH:52].[ClH:1].[NH:2]1[C:6]2=[N:7][CH:8]=[CH:9][C:10]([O:11][C:12]3[CH:17]=[CH:16][C:15]([NH:18][C:47]4[N:48]=[CH:49][CH:50]=[CH:51][C:46]=4[C:45]([NH:44][CH2:37][C:38]4[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=4)=[O:53])=[CH:14][C:13]=3[F:36])=[C:5]2[CH:4]=[CH:3]1
Reactant: O=C(NCc1ccccc1)c1cccnc1Cl
Reactant: O=C(Nc1ccc(F)cc1F)c1cnccc1Nc1ccc(Oc2ccnc3[nH]ccc23)c(F)c1
Agent: Cl
Product: O=C(NCc1ccccc1)c1cccnc1Nc1ccc(Oc2ccnc3[nH]ccc23)c(F)c1
Yield: 15.8 %

Procedure:
4-(1H-Pyrrolo[2,3-b]pyridin-4-yloxy)-3-fluorobenzenamine (0.043 g, 0.18 mmol, Compound C of Example 1) was converted to the title compound (0.015 g, 17%) in a manner similar to the preparation of 4-(4-(1H-pyrrolo[2,3-b]pyridin-4-yloxy)-3-fluorophenylamino)-N-(2,4-difluorophenyl)nicotinamide hydrochloride salt (Compound D of Example 1), except that N-benzyl-2-chloronicotinamide (Maybridge, 0.043 g, 0.18 mmol) was used instead of 4-chloro-N-(2,4-difluorophenyl)nicotinamide.
Reaction SMILES: [Cl:1][C:2]([C:6]1[CH:7]=[C:8]([CH3:17])[CH:9]=[C:10]([C:12]([Cl:16])=[C:13]([Cl:15])[Cl:14])[CH:11]=1)=[C:3]([Cl:5])[Cl:4].C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1.[Br:36]N1C(=O)CCC1=O>C1C=CC=CC=1>[Cl:1][C:2]([C:6]1[CH:7]=[C:8]([CH:9]=[C:10]([C:12]([Cl:16])=[C:13]([Cl:15])[Cl:14])[CH:11]=1)[CH2:17][Br:36])=[C:3]([Cl:5])[Cl:4]
Reactant: Cc1cc(C(Cl)=C(Cl)Cl)cc(C(Cl)=C(Cl)Cl)c1
Reactant: O=C1CCC(=O)N1Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: c1ccccc1
Product: ClC(Cl)=C(Cl)c1cc(CBr)cc(C(Cl)=C(Cl)Cl)c1

Procedure:
A solution of 3,5-di(trichlorovinyl)toluene (6.0 g) and dibenzoyl peroxide (200 mg) in 150 ml of benzene was heated at reflux. N-Bromosuccinimide (3.6 g) was added in portions and the reaction mixture stirred at reflux for 3 hours. The mixture was evaporated and the residue triturated with 200 ml of hexane. The precipitated succinimide was collected and the filtrate concentrated to five 7.9 g of crude benzyl bromide.
Reaction SMILES: C(=O)([O-])[O-].[Na+].[Na+].[F:7][C:8]1[C:21]2[O:20][C:19]3[C:14](=[CH:15][C:16]([C:22]4[C:23]([F:28])=[N:24][CH:25]=[CH:26][CH:27]=4)=[CH:17][CH:18]=3)[C@@:13]3([CH2:32][O:31][C:30]([NH2:33])=[N:29]3)[C:12]=2[CH:11]=[C:10](B2OC(C)(C)C(C)(C)O2)[CH:9]=1.Br[C:44]1[N:45]=[N:46][C:47]([CH3:50])=[CH:48][CH:49]=1>CN(C=O)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[F:7][C:8]1[C:21]2[O:20][C:19]3[C:14](=[CH:15][C:16]([C:22]4[C:23]([F:28])=[N:24][CH:25]=[CH:26][CH:27]=4)=[CH:17][CH:18]=3)[C@@:13]3([CH2:32][O:31][C:30]([NH2:33])=[N:29]3)[C:12]=2[CH:11]=[C:10]([C:44]2[N:45]=[N:46][C:47]([CH3:50])=[CH:48][CH:49]=2)[CH:9]=1
Reactant: CC1(C)OB(c2cc(F)c3c(c2)[C@]2(COC(N)=N2)c2cc(-c4cccnc4F)ccc2O3)OC1(C)C
Reactant: Cc1ccc(Br)nn1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1ccc(-c2cc(F)c3c(c2)[C@]2(COC(N)=N2)c2cc(-c4cccnc4F)ccc2O3)nn1
Temperature: 85 °C

Procedure:
Sodium carbonate (saturated, 1 mL), Pd(PPh3)4 (23.52 mg, 0.020 mmol), (S)-4′-fluoro-7′-(2-fluoropyridin-3-yl)-2′-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5H-spiro[oxazole-4,9′-xanthen]-2-amine (200 mg, 0.407 mmol), and 3-bromo-6-methylpyridazine (141 mg, 0.814 mmol) were combined in DMF (5 mL). The solution was heated at 85° C. overnight. The solution was filtered through celite and the derived residue was purified via Gilson HPLC (gradient elution 25-65% MeCN/H2O, 0.1% TFA) to afford (S)-4′-fluoro-7′-(2-fluoropyridin-3-yl)-2′-(6-methylpyridazin-3-yl)-5H-spiro[oxazole-4,9′-xanthen]-2-amine as an off white solid. MS m/z=458.0 [M+H].
Reaction SMILES: [O:1]=[C:2]1[CH2:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([NH:11][C:12](=[O:16])[C:13]([OH:15])=O)[CH:8]=2)[NH:3]1.[O:17]([CH:24]1[CH2:29][CH2:28]N(C)CC1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>C(OCC)C>[O:15]=[C:13]([N:3]1[CH2:4][CH2:28][CH:29]([CH2:24][O:17][C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH2:10][CH2:2]1)[C:12]([NH:11][C:7]1[CH:8]=[C:9]2[C:4](=[CH:5][CH:6]=1)[NH:3][C:2](=[O:1])[CH2:10]2)=[O:16]
Reactant: O=C1Cc2cc(NC(=O)C(=O)O)ccc2N1
Reactant: CN1CCC(Oc2ccccc2)CC1
Solvent: CCOCC
Product: O=C1Cc2cc(NC(=O)C(=O)N3CCC(COc4ccccc4)CC3)ccc2N1

Procedure:
The title compound is prepared from N-(2-oxo-2,3-dihydro-1H-indol-5-yl)-oxalamic acid (Example 101b) and 4-phenoxy-methyl-piperidine according to the method described in Example 1c. Melting Point: 200-202° C. (diethylether)
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][N:14]([CH2:17][CH2:18][CH2:19][CH2:20][OH:21])[C:13](=[O:22])[C@@H:12]1[CH3:23])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.ClN1C(=O)N(Cl)C(=O)N(Cl)C1=O>ClCCl.CC1(C)N([O])C(C)(C)CCC1>[CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][N:14]([CH2:17][CH2:18][CH2:19][CH:20]=[O:21])[C:13](=[O:22])[C@@H:12]1[CH3:23])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: C[C@H]1C(=O)N(CCCCO)CCN1C(=O)OCc1ccccc1
Agent: CC1(C)CCCC(C)(C)N1[O]
Agent: O=c1n(Cl)c(=O)n(Cl)c(=O)n1Cl
Solvent: ClCCl
Product: C[C@H]1C(=O)N(CCCC=O)CCN1C(=O)OCc1ccccc1
Reaction time: 0.08 h
Yield: 94 %

Procedure:
To a solution of (S)-4-(4-hydroxy-butyl)-2-methyl-3-oxo-piperazine-1-carboxylic acid benzyl ester (1.67 g, 5.21 mmol) in dichloromethane (18 mL) were added at room temperature trichloroisocyanuric acid (1.28 g, 5.21 mmol) and 2,2,6,6-tetramethylpiperidin-1-oxyl (8 mg, 0.05 mmol), upon which an exothermic reaction (Tmax=36° C.) under gas evolution started. The reaction mixture was stirred for 5 min, then insoluble material was removed by filtration. The filtrate was washed with 1 M aq. sodium thiosulfate solution and brine, dried (MgSO4), filtered, and evaporated to afford (S)-4-(4-oxo-butyl)-2-methyl-3-oxo-piperazine-1-carboxylic acid benzyl ester (1.56 g). This aldehyde (MS (ISP)=319.1 (M+H)+) was taken up in dichloromethane (9 mL) and added at room temperature to a suspension of (S)-6-aza-spiro[2.5]octan-4-ol hydrochloride (intermediate 2; 853 mg, 5.21 mmol), triethylamine (527 mg, 5.21 mmol), acetic acid (626 mg, 10.4 mmol), and sodium triacetoxyborohydride (1.21 g, 5.73 mmol) in dichloromethane (9 mL). The reaction mixture was stirred for 30 min, then cooled to 0° C. and treated with 25% aq. ammonia solution (1.07 mL), then allowed to reach room temperature and concentrated in vacuo. Chromatography (SiO2; dichloromethane→dichloromethane/methanol/25% aq. ammonia solution 90:10:0.25) afforded the title compound (1.26 g, 56%). Colorless gum, MS (ISP)=430.3 (M+H)+.
Reaction SMILES: C(Cl)CCl.[NH2:5][C:6]1[N:11]=[CH:10][C:9](/[CH:12]=[CH:13]/[C:14]([OH:16])=O)=[CH:8][CH:7]=1.Cl.[CH3:18][C:19]1[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH2:21][C:20]=1[CH2:28][NH:29][CH3:30].C1C=CC2N(O)N=NC=2C=1.O.C(N(CC)CC)C>CN(C=O)C>[NH2:5][C:6]1[N:11]=[CH:10][C:9](/[CH:12]=[CH:13]/[C:14]([N:29]([CH3:30])[CH2:28][C:20]2[C:19]([CH3:18])=[C:27]3[C:22](=[CH:23][CH:24]=[CH:25][CH2:26]3)[CH:21]=2)=[O:16])=[CH:8][CH:7]=1
Reactant: CNCC1=C(C)c2ccccc2C1
Reactant: Nc1ccc(/C=C/C(=O)O)cn1
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: CCN(CC)CC
Solvent: O
Product: CC1=C2CC=CC=C2C=C1CN(C)C(=O)/C=C/c1ccc(N)nc1
Reaction time: 8 h
Yield: 51.7 %

Procedure:
EDC (0.383 g, 2.0 mmole) was added to a solution of (E)-3-(6-aminopyridin-3-yl)acrylic acid (0.328 g, 2.0 mmole), 3-methyl-2-(methylaminomethyl)indene hydrochloride (0.420 g, 2.0 mmole), HOBt.H2O (0.306 g, 2.0 mmole), and triethylamine (0.57 mL, 4.0 mmole) in anhydrous DMF (18 mL) at RT. The reaction was stirred overnight and concentrated in vacuo. The residue was diluted with 5% NaHCO3 and extracted with CH2Cl2. The combined organic extracts were washed with brine and dried over MgSO4. Flash chromatography on silica gel (3% MeOH/CH2Cl2) gave the title compound (0.33 g, 52%) as a colorless solid: MS (ES) m/e 320.2 (M+H)+. Anal. Calcd for C20H21N3O.0.4H2O: C, 73.57; H, 6.72; N, 12.86. Found: C, 73.94; H, 6.92; N, 12.50.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([S:9][C:10]2[N:14]([CH2:15][CH3:16])[N:13]=[C:12]([CH3:17])[C:11]=2[CH2:18]O)[CH:5]=[C:6]([Cl:8])[CH:7]=1.[C:20](Br)(Br)(Br)[Br:21].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>ClCCl>[Br:21][CH2:20][CH2:18][C:11]1[C:12]([CH3:17])=[N:13][N:14]([CH2:15][CH3:16])[C:10]=1[S:9][C:4]1[CH:3]=[C:2]([Cl:1])[CH:7]=[C:6]([Cl:8])[CH:5]=1
Reactant: CCn1nc(C)c(CO)c1Sc1cc(Cl)cc(Cl)c1
Reactant: BrC(Br)(Br)Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: CCn1nc(C)c(CCBr)c1Sc1cc(Cl)cc(Cl)c1
Temperature: 25 °C
Reaction time: 24 h
Yield: 68.6 %

Procedure:
A mixture of 460 mg of [5-(3,5-dichloro-phenylsulphanyl)-1-ethyl-3-methyl-1H-pyrazol-4-yl-]methanol, 481 mg of carbon tetrabromide and 380 mg of triphenylphosphine in 20 ml of dichloromethane was stirred at room temperature for 24 hours. The solvent was evaporated. The residue was purified by flash chromatography on silica gel using ethyl acetate/petroleum ether (bp 40–60° C.) (1:4) for the elution to give 392 mg of 4-bromoethyl-5-(3,5-dichloro-phenylsulfanyl)-1-ethyl-3-methyl-1H-pyrazole as a pale yellow oil. Mass spectrum (ES) m/z 317 [M−Br+H2O]+.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:12]3[N:13]=[C:14]4[C:20]([C:21](O)=[O:22])=[CH:19][N:18]([CH2:24][O:25][CH2:26][CH2:27][Si:28]([CH3:31])([CH3:30])[CH3:29])[C:15]4=[N:16][CH:17]=3)=[N:7][N:8]2[CH3:11])=[CH:4][CH:3]=1.[NH2:32][C@@H:33]([CH3:36])[CH2:34][OH:35].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C1C=CC2N(O)N=NC=2C=1.C(N(CC)C(C)C)(C)C>CN(C=O)C>[OH:35][CH2:34][C@@H:33]([NH:32][C:21]([C:20]1[C:14]2[C:15](=[N:16][CH:17]=[C:12]([C:6]3[C:5]4[C:9](=[CH:10][C:2]([Cl:1])=[CH:3][CH:4]=4)[N:8]([CH3:11])[N:7]=3)[N:13]=2)[N:18]([CH2:24][O:25][CH2:26][CH2:27][Si:28]([CH3:29])([CH3:31])[CH3:30])[CH:19]=1)=[O:22])[CH3:36]
Reactant: Cn1nc(-c2cnc3c(n2)c(C(=O)O)cn3COCC[Si](C)(C)C)c2ccc(Cl)cc21
Reactant: C[C@H](N)CO
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: C[C@@H](CO)NC(=O)c1cn(COCC[Si](C)(C)C)c2ncc(-c3nn(C)c4cc(Cl)ccc34)nc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 65.7 %

Procedure:
A 25 mL round-bottomed flask was charged with 2-(6-chloro-1-methyl-1H-indazol-3-yl)-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid (0.20 g, 0.44 mmol), (S)-2-aminopropan-1-ol (0.10 ml, 1.31 mmol), HBTU (331 mg, 0.87 mmol), and HOBT (134 mg, 0.87 mmol). Then added DMF (1 mL) followed by N,N-diisopropylethylamine (0.31 mL, 1.75 mmol). The yellow reaction mixture was stirred at room temperature overnight then quenched with water and extracted with EtOAc (30 mL). The organic layer was washed once with saturated NaHCO3 and water. The combined aqueous layers were back extracted with EtOAc (25 mL). The combined organic layers was dried over sodium sulfate, filtered and concentrated. The residue was purified by chromatography over SiO2 with EtOAc/hexanes (gradient: 0-100% EtOAc) to afford 149 mg (66%) of 2-(6-chloro-1-methyl-1H-indazol-3-yl)-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid ((S)-2-hydroxy-1-methyl-ethyl)-amide as a white solid.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:11])[CH2:9][CH3:10])=[CH:4][CH:3]=1.[C:12]([Si:14]([CH3:17])([CH3:16])[CH3:15])#[CH:13].C(NC(C)C)(C)C>O1CCCC1.O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I>[CH3:15][Si:14]([C:12]#[C:13][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:11])[CH2:9][CH3:10])=[CH:4][CH:3]=1)([CH3:17])[CH3:16]
Reactant: C#C[Si](C)(C)C
Reactant: CCC(=O)c1ccc(Br)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: C1CCOC1
Solvent: O
Solvent: CC(C)NC(C)C
Product: CCC(=O)c1ccc(C#C[Si](C)(C)C)cc1

Procedure:
A mixture of 1.74 g 4′-bromopropiophenone, 2.0 g ethynyltrimethylsilane, 260 mg bis(triphenylphosphine)palladium(II) dichloride, 260 mg copper(I) iodide and 15 ml diisopropylamine in 40 ml tetrahydrofuran is heated at reflux for 1 h. After cooling the reaction mixture is diluted with water and extracted with ethyl acetate. The combined organic layer is washed with brine, dried over sodium sulfate and evaporated under reduced pressure. The residue is purified by chromatography on silica gel, using a mixture of heptane/ethyl acetate 9:1 as eluent to obtain 1-(4-trimethylsilanylethynylphenyl)propan-1-one, m.p. 36-37° C.
Reaction SMILES: [C:1]([C:4]1[CH2:8][C:7](=[O:9])[N:6]([C:10]2[CH:15]=[CH:14][C:13]([S:16]([NH2:19])(=[O:18])=[O:17])=[CH:12][CH:11]=2)[N:5]=1)(=[O:3])[CH3:2].C(O)(=[O:22])C>>[CH3:8][C:4]1[C:1](=[O:3])[C:2](=[O:22])[C:7](=[O:9])[N:6]([C:10]2[CH:11]=[CH:12][C:13]([S:16]([NH2:19])(=[O:17])=[O:18])=[CH:14][CH:15]=2)[N:5]=1
Reactant: CC(=O)O
Reactant: CC(=O)C1=NN(c2ccc(S(N)(=O)=O)cc2)C(=O)C1
Product: CC1=NN(c2ccc(S(N)(=O)=O)cc2)C(=O)C(=O)C1=O
Reaction time: 2 h

Procedure:
To a suspension of 1.5 g. (4.09 mmole) of 4-(3-acetyl-5-oxo-2-pyrazolin-1-yl)benzene sulfonamide in 5 ml. of acetic acid was added 1.94 g. (12 mmoles) of FeCl3 and the mixture was heated to 90° C. for 12 hours. After cooling, the solids were collected by filtration and washed with water and dried. The material was then dissolved in 10 ml. of water and triethylamine and 2 g. of sodium sulfide added. After 2 hours, the mixture was acidified with 6 N hydrochloric acid and the solid collected by centrifugation, there was obtained 1.1 g. of material.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH:11]1[CH2:16][CH2:15][N:14]([CH3:17])[CH2:13][CH2:12]1)[CH:6]=[CH:5]2.C(P(C(C)(C)C)C(C)(C)C)(C)(C)C.C[Si]([N-:35][Si](C)(C)C)(C)C.[Li+]>[Pd].[Pd].C(=CC(C=CC1C=CC=CC=1)=O)C1C=CC=CC=1.C(=CC(C=CC1C=CC=CC=1)=O)C1C=CC=CC=1.C(=CC(C=CC1C=CC=CC=1)=O)C1C=CC=CC=1.O1CCCC1>[CH3:17][N:14]1[CH2:15][CH2:16][CH:11]([N:7]2[C:8]3[C:4](=[CH:3][C:2]([NH2:35])=[CH:10][CH:9]=3)[CH:5]=[CH:6]2)[CH2:12][CH2:13]1
Reactant: C[Si](C)(C)[N-][Si](C)(C)C
Reactant: CN1CCC(n2ccc3cc(Br)ccc32)CC1
Agent: [Pd]
Agent: CC(C)(C)P(C(C)(C)C)C(C)(C)C
Agent: O=C(C=Cc1ccccc1)C=Cc1ccccc1
Solvent: C1CCOC1
Product: CN1CCC(n2ccc3cc(N)ccc32)CC1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 49.2 %

Procedure:
Compound 80 (265 mg, 0.904 mmol), Tris(dibenzylideneacetone) dipalladium (0) (82.7 mg, 0.0904 mmol) and anhydrous tetrahydrofuran (20 mL) were charged to a dry argon purged flask fitted with magnetic stir bar and condenser. A solution of tri-tert-butylphosphine (10 wt % in hexane, 365.7 mg, 538 ul, 0.1808 mmol) is added followed by dropwise addition of a 1 M tetrahydrofuran solution of lithium bis(trimethylsilyl)amide (2.71 ml, 2.710 mmol) and mixture refluxed for a period of 45 minutes. The mixture was cooled to room temperature then to 0° C., quenched with 1M HCl (10 mL) and stirred for 10 minutes. The solution was diluted with ethyl acetate and 5M NH4OH added to adjust pH to 9. The mixture was transferred to a separatory funnel and the organic layer collected. The aqueous layer was further extracted with ethyl acetate and the combined organic layers were washed with brine, dried over magnesium sulphate, filtered, concentrated and the residue purified via chromatography on silica gel (EtOAc:methanol:Et3N, 8:1:1) to yield a pale yellow solid 81 (102 mg, 49.2%). 1H NMR (DMSO-d6) δ: 1.80-1.98 (m, 4H), 2.11 (dt, 2H, J=11.2, 3.5 Hz), 2.23 (s, 3H), 2.88 (d, 2H, J=11.6 Hz), 4.08-4.19 (m, 1H), 4.46 (brs, 2H), 6.13 (d, 1H, J=3.0 Hz), 6.51 (dd, 1H, J=8.8, 2.1 Hz), 6.67 (d, 1H, J=2.0 Hz), 7.18 (d, 1H, J=8.6 Hz), 7.24 (d, 1H, J=3.1 Hz); EI-MS (m/z, %): 229 (M+, 100%).
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:6]=[CH:7][C:8]2[O:12][CH2:11][C:10]([CH2:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)([CH3:13])[C:9]=2[CH:21]=1)=[O:4].[OH-].[Na+].C(O)C.Cl>O1CCCC1.O>[CH2:14]([C:10]1([CH3:13])[C:9]2[CH:21]=[C:5]([C:3]([OH:4])=[O:2])[CH:6]=[CH:7][C:8]=2[O:12][CH2:11]1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: COC(=O)c1ccc2c(c1)C(C)(Cc1ccccc1)CO2
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Solvent: C1CCOC1
Product: CC1(Cc2ccccc2)COc2ccc(C(=O)O)cc21
Temperature: 25 °C
Reaction time: 12 h
Yield: 98.3 %

Procedure:
A mixture of 3-Benzyl-3-methyl-2,3-dihydro-benzofuran-5-carboxylic acid methyl ester (125 mg, 0.44 mmol), sodium hydroxide (120 mg, 3 mmol), ethanol (6 mL) and water (1 mL) in tetrahydrofuran (6 mL), is stirred for 12 h at room temperature. The reaction medium is acidified by adding a 1.2 M hydrochloric acid solution and extracted with ethyl acetate. The organic phase is washed with water, dried (Na2SO4), and concentrated in a rotary evaporator. The product is obtained as slightly brown oil (116 mg, 97%).
Reaction SMILES: C[O:2][C:3](=[O:37])[CH:4]=[CH:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[CH:17]=[CH:16][C:15]([O:18][CH2:19][C:20]3[N:21]([C:28]4[C:33]([Cl:34])=[CH:32][CH:31]=[CH:30][C:29]=4[Cl:35])[N:22]=[CH:23][C:24]=3[CH:25]([CH3:27])[CH3:26])=[CH:14][C:13]=2[CH3:36])=[CH:8][CH:7]=1.[OH-].[Na+]>O.C1COCC1.CO>[Cl:34][C:33]1[CH:32]=[CH:31][CH:30]=[C:29]([Cl:35])[C:28]=1[N:21]1[C:20]([CH2:19][O:18][C:15]2[CH:16]=[CH:17][C:12]([C:9]3[CH:10]=[CH:11][C:6]([CH:5]=[CH:4][C:3]([OH:37])=[O:2])=[CH:7][CH:8]=3)=[C:13]([CH3:36])[CH:14]=2)=[C:24]([CH:25]([CH3:27])[CH3:26])[CH:23]=[N:22]1
Reactant: COC(=O)C=Cc1ccc(-c2ccc(OCc3c(C(C)C)cnn3-c3c(Cl)cccc3Cl)cc2C)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: Cc1cc(OCc2c(C(C)C)cnn2-c2c(Cl)cccc2Cl)ccc1-c1ccc(C=CC(=O)O)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 30.2 %

Procedure:
A mixture of 3-{4′-[2-(2,6-dichloro-phenyl)-4-isopropyl-2H-pyrazol-3-ylmethoxy]-2′-methyl-biphenyl-4-yl}-acrylic acid methyl ester (510 mg, 0.928 mmol), 5 N sodium hydroxide (928 μL, 4.64 mmol), methanol (15 mL) and THF (12 mL) is stirred overnight at room temperature. The reaction mixture is diluted with water and most of the THF and methanol is evaporated. The remaining aqueous portion is washed with ether and the ether layer is discarded. The aqueous layer is acidified with 1 N HCl and extracted with ether. The combined ether layers are washed with brine, dried over anhydrous magnesium sulfate, and concentrated. The residue is purified using flash chromatography with 5% MeOH/CH2Cl2 and triturated in ether-hexane to give 146 mg (30%) of the title compound. ES/MS m/e (35Cl) 521.3 (M+1)
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][CH:11]=1)[C:5]([O:7][CH3:8])=[O:6].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C.[C:45]1([C:51]#[C:52][C:53]2[N:57]3[CH:58]=[CH:59][CH:60]=[CH:61][C:56]3=[N:55][C:54]=2[CH2:62]O)[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=1>O1CCCC1>[C:45]1([C:51]#[C:52][C:53]2[N:57]3[CH:58]=[CH:59][CH:60]=[CH:61][C:56]3=[N:55][C:54]=2[CH2:62][O:1][C:2]2[CH:3]=[C:4]([CH:9]=[CH:10][CH:11]=2)[C:5]([O:7][CH3:8])=[O:6])[CH:46]=[CH:47][CH:48]=[CH:49][CH:50]=1
Reactant: COC(=O)c1cccc(O)c1
Reactant: OCc1nc2ccccn2c1C#Cc1ccccc1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COC(=O)c1cccc(OCc2nc3ccccn3c2C#Cc2ccccc2)c1
Yield: 42.3 %

Procedure:
0.09 g (0.594 mmol) of methyl 3-hydroxybenzoate were dissolved in 1 ml of tetrahydrofurane with magnetic stirring and then 0.312 g (1.188 mmol) of triphenylphosphine and 0.231 ml (1.188 mmol) of DIAD were added. The mixture was stirred at r.t. for 15 min and then a solution of 0.076 g (0.297 mmol) of (3-(phenylethynyl)imidazo[1,2-a]pyridin-2-yl)methanol in 4 ml of tetrahydrofurane was added and the mixture was stirred at r.t. for 16 h. A mixture of 0.09 g (0.594 mmol) of methyl 3-hydroxybenzoate, 0.312 g (1.188 mmol) of triphenylphosphine and 0.231 ml (1.188 mmol) of DIAD dissolved in 1 ml of tetrahydrofurane was added and the reaction medium was stirred at r.t. for a further 2 h. The reaction medium was treated with 10 ml. The aqueous phase was extracted with 3×10 ml of ethyl acetate and then the combined organic phases were washed with 10 ml of a saturated NaCl solution and then dried on Na2SO4 which was then removed by filtration. The obtained filtrate was concentrated in vacuo. The crude residue was purified by flash chromatography on a silica gel cartridge (eluent: heptane/ethyl acetate, from 70% to 40% heptane, v/v). 0.048 g (yield=42%) of methyl 3-((3-(phenylethynyl)imidazo[1,2-a]pyridin-2-yl)methoxy)benzoate were obtained as a pale yellow solid. LC-MS: m/z=383 (MH+); UV purity at 254 nm=99%. 1H NMR (300 MHz, DMSO) δ 8.64 (d, J=6.8 Hz, 1H), 7.68 (dd, J=17.0, 7.2 Hz, 4H), 7.55 (d, J=8.7 Hz, 1H), 7.52-7.34 (m, 6H), 7.15 (t, J=7.3 Hz, 1H), 5.42 (s, 2H), 3.80 (s, 3H).
Reaction SMILES: Br[CH2:2][CH:3]1[CH:5]([C:6]2[CH:11]=[CH:10][CH:9]=[C:8]([N+:12]([O-:14])=[O:13])[CH:7]=2)[CH:4]1[C:15]([O:17]CC)=O.C(=O)([O-])O.[Na+].[C:25]1([CH2:31][CH2:32][CH2:33][NH2:34])[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.O>CN(C)C=O>[N+:12]([C:8]1[CH:7]=[C:6]([CH:5]2[CH:4]3[CH:3]2[CH2:2][N:34]([CH2:33][CH2:32][CH2:31][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C:15]3=[O:17])[CH:11]=[CH:10][CH:9]=1)([O-:14])=[O:13]
Reactant: CCOC(=O)C1C(CBr)C1c1cccc([N+](=O)[O-])c1
Reactant: NCCCc1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: O=C1C2C(CN1CCCc1ccccc1)C2c1cccc([N+](=O)[O-])c1
Temperature: 150 °C
Reaction time: 16 h
Yield: 90.8 %

Procedure:
To a solution of ethyl 2-(bromomethyl)-3-(3-nitrophenyl)cyclopropane carboxylate (Preparation 23, 60 mg, 0.18 mmol) in N,N-dimethylformamide (2 ml) was added sodium hydrogen carbonate (30 mg, 0.36 mmol) and 3-phenylpropylamine (30 mg, 31 μl, 0.22 mmol). The mixture was heated to 150° C. for 1 hour, then cooled to room temperature and stirred for 16 hours. Water (30 ml) was added and the mixture was extracted with diethyl ether (2×50 ml). The combined extracts were concentrated in vacuo and the residue was purified by silica (5 g) column chromatography eluting with dichloromethane then 4:1 dichloromethane:ethyl acetate. Product-containing fractions were combined and concentrated in vacuo to give the title compound as a colourless glassy solid (55 mg, 90%).
Reaction SMILES: [OH:1][CH2:2][C@H:3]([N:5]1[C:13]2[C:8](=[C:9]([C:16]([F:19])([F:18])[F:17])[C:10]([C:14]#[N:15])=[CH:11][CH:12]=2)[CH:7]=[C:6]1[CH3:20])[CH3:4].[H-].[Na+].I[CH3:24]>C1COCC1>[CH3:20][C:6]1[N:5]([C@H:3]([CH3:4])[CH2:2][O:1][CH3:24])[C:13]2[C:8]([CH:7]=1)=[C:9]([C:16]([F:19])([F:17])[F:18])[C:10]([C:14]#[N:15])=[CH:11][CH:12]=2
Reactant: CI
Reactant: Cc1cc2c(C(F)(F)F)c(C#N)ccc2n1[C@H](C)CO
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COC[C@@H](C)n1c(C)cc2c(C(F)(F)F)c(C#N)ccc21
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 40.8 %

Procedure:
To a solution of 1-[(1R)-2-hydroxy-1-methylethyl]-2-methyl-4-(trifluoromethyl)-1H-indole-5-carbonitrile (Example 329) (0.035 g, 0.124 mmol) in dry THF (5 mL) was added sodium hydride (60%, 0.0075 g, 0.188 mmol) at 0° C. The mixture was stirred at rt for 0.5 h and then was added iodomethane (77 uL, 1.24 mmol). The mixture was stirred at 50° C. in a sealed tube overnight. The resulting solids were filtered and the filtrate was then concentrated in vacuo. The residue was purified by radial chromatography (0-60% EtOAc-hexanes gradient) to afford the title compound (0.015 g, 41% yield): MS (ES) m/z 297 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:9][N:10]2[CH:14]=[C:13]([CH2:15]O)[N:12]=[N:11]2)[CH:5]=[CH:6][C:7]=1[Cl:8].P(Br)(Br)[Br:18].O.C([O-])(O)=O.[Na+]>C(Cl)Cl>[Br:18][CH2:15][C:13]1[N:12]=[N:11][N:10]([CH2:9][C:4]2[CH:5]=[CH:6][C:7]([Cl:8])=[C:2]([Cl:1])[CH:3]=2)[CH:14]=1
Reactant: OCc1cn(Cc2ccc(Cl)c(Cl)c2)nn1
Reactant: BrP(Br)Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Product: Clc1ccc(Cn2cc(CBr)nn2)cc1Cl
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of {1-[(3,4-dichlorophenyl)methyl]-1H-1,2,3-triazol-4-yl}methanol (Intermediate 16) (0.17 g, 0.66 mmol) in DCM was added PBr3 (125 μL, 2 eq) and the reaction was stirred at room temperature for 3 hours. Water was added, followed by solid NaHCO3. The organic phase was dried over sodium sulphate and evaporated. The title compound was obtained as a colorless oil (0.21 g, 99%) and used in the next step without purification. LC/MS: m/z 320 (M−H)+. Rt: 2.13 min.