Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][CH:10]=1)[CH2:6]N)#[N:2].C=[O:12].N>C(O)(=O)C>[C:1]([C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][CH:10]=1)[CH:6]=[O:12])#[N:2]
Reactant: C=O
Reactant: N#Cc1cccc(CN)c1
Agent: N
Solvent: CC(=O)O
Product: N#Cc1cccc(C=O)c1
Yield: 54 %

Procedure:
13.2 g of m-cyanobenzylamine, 51 g of a 35% aqueous formalin solution, 24 g of a 28% aqueous ammonia solution and 50 ml of acetic acid were mixed and reacted at 100° C. for 3 hours while stirring. The reaction solution was concentrated to dry in an evaporator and thereto 100 ml of water was added to precipitate crystals. The crystals precipitated were collected by filtration, washed with water and dried to obtain 7 g (yield: 54%) of m-cyanobenzaldehyde. The purity was 99% or more.
Reaction SMILES: [CH2:1]([C:3]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][C:10]=2[NH:12][C:13]([C:15]2[N:19]3[CH:20]=[CH:21][CH:22]=[CH:23][C:18]3=[N:17][CH:16]=2)=[O:14])[N:5]([CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[C:27]([OH:31])[N:26]=2)[N:4]=1)[CH3:2].O[CH2:33][CH2:34][N:35]1[CH2:40][CH2:39][N:38]([C:41]([O:43][C:44]([CH3:47])([CH3:46])[CH3:45])=[O:42])[CH2:37][CH2:36]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>C1COCC1>[CH2:1]([C:3]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][C:10]=2[NH:12][C:13]([C:15]2[N:19]3[CH:20]=[CH:21][CH:22]=[CH:23][C:18]3=[N:17][CH:16]=2)=[O:14])[N:5]([CH2:24][C:25]2[N:26]=[C:27]([O:31][CH2:33][CH2:34][N:35]3[CH2:40][CH2:39][N:38]([C:41]([O:43][C:44]([CH3:45])([CH3:47])[CH3:46])=[O:42])[CH2:37][CH2:36]3)[CH:28]=[CH:29][CH:30]=2)[N:4]=1)[CH3:2]
Reactant: CCc1nn(Cc2cccc(O)n2)c2cccc(NC(=O)c3cnc4ccccn34)c12
Reactant: CC(C)(C)OC(=O)N1CCN(CCO)CC1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CCc1nn(Cc2cccc(OCCN3CCN(C(=O)OC(C)(C)C)CC3)n2)c2cccc(NC(=O)c3cnc4ccccn34)c12
Reaction time: 16 h

Procedure:
To a suspension of N-(3-ethyl-1-((6-hydroxypyridin-2-yl)methyl)-1H-indazol-4-yl)imidazo[1,2-a]pyridine-3-carboxamide (26 mg, 0.0630 mmol; prepared as in Example 17, Step A) in THF (5 mL) was added tert-butyl 4-(2-hydroxyethyl)piperazine-1-carboxylate (43.6 mg, 0.189 mmol), triphenylphosphine (41.3 mg, 0.158 mmol) and diethyl azodicarboxylate (62.0 μL, 0.158 mmol). The suspension became a clear solution and was stirred for 16 hours. The reaction mixture was concentrated under reduced pressure and the residue was purified by silica gel chromatography (DCM/MeOH 10:1) to provide the intermediate tert-butyl 4-(2-(6-((3-ethyl-4-(imidazo[1,2-a]pyridine-3-carboxamido)-1H-indazol-1-yl)methyl)pyridin-2-yloxy)ethyl)piperazine-1-carboxylate mixed with triphenyl phosphine oxide, to which was added DCM/TFA (2 mL/1 mL). The reaction mixture was stirred for 30 minutes and then concentrated under reduced pressure. Silica gel chromatography (DCM/MeOH/NH4OH 10:1:0.1) provided the desired product (10 mg). MS (ES+APCI) m/z=525 (M+H).
Reaction SMILES: [NH:1]1[C:5]2=[N:6][CH:7]=[CH:8][CH:9]=[C:4]2[C:3]([CH:10]=[C:11]2[S:15][C:14](=[S:16])[NH:13][C:12]2=[O:17])=[CH:2]1.IC.[CH3:20]CN(C(C)C)C(C)C.O>C(O)C>[CH3:20][S:16][C:14]1[S:15][C:11](=[CH:10][C:3]2[C:4]3[C:5](=[N:6][CH:7]=[CH:8][CH:9]=3)[NH:1][CH:2]=2)[C:12](=[O:17])[N:13]=1
Reactant: CCN(C(C)C)C(C)C
Reactant: O=C1NC(=S)SC1=Cc1c[nH]c2ncccc12
Solvent: CI
Solvent: CCO
Solvent: O
Product: CSC1=NC(=O)C(=Cc2c[nH]c3ncccc23)S1
Temperature: 100 °C
Reaction time: 2 h
Yield: 65.4 %

Procedure:
The suspension of 5-(1H-pyrrolo[2,3-b]pyridin-3-ylmethylene)-2-thioxo-thiazolidin-4-one (2.2 g, 8.22 mmol), iodomethane (1.05 mL, 16.8 mmol) and DIEA (3.0 mL, 16.8 mmol) in anhydrous ethanol (110 mL) was stirred at 100° C. for 2 h. After adding water (200 mL), the solid was collected by filtration, washed with water and dried to obtain 2-methylsulfanyl-5-(1H-pyrrolo[2,3-b]pyridin-3-ylmethylene)-thiazol-4-one (1.48 g, 60.8%) as a grey solid. LC-MS m/e 276 (MH+).
Reaction SMILES: [C:1]([O:5][C:6](=[O:19])[N:7]([CH2:9][CH2:10][C@H:11]1[CH2:16][CH2:15][C@H:14]([CH2:17][OH:18])[CH2:13][CH2:12]1)[CH3:8])([CH3:4])([CH3:3])[CH3:2].[CH3:20][S:21](Cl)(=[O:23])=[O:22]>>[C:1]([O:5][C:6]([N:7]([CH3:8])[CH2:9][CH2:10][C@H:11]1[CH2:12][CH2:13][C@H:14]([CH2:17][O:18][S:21]([CH3:20])(=[O:23])=[O:22])[CH2:15][CH2:16]1)=[O:19])([CH3:3])([CH3:2])[CH3:4]
Reactant: CS(=O)(=O)Cl
Reactant: CN(CC[C@H]1CC[C@H](CO)CC1)C(=O)OC(C)(C)C
Product: CN(CC[C@H]1CC[C@H](COS(C)(=O)=O)CC1)C(=O)OC(C)(C)C

Procedure:
In analogy to the procedures described in examples 11.13 and 11.14, trans-[2-(4-hydroxymethyl-cyclohexyl)-ethyl]-methyl-carbamic acid tert-butyl ester (example 11.8) was reacted with methanesulfonyl chloride to give trans-methanesulfonic acid 4-[2-(tert-butoxycarbonyl-methyl-amino)-ethyl]-cyclohexylmethyl ester, which was subsequently treated with 4N hydrogen chloride in dioxan to yield trans-methanesulfonic acid 4-(2-methylamino-ethyl)-cyclohexylmethyl ester HCl salt as colorless solid, MS: 250 (MH+).
Reaction SMILES: [CH2:1]([O:8][CH2:9][CH2:10][CH2:11][O:12][C:13]1[CH:18]=[CH:17][C:16]([CH:19]2[CH2:24][CH2:23][N:22](C([O-])=O)[CH2:21][CH:20]2[C:28](=[O:40])[CH2:29][C:30]2[CH:39]=[CH:38][C:37]3[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=3)[CH:31]=2)=[CH:15][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[ClH:41]>CO>[ClH:41].[CH2:1]([O:8][CH2:9][CH2:10][CH2:11][O:12][C:13]1[CH:14]=[CH:15][C:16]([CH:19]2[CH2:24][CH2:23][NH:22][CH2:21][CH:20]2[C:28](=[O:40])[CH2:29][C:30]2[CH:39]=[CH:38][C:37]3[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=3)[CH:31]=2)=[CH:17][CH:18]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(Cc1ccc2ccccc2c1)C1CN(C(=O)[O-])CCC1c1ccc(OCCCOCc2ccccc2)cc1
Agent: Cl
Solvent: CO
Product: O=C(Cc1ccc2ccccc2c1)C1CNCCC1c1ccc(OCCCOCc2ccccc2)cc1

Procedure:
In an analogous manner to that described in Example 22(l), from tert-butyl 3RS,4SR)-4-[4-(3-benzyloxy-propoxy)-phenyl]-3-(naphthalen-2-yl-acetyl)-piperidine-1-carboxylate by cleavage of the BOC protecting group with hydrogen chloride in methanol there was obtained [(3RS,4SR)-4-[4-(3-benzyloxy-propoxy)-phenyl]-piperidin-3-yl]-2-naphthalen-2-yl-ethanone hydrochloride (1:1) in in the form of colourless crystals; MS: 494 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([N:24]2[CH2:28][CH2:27][C@H:26]([NH:29][C:30](=[O:36])[O:31][C:32]([CH3:35])([CH3:34])[CH3:33])[CH2:25]2)[CH:5]=[CH:6][C:7]=1[NH:8][C:9]([C:11]1[S:12][C:13]([C:16]2[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=2)=[CH:14][CH:15]=1)=[O:10].[H-].[Na+].[CH3:39][Si:40]([CH3:47])([CH3:46])[CH2:41][CH2:42][O:43][CH2:44]Cl>C1COCC1>[Br:1][C:2]1[CH:3]=[C:4]([N:24]2[CH2:28][CH2:27][C@H:26]([NH:29][C:30](=[O:36])[O:31][C:32]([CH3:33])([CH3:35])[CH3:34])[CH2:25]2)[CH:5]=[CH:6][C:7]=1[N:8]([CH2:44][O:43][CH2:42][CH2:41][Si:40]([CH3:47])([CH3:46])[CH3:39])[C:9]([C:11]1[S:12][C:13]([C:16]2[CH:17]=[CH:18][C:19]([O:22][CH3:23])=[CH:20][CH:21]=2)=[CH:14][CH:15]=1)=[O:10]
Reactant: C[Si](C)(C)CCOCCl
Reactant: COc1ccc(-c2ccc(C(=O)Nc3ccc(N4CC[C@H](NC(=O)OC(C)(C)C)C4)cc3Br)s2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COc1ccc(-c2ccc(C(=O)N(COCC[Si](C)(C)C)c3ccc(N4CC[C@H](NC(=O)OC(C)(C)C)C4)cc3Br)s2)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 82.5 %

Procedure:
A solution of (S)-tert-butyl 1-{3-bromo-4-[5-(4-methoxyphenyl)thiophene-2-carboxamido]phenyl}pyrrolidin-3-ylcarbamate (400 mg, 0.69 mmol) in THF (20 mL) was cooled to 0° C. and sodium hydride (60 wt %, 140 mg, 3.5 mmol) was added. The reaction was warmed to room temperature followed by the addition of 2-(trimethylsilyl)ethoxymethyl chloride (370 mL, 2.1 mmol) and the reaction mixture was stirred at room temperature for 18 h. The reaction mixture was quenched with water and diluted with ethyl acetate. The layers were separated and the organic layer was dried over anhydrous sodium sulfate, filtered, concentrated and the residue was purified by column chromatography (silica, 0-30% ethyl acetate/heptane) to afford the desired product (400 mg, 87%): ESI MS m/z 703 [C33H44BrN3O5SSi+H]+.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6](=[NH:29])[NH:7][C:8]1[CH:9]=[CH:10][C:11]2[N:16]([CH2:17][CH2:18][N:19](C)[C:20](=O)OC(C)(C)C)[CH2:15][CH2:14][S:13][C:12]=2[CH:28]=1.FC(F)(F)C(O)=O>C(Cl)Cl>[CH3:20][NH:19][CH2:18][CH2:17][N:16]1[CH2:15][CH2:14][S:13][C:12]2[CH:28]=[C:8]([NH:7][C:6]([C:2]3[O:1][CH:5]=[CH:4][CH:3]=3)=[NH:29])[CH:9]=[CH:10][C:11]1=2
Reactant: CN(CCN1CCSc2cc(NC(=N)c3ccco3)ccc21)C(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CNCCN1CCSc2cc(NC(=N)c3ccco3)ccc21
Temperature: 0 °C
Reaction time: 2 h
Yield: 75.1 %

Procedure:
A solution of tert-butyl 2-(7-(furan-2-carboximidamido)-2H-benzo[b][1,4]thiazin-4(3H)-yl)ethyl(methyl)carbamate (0.823 g, 1.978 mmol) in CH2Cl2 (20 mL) was cooled to 0° C. and was treated with trifluoroacetic acid (5 mL). The mixture was stirred at 0° C. under argon atmosphere for 2 hours. The mixture was quenched with 1N NaOH solution (70 mL) and transferred to a separatory funnel. The solution was diluted with water (50 mL) and extracted with CH2Cl2 (2×50 mL). The organic phase was washed with brine (50 mL) and dried (Na2SO4). The crude material was concentrated and subjected to flash chromatography on silica gel (5-15% (2M NH3 MeOH):CH2Cl2). The collected fractions were concentrated to give compound 20 as a yellow viscous oil (0.47 g, 76%). 1H NMR (CDCl3) δ 7.85 (s, 1H), 7.44-7.43 (m, 1H), 6.77-6.74 (m, 2H), 6.70 (d, J=2.4 Hz, 1H), 6.62 (dd, J=2.4, 8.7 Hz, 1H), 3.59-3.56 (m, 2H), 3.47 (s, 1H), 3.40 (t, J=6.6 Hz, 2H), 3.05-3.01 (m, 2H), 2.81 (t, J=6.3, 2H), 2.48 (s, 3H); ESI-MS (m/z, %): 319, 317 (MH+, 96), 260 (100).
Reaction SMILES: N1C=CC=CC=1.C(OC(=O)C)(=O)C.[CH2:14]([O:16][C:17]([C:19]([C:30]([O:32][CH2:33][CH3:34])=[O:31])([CH2:25][CH2:26][C:27]([OH:29])=O)[CH2:20][CH2:21]C(O)=O)=[O:18])[CH3:15].C(=O)([O-])[O-].[K+].[K+]>O>[O:29]=[C:27]1[CH2:21][CH2:20][C:19]([C:17]([O:16][CH2:14][CH3:15])=[O:18])([C:30]([O:32][CH2:33][CH3:34])=[O:31])[CH2:25][CH2:26]1
Reactant: CCOC(=O)C(CCC(=O)O)(CCC(=O)O)C(=O)OCC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: c1ccncc1
Solvent: O
Solvent: CC(=O)OC(C)=O
Product: CCOC(=O)C1(C(=O)OCC)CCC(=O)CC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 62.6 %

Procedure:
(Kutsuma, T., Sugasawa, S., Tetrahedron, 3, 175 (1958).) To 100 mL of a pre-mixed solution of 10% (v/v) pyridine and acetic anhydride was added 4,4-bis(ethoxycarbonyl)heptanedioic acid (23.6 g, 78 mmol), and the resulting mixture heated at reflux in a pre-heated oil bath. The reaction was stirred for 3 hrs then cooled to room temperature and concentrated under reduced pressure. The resulting oil was azeotroped twice with CH2Cl2, then dissolved in 95% EtOH (300 mL) and water (300 mL) and treated with solid potassium carbonate (12.9 g, 93.6 mmol). The mixture was stirred for 16 hrs. The reaction was concentrated under reduced pressure to remove EtOH, and the remaining water layer was diluted to re-dissolve the solids, then extracted with Et2O (2×150 mL). The combined extracts were dried (MgSO4), filtered, and concentrated under reduced pressure, to afford the title compound (11.82 g, 48.8 mmol, 62.9% yield), as an amber oil. HPLC: 2.00 min (AP 74%); 1H NMR (500 MHz, CDCl3) δ ppm 4.24 (4H, q, J=7.12 Hz), 2.44 (4H, t, J=6.56 Hz), 2.37 (4H, t, J=6.41 Hz), 1.27 (6H, t, J=7.17 Hz).
Reaction SMILES: [OH:1][CH2:2][C:3]#[C:4][C:5]1[CH:10]=[CH:9][C:8]([CH:11]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=2[CH3:28])[CH2:12][C:13]([C:15]2[CH:20]=[CH:19][N:18]=[C:17]([CH3:21])[CH:16]=2)=O)=[CH:7][CH:6]=1.Cl.[NH2:30][OH:31].C([O-])(O)=O.[Na+]>>[OH:1][CH2:2][C:3]#[C:4][C:5]1[CH:6]=[CH:7][C:8]([CH:11]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=2[CH3:28])[CH2:12][C:13]([C:15]2[CH:20]=[CH:19][N:18]=[C:17]([CH3:21])[CH:16]=2)=[N:30][OH:31])=[CH:9][CH:10]=1
Reactant: NO
Reactant: Cc1cc(C(=O)CC(c2ccc(C#CCO)cc2)c2ccccc2C)ccn1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Product: Cc1cc(C(CC(c2ccc(C#CCO)cc2)c2ccccc2C)=NO)ccn1

Procedure:
In analogy to example 74, step 7, from 3-[4-(3-hydroxy-prop-1-ynyl)-phenyl]-1-(2-methyl-pyridin-4-yl)-3-o-tolyl-propan-1-one and hydroxylamine hydrochloride in the presence of NaHCO3 was prepared the title compound as a mixture of E and Z isomers (6.4:1) as a colorless oil, MS (ESI+): m/z=385.1908 ([M+H]+).
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].O1CCCC1.[C:12]1([CH2:18][N:19]2[CH2:24][CH2:23][O:22][CH:21]([CH2:25][C:26](OCC)=[O:27])[CH2:20]2)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.[OH-].[Na+]>O>[C:12]1([CH2:18][N:19]2[CH2:24][CH2:23][O:22][CH:21]([CH2:25][CH2:26][OH:27])[CH2:20]2)[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: CCOC(=O)CC1CN(Cc2ccccc2)CCO1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: OCCC1CN(Cc2ccccc2)CCO1
Reaction time: 8 h
Yield: 99.1 %

Procedure:
To a refluxing mixture of 15 parts of lithium aluminum hydride and 534 parts of tetrahydrofuran was added dropwise a solution of 80 parts of ethyl 4-(phenylmethyl)-2-morpholineacetate (described in C.A.; 93, 26362g) in 89 parts of tetrahydrofuran under a nitrogen atmosphere. Refluxing was continued overnight. After cooling to 0°-5° C., there were added successively 15.6 parts of water, 14.6 parts of NaOH 20% and 51 parts of water. The whole was stirred for 1/2 hour and then filtered over diatomaceous earth. The filtrate was evaporated, yielding 68 parts (99.1%) of 4-(phenylmethyl)-2-morpholineethanol (interm. 4).
Reaction SMILES: [OH:1][CH2:2][C:3]1[O:7][N:6]=[C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][N:9]=2)[CH:4]=1.C(N(CC)CC)C.[CH3:21][S:22](Cl)(=[O:24])=[O:23]>ClCCl>[CH3:21][S:22]([O:1][CH2:2][C:3]1[O:7][N:6]=[C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][N:9]=2)[CH:4]=1)(=[O:24])=[O:23]
Reactant: OCc1cc(-c2ccccn2)no1
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CS(=O)(=O)OCc1cc(-c2ccccn2)no1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a mixture of 2-(5-hydroxymethyl-isoxazol-3-yl)-pyridine (4.0 gm), and triethylamine (6.5 ml) in dichloromethane (40 ml) was added methanesulfonyl chloride (2.8 ml) at 0° C. The reaction mixture was stirred at 0° C. over a period of 1 h. The reaction was quenched by addition of water and layers were separated. Aqueous layer was extracted with dichloromethane (40 ml×2). Combined organic layer was washed with aqueous sodium bicarbonate solution followed by water and evaporated under vacuum to provide the title compound in 5.1 gm quantity (84%) as a semisolid, which was used without purification for the next reaction.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([N:8]2[CH2:13][CH2:12][O:11][CH2:10][C@@H:9]2[CH3:14])[CH:5]=[CH:4][N:3]=1.[CH2:15]([NH:17][C:18](=[O:35])[NH:19][C:20]1[CH:25]=[CH:24][C:23](B2OC(C)(C)C(C)(C)O2)=[CH:22][CH:21]=1)C.C([O-])([O-])=O.[Na+].[Na+]>COCCOC.CCO.O>[CH3:15][NH:17][C:18]([NH:19][C:20]1[CH:25]=[CH:24][C:23]([C:2]2[N:7]=[C:6]([N:8]3[CH2:13][CH2:12][O:11][CH2:10][C@@H:9]3[CH3:14])[CH:5]=[CH:4][N:3]=2)=[CH:22][CH:21]=1)=[O:35]
Reactant: C[C@H]1COCCN1c1ccnc(Cl)n1
Reactant: CCNC(=O)Nc1ccc(B2OC(C)(C)C(C)(C)O2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Solvent: COCCOC
Product: CNC(=O)Nc1ccc(-c2nccc(N3CCOC[C@@H]3C)n2)cc1
Temperature: 120 °C
Yield: 7.8 %

Procedure:
To a solution of (S)-4-(2-chloropyrimidin-4-yl)-3-methylmorpholine (Intermediate 3) (100 mg, 0.47 mmol) and 4-(3-ethylureido)phenylboronic acid pinacol ester (143 mg, 0.52 mmol) in DME:EtOH:H2O (12:5:3, 2 mL) was added Pd(PPh3)2(Cl)2 (17 mg, 0.024 mmol) and Na2CO3 (149 mg, 1.41 mmol). The reaction mixture was then heated by microwave at 120° C. for 1 h. The crude reaction mixture was then partitioned between water and EtOAc, the phases separated and the organic layer washed with aqueous NaHCO3 and brine, dried over magnesium sulfate, filtered and the solvent removed in vacuo. The residue was purified by flash chromatography (2-5% MeOH/DCM) to yield a white solid (12 mg, 8%).
Reaction SMILES: [CH3:1][C:2]1([CH3:13])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]([CH2:11][OH:12])[CH2:3]1.[H][H]>C(O)C>[CH3:1][C:2]1([CH3:13])[CH2:3][CH:4]([CH2:11][OH:12])[CH:5]2[CH:10]1[CH2:9][CH2:8][CH2:7][CH2:6]2
Reactant: CC1(C)CC(CO)c2ccccc21
Reactant: [H][H]
Solvent: CCO
Product: CC1(C)CC(CO)C2CCCCC21
Reaction time: 7 h
Yield: 82.8 %

Procedure:
11.3 g (64 mmol) of 1,1-dimethyl-3-hydroxymethylindane (IX), 3 g of 5% luthenium-carbon (manufactured by Engerhard Industries Corp.), and 300 ml of ethanol was placed in a 100 ml autoclave. After internal air was displaced by hydrogen, the mixture was heated at an initial hydrogen pressure of 100 kg/cm2. The reaction temperature reached 140° C. 1 hour after the heating was started. The absorption of hydrogen terminated when the reaction was continued at this temperature for 7 hours. After cooling, the pressure was released and the catalyst was separated out by filtration. The filtrate was distilled under reduced pressure to produce 9.7 g (53 mmol) of the title compound (Ic) at a yield of 83%. Capillary gas chromatography analysis revealed that the compound is comprised of two major components each having a peak of which the area ratio was 59:41.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[CH:4][C:3]=1[CH2:12][C:13]([OH:15])=[O:14].OS(O)(=O)=O.[CH3:21]O>>[Br:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[CH:4][C:3]=1[CH2:12][C:13]([O:15][CH3:21])=[O:14]
Reactant: CO
Reactant: O=C(O)Cc1ccc(C(F)(F)F)cc1Br
Agent: O=S(=O)(O)O
Product: COC(=O)Cc1ccc(C(F)(F)F)cc1Br

Procedure:
A solution of 2-bromo-4-trifluoromethylphenylacetic acid (2.00 g, 7.07 mmol) and concentrated aqueous H2SO4 (1 mL) in MeOH (30 mL) was heated at reflux for 16 hours. The volatiles were removed under reduced pressure then the residue taken up in EtOAc. The resulting solution was washed with 10% NaHCO3, dried (MgSO4) and evaporated under reduced pressure to give the title compound A57 as a clear liquid (2.07 g, 98%); 1H NMR (400 MHz, CDCl3) δ 7.83 (d, J=1.1 Hz, 1H), 7.53 (dd, J=8.0, 1.1 Hz, 1H), 7.41 (d, J=8.0 Hz, 1H), 3.84 (s, 2H), 3.72 (s, 3H). LCMS-A: rt 6.236 min; m/z 297/299 [M+H]+.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8].C([Cu])#N.[Li+].[Cl-].Cl[C:20](=[O:25])[C:21]([O:23][CH3:24])=[O:22].[Cl-].[NH4+]>C1COCC1.[Zn]>[C:10]([O:9][C:7]([CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][C:20](=[O:25])[C:21]([O:23][CH3:24])=[O:22])=[O:8])([CH3:13])([CH3:12])[CH3:11]
Reactant: COC(=O)C(=O)Cl
Reactant: CC(C)(C)OC(=O)CCCCCBr
Agent: N#C[Cu]
Agent: [Cl-]
Agent: [Li+]
Solvent: C1CCOC1
Product: COC(=O)C(=O)CCCCCC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 15 h
Yield: 77.4 %

Procedure:
To a suspension of activated zinc (0.65 g, 10 mmol) in THF (20 ml) was added t-butyl 6-bromohexanoate (1.38 g, 5.5 mmol). The mixture was stirred at room temperature for 15 hours. The excess zinc was allowed to settle for 2 hours. The solution was then transferred to a pre-formed solution of CuCN (0.45 g, 10.7 mmol) and LiCl (0.45 g, 10.7 mmol) at −20° C. The resulting mixture was stirred at 0° C. for 5 minutes and cooled to −60° C., and methyl chlorooxoacetate (0.68 ml, 5.5 mmol) was added. The resulting mixture was stirred at −60° C. for 1 hour, and reaction temperature allowed to rise gradually to 0° C. over 4 hours. The mixture was then poured into aqueous ammonium chloride, extracted 3 times with ether. The combined organic phase was washed with aqueous ammonium chloride, brine, dried over sodium sulfate and concentrated in vacuo to afford the title material (1.1 g) as a pale yellow liquid, which is used directly in next step.
Reaction SMILES: I[C:2]1[S:3][C:4]2[CH:10]=[C:9]([O:11][CH3:12])[CH:8]=[CH:7][C:5]=2[N:6]=1.[C:13]([C:15]1[CH:22]=[CH:21][C:18]([NH:19][CH3:20])=[C:17]([N+:23]([O-:25])=[O:24])[CH:16]=1)#[CH:14]>C(#N)C.[Cu]I>[CH3:12][O:11][C:9]1[CH:8]=[CH:7][C:5]2[N:6]=[C:2]([C:14]#[C:13][C:15]3[CH:22]=[CH:21][C:18]([NH:19][CH3:20])=[C:17]([N+:23]([O-:25])=[O:24])[CH:16]=3)[S:3][C:4]=2[CH:10]=1
Reactant: COc1ccc2nc(I)sc2c1
Reactant: C#Cc1ccc(NC)c([N+](=O)[O-])c1
Agent: [Cu]I
Solvent: CC#N
Product: CNc1ccc(C#Cc2nc3ccc(OC)cc3s2)cc1[N+](=O)[O-]
Temperature: 25 °C

Procedure:
A 5 mL microwave tube is charged with 2 (1 equiv), 4-ethynyl-N-methyl-2-nitroaniline (1 equiv) [Pd(PPh3)4] (0.05 equiv), CuI (0.05 equiv) and TEA (5 equiv) in ACN (5 vol). The suspension is irradiated in a Biotage Emrys Optimizer microwave reactor (250 W) at 100° C. for 5 min. After cooling to room temperature, the solvent is evaporated in vacuo. The residue is purified over silica gel using Hexanes:DCM (0-100%) as the eluent to afford the coupling product.
Reaction SMILES: [Br:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[C:4]([F:10])[CH:3]=1.[CH3:11][Mg]Br>O1CCCC1>[Br:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]([OH:7])[CH3:11])=[C:4]([F:10])[CH:3]=1
Reactant: C[Mg]Br
Reactant: O=Cc1ccc(Br)cc1F
Solvent: C1CCOC1
Product: CC(O)c1ccc(Br)cc1F
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 92.2 %

Procedure:
To a solution of 4-bromo-2-fluorobenzaldehyde (2.01 g, 9.9 mmol) in tetrahydrofuran (20 mL) was dropped methylmagnesium bromide (10 mmol, 1N in tetrahydrofuran) and the mixture was stirred at room temperature for 30 minutes. TLC showed all starting material was consumed, then the mixture was quenched with aqueous ammonium chloride (1N, 5 mL). To the mixture, water (50 mL) was added and extracted with dichloromethane (2*50 mL). The combined organic phase was separated, dried over sodium sulfate, filtered and concentrated. The residue was purified by column chromatography (silica gel, petroleum ether/ethyl acetate=20:1) to give the product 1-(4-bromo-2-fluorophenyl)ethanol as colorless oil (2.0 g, 92%). 1H NMR (300 MHz, CDCl3): δ 7.40-7.19 (m, 3H), 5.16 (q, J=6.3 Hz, 1H), 1.76 (s, 1H), 1.49 (d, J=6.3 Hz, 3H).
Reaction SMILES: [C:1]1(B(O)O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(=O)([O-])[O-].[Na+].[Na+].Br[C:17]1[CH:18]=[C:19]2[C:23](=[CH:24][C:25]=1[Cl:26])[N:22]([CH2:27][O:28][CH2:29][CH2:30][Si:31]([CH3:34])([CH3:33])[CH3:32])[N:21]=[C:20]2[NH:35][C:36](=[O:40])[CH2:37][CH2:38][CH3:39].C(OCC)(=O)C>O.O1CCOCC1.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>[C:1]1([C:17]2[CH:18]=[C:19]3[C:23](=[CH:24][C:25]=2[Cl:26])[N:22]([CH2:27][O:28][CH2:29][CH2:30][Si:31]([CH3:33])([CH3:34])[CH3:32])[N:21]=[C:20]3[NH:35][C:36](=[O:40])[CH2:37][CH2:38][CH3:39])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: OB(O)c1ccccc1
Reactant: CCCC(=O)Nc1nn(COCC[Si](C)(C)C)c2cc(Cl)c(Br)cc12
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: O
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: CCCC(=O)Nc1nn(COCC[Si](C)(C)C)c2cc(Cl)c(-c3ccccc3)cc12

Procedure:
821 mg of phenylboronic acid, 1.14 g of sodium carbonate in 30 cm3 of distilled water and finally 347 mg of tetrakis(triphenylphosphine)palladium are added to 2 g of N-[5-bromo-6-chloro-1-[[2-(trimethylsilyl)ethoxy]methyl]-1H-indazol-3-yl]butanamide, described in Example 58, in 180 cm3 of dioxane. The mixture is refluxed for 90 minutes and is then allowed to return to 20° C. to add 100 cm3 of ethyl acetate and 100 cm3 of distilled water. The organic phase is washed with 100 cm3 of saturated aqueous sodium chloride solution and then separated out after settling of the phases has taken place and dried over magnesium sulphate. After filtration, the filtrate is concentrated to dryness under reduced pressure (2 kPa; 50° C.) and the residue is purified by chromatography under an argon pressure of 50 kPa, on a column of silica gel (particle size 40-60 μm; diameter 4.5 cm), eluting with a cyclohexane/ethyl acetate mixture (80/20 by volume). The fractions containing the expected product are combined and evaporated under reduced pressure (2 kPa; 50° C.). After drying (90 Pa; 45° C.), 2 g of N-[5-phenyl-6-chloro-1-[[2-(trimethylsilyl)ethoxy]methyl]-1H-indazol-3-yl]butanamide are thus obtained in the form of a yellow oil.