Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[C:2]([C:6]1[CH:11]=[CH:10][C:9]([S:12]([NH:15][C:16]2[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][C:17]=2[C:23]2[N:27]([C@H:28]3[CH2:32][CH2:31][NH:30][CH2:29]3)[CH:26]=[N:25][N:24]=2)(=[O:14])=[O:13])=[CH:8][CH:7]=1)([CH3:5])([CH3:4])[CH3:3].N1C=CC=CC=1.[CH3:39][S:40](Cl)(=[O:42])=[O:41]>C1COCC1>[C:2]([C:6]1[CH:11]=[CH:10][C:9]([S:12]([NH:15][C:16]2[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][C:17]=2[C:23]2[N:27]([C@H:28]3[CH2:32][CH2:31][N:30]([S:40]([CH3:39])(=[O:42])=[O:41])[CH2:29]3)[CH:26]=[N:25][N:24]=2)(=[O:13])=[O:14])=[CH:8][CH:7]=1)([CH3:5])([CH3:3])[CH3:4]
Reactant: CC(C)(C)c1ccc(S(=O)(=O)Nc2ccc(Cl)cc2-c2nncn2[C@H]2CCNC2)cc1
Reactant: CS(=O)(=O)Cl
Agent: Cl
Solvent: C1CCOC1
Solvent: c1ccncc1
Product: CC(C)(C)c1ccc(S(=O)(=O)Nc2ccc(Cl)cc2-c2nncn2[C@H]2CCN(S(C)(=O)=O)C2)cc1
Temperature: 0 °C
Reaction time: 8 h
Yield: 67.3 %

Procedure:
To 4-tert-butyl-N-[4-chloro-2-((S)-4-pyrrolidin-3-yl-4H-[1,2,4]triazol-3-yl)-phenyl]-benzenesulfonamide hydrochloride (0.25 g, 0.505 mmol) in THF (8 mL) was added pyridine (0.60 mL, 7.4 mmol). The resultant solution was stirred for 20 minutes at room temperature. The reaction mixture was subsequently cooled to 0° C., methanesulfonyl chloride (0.595 mL, 7.6 mmol) was added, and the mixture was stirred overnight at room temperature. The following day, the volatiles were evaporated and the resultant residue was adsorbed onto silica gel and purified by automated normal-phase chromatography (using 50→100% EtOAc in hexanes) to obtain the title compound (0.183 g) in 67.5% yield: MS (ES) M+H expected 538.0, found 538.1.
Reaction SMILES: [NH:1]([C:5]1[S:6][CH:7]=[C:8]([CH2:10][S:11][CH2:12][CH2:13][NH2:14])[N:9]=1)[C:2]([NH2:4])=[NH:3].CS[C:17]1[NH:18][CH2:19][CH2:20][CH2:21][C:22]=1[N+:23]([O-:25])=[O:24]>C(O)C>[NH:1]([C:5]1[S:6][CH:7]=[C:8]([CH2:10][S:11][CH2:12][CH2:13][NH:14][C:17]2[NH:18][CH2:19][CH2:20][CH2:21][C:22]=2[N+:23]([O-:25])=[O:24])[N:9]=1)[C:2]([NH2:4])=[NH:3]
Reactant: N=C(N)Nc1nc(CSCCN)cs1
Reactant: CSC1=C([N+](=O)[O-])CCCN1
Solvent: CCO
Product: N=C(N)Nc1nc(CSCCNC2=C([N+](=O)[O-])CCCN2)cs1
Reaction time: 8 h

Procedure:
A solution of 2-(2-guanidino-4-thiazolylmethylthio)ethylamine (0.8 g, 3.5 mmol) and 2-methylthio-3-nitro-1,4,5,6-tetrahydropyridine (0.5 g, 2.9 mmol) in ethanol (50 ml) was refluxed for 3 hours then left to stand at room temperature overnight. The solvent was removed in vacuo and the residue chromatographed on a silica-gel column. The product was eluted with ethyl acetate/propan-2-ol (8:2) and recrystallised twice from methanol/ether. Yield: 0.16 g, 15%. M.P. 211°-212.5° C.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([N:18]2[CH2:23][CH2:22][O:21][CH2:20][CH2:19]2)[C:5]2[S:10][C:9]([C:11]3[CH:12]=[C:13]([NH2:17])[CH:14]=[CH:15][CH:16]=3)=[CH:8][C:6]=2[N:7]=1.[CH3:24][O:25][CH2:26][C:27](Cl)=[O:28].C(N(CC)CC)C>ClCCl>[Cl:1][C:2]1[N:3]=[C:4]([N:18]2[CH2:23][CH2:22][O:21][CH2:20][CH2:19]2)[C:5]2[S:10][C:9]([C:11]3[CH:12]=[C:13]([NH:17][C:27](=[O:28])[CH2:26][O:25][CH3:24])[CH:14]=[CH:15][CH:16]=3)=[CH:8][C:6]=2[N:7]=1
Reactant: COCC(=O)Cl
Reactant: Nc1cccc(-c2cc3nc(Cl)nc(N4CCOCC4)c3s2)c1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COCC(=O)Nc1cccc(-c2cc3nc(Cl)nc(N4CCOCC4)c3s2)c1

Procedure:
3-(2-Chloro-4-morpholinothieno[3,2-d]pyrimidin-6-yl)benzenamine (60 mg), methoxyacetyl chloride (23 mg), and 36 μL of triethylamine in dichloromethane was stirred for 1 h. The reaction mixture was evaporated to give N-(3-(2-chloro-4-morpholinothieno[3,2-d]pyrimidin-6-yl)phenyl)-2-methoxyacetamide. 70 mg of the crude N-(3-(2-chloro-4-morpholinothieno[3,2-d]pyrimidin-6-yl)phenyl)-2-methoxyacetamide was coupled to 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indazole 7 via General Procedure A. The product was purified by reverse phase HPLC to yield 17.3 mg of 120. MS (Q1) 501 (M)+.
Reaction SMILES: [CH3:1][O:2][CH:3]([O:15][CH3:16])[C:4]1[CH:9]=[C:8]([O:10][CH3:11])[C:7]([O:12][CH3:13])=[CH:6][C:5]=1Br.C([Li])CCC.[Br:22][C:23]1[CH:24]=[C:25]([CH:31]=[CH:32][N:33]=1)[C:26](N(C)C)=[O:27].C(O)(=O)C>O1CCCC1.O>[CH3:1][O:2][CH:3]([O:15][CH3:16])[C:4]1[C:5]([C:26](=[O:27])[C:25]2[CH:31]=[CH:32][N:33]=[C:23]([Br:22])[CH:24]=2)=[CH:6][C:7]([O:12][CH3:13])=[C:8]([O:10][CH3:11])[CH:9]=1
Reactant: CN(C)C(=O)c1ccnc(Br)c1
Reactant: COc1cc(Br)c(C(OC)OC)cc1OC
Agent: [Li]CCCC
Solvent: CC(=O)O
Solvent: C1CCOC1
Solvent: O
Product: COc1cc(C(=O)c2ccnc(Br)c2)c(C(OC)OC)cc1OC
Reaction time: 0.33 h
Yield: 46.8 %

Procedure:
To a solution of 2-bromo-4,5-dimethoxybenzaldehyde dimethyl acetal (21.8 g) in tetrahydrofuran (80 ml) is added dropwise a solution of n-butyl lithium (1.6 M hexane solution, 46.8 ml) at a temperature below -50° C. under nitrogen atmosphere, and the mixture is stirred for 20 minutes. The resulting solution is added dropwise into a solution of 2-bromo-N,N-dimethylisonicotinamide (18.1 g) in tetrahydrofuran (80 ml) at a temperature below -60° C., and the mixture is stirred for 30 minutes. To the reaction mixture is added acetic acid (4.5 ml), and the mixture is poured into water, and extracted with ethyl acetate. The extract is washed, dried, and concentrated, and the residue is purified by silica gel column chromatography (solvent; hexane:ethyl acetate=2:1) to give 3,4-dimethoxy-6-(2-bromoisonicotinoyl)benzaldehyde dimethyl acetal (13.9 g) as an oily product.
Reaction SMILES: [OH:1][CH:2]([C:4]1[CH:12]=[CH:11][C:7]([C:8]([O-:10])=[O:9])=[CH:6][CH:5]=1)[CH3:3].[C:13]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[N:32]1[CH:37]=[CH:36][C:35](O)=[CH:34][CH:33]=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>O1CCCC1>[N:32]1[CH:37]=[CH:36][C:35]([O:1][CH:2]([C:4]2[CH:12]=[CH:11][C:7]([C:8]([O:10][CH3:13])=[O:9])=[CH:6][CH:5]=2)[CH3:3])=[CH:34][CH:33]=1
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Reactant: Oc1ccncc1
Reactant: CC(O)c1ccc(C(=O)[O-])cc1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Solvent: C1CCOC1
Product: COC(=O)c1ccc(C(C)Oc2ccncc2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 35.1 %

Procedure:
To a solution of 4-(1-hydroxyethyl)benzoate (300 mg. 1.67 mmol) in tetrahydrofuran (80 mL) were added triphenylphosphine (570 mg, 2.2 mmol) and pyridin-4-ol (159 mg, 1.67 mmol). The mixture was stirred for 30 minutes at room temperature, and then cooled to 0° C. And diisopropylazodicarboxylate (568.3 mg, 2.8 mmol) was added dropwise to the solution at 0° C. The resultant mixture was stirred at room temperature for 12 hours. Then the mixture was concentrated to give a residue and the residue was purified by column chromatography (silica gel, ethyl acetate/petroleum ether=1:10) to give methyl 4-(1-(pyridin-4-yloxy)ethyl)benzoate as an oil (151 mg, 35%). LRMS (M+H) m/z: calcd 257.1. found 257.
Reaction SMILES: [NH2:1][C:2]1[C:3]([N+:12]([O-:14])=[O:13])=[C:4]([CH:8]=[C:9]([Cl:11])[CH:10]=1)[C:5]([OH:7])=[O:6].[CH3:15]N(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C[NH3+].F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.F[P-](F)(F)(F)(F)F.CCN(CC)CC>CO.C1COCC1>[NH2:1][C:2]1[C:3]([N+:12]([O-:14])=[O:13])=[C:4]([CH:8]=[C:9]([Cl:11])[CH:10]=1)[C:5]([O:7][CH3:15])=[O:6]
Reactant: Nc1cc(Cl)cc(C(=O)O)c1[N+](=O)[O-]
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: C[NH3+]
Agent: F[P-](F)(F)(F)(F)F
Solvent: CO
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: COC(=O)c1cc(Cl)cc(N)c1[N+](=O)[O-]
Yield: 64 %

Procedure:
A mixture of 3-amino-5-chloro-2-nitrobenzoic acid (43.2 g) and HATU (2-(1H-7-Azabenzotriazol-1-yl)--1,1,3,3-tetramethyl uronium hexafluorophosphate Methanaminium, commercially available) (76 g) in MeOH (81 mL), Et3N (83 mL) and THF (300 mL) was stirred at room temperature for 3 h. When TLC showed no starting material, the solvent was removed in-vacuo and the residue was then diluted with EtOAc (2 L). It was then washed with brine (1 L×3) and dried over anhydrous Na2SO4, filtered and concentrated in-vacuo. The residue was then purified by silica gel chromatography eluted with EtOAc:petroleum ether=1:8 to afford the desired product as a yellow solid (29.5 g, yield 64%). 1H NMR (300 MHz, CDCl3): δ ppm 3.90 (s, 3H, s), 5.85 (br s, 2H), 6.80 (d, 1H, J=2.4 Hz), 6.90 (d, 1H, J=2.4 Hz); LC-MS: m/e=231 [M+1]+.
Reaction SMILES: [CH2:1]([N:8]([CH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)[S:9]([C:12]1[CH:21]=[C:20]2[C:15]([CH:16]=[CH:17][C:18]([NH:22][C:23](=[O:29])[O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[CH:19]2)=[CH:14][CH:13]=1)(=[O:11])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1C(=O)N([Br:44])C(=O)C1.C([O-])([O-])=O.[K+].[K+]>CC#N>[Br:44][C:19]1[C:20]2[C:15](=[CH:14][CH:13]=[C:12]([S:9]([N:8]([CH2:1][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)[CH2:30][C:31]3[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=3)(=[O:11])=[O:10])[CH:21]=2)[CH:16]=[CH:17][C:18]=1[NH:22][C:23](=[O:29])[O:24][C:25]([CH3:28])([CH3:27])[CH3:26]
Reactant: O=C1CCC(=O)N1Br
Reactant: CC(C)(C)OC(=O)Nc1ccc2ccc(S(=O)(=O)N(Cc3ccccc3)Cc3ccccc3)cc2c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CC(C)(C)OC(=O)Nc1ccc2ccc(S(=O)(=O)N(Cc3ccccc3)Cc3ccccc3)cc2c1Br
Temperature: 40 °C
Reaction time: 0.5 h

Procedure:
A mixture of 211 (1.15 g, 2.29 mmol), NBS (450 mg, 2.52 mmol), and K2CO3 (380 mg, 2.75 mmol) in MeCN (25 mL) was stirred at 40° C. under nitrogen for 30 min. The solvent was removed under reduced pressure and the residue was partitioned between EtOAc and H2O. The EtOAc layer was washed with H2O, brine, then dried and evaporated. The residue was recrystallised from EtOAc/Et2O/petroleum ether to give tert-butyl 1-bromo-7-[(dibenzylamino)sulfonyl]-2-naphthylcarbamate (212) as colorless crystals: mp 150-151° C.; 1H NMR (CDCl3) δ 8.69 (d, J=1.6 Hz, 1H), 8.57 (d, J=9.1 Hz, 1H), 7.89 (d, J=8.6 Hz, 1H), 7.85 (d, J=9.1 Hz, 1H), 7.74 (dd, J=8.6, 1.8 Hz, 1H), 7.38 (s, 1H), 7.22-7.15 (m, 6H), 7.12-7.05 (m, 4H), 4.40 (s, 4H), 1.58 (s, 9H); 13C NMR δ 152.4, 139.6, 136.5, 135.5, 132.0, 131.5, 129.7, 128.6, 128.5, 128.1, 127.7, 126.8, 122.1, 121.8, 110.4, 81.8, 50.6, 28.3. Anal. (C29H29BrN2O4S) C, H, N.
Reaction SMILES: F[C:2]1[CH:3]=[CH:4][C:5]([C:12]([F:15])([F:14])[F:13])=[C:6]([CH2:8][C:9]([OH:11])=[O:10])[CH:7]=1.[CH2:16]([OH:23])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>>[CH2:16]([O:23][C:2]1[CH:3]=[CH:4][C:5]([C:12]([F:15])([F:14])[F:13])=[C:6]([CH2:8][C:9]([OH:11])=[O:10])[CH:7]=1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: O=C(O)Cc1cc(F)ccc1C(F)(F)F
Reactant: OCc1ccccc1
Product: O=C(O)Cc1cc(OCc2ccccc2)ccc1C(F)(F)F

Procedure:
Prepared according to the procedure described in Example 24, Step 1, using the following starting materials: 5-fluoro-2-(trifluoromethyl)phenylacetic acid and benzyl alcohol.
Reaction SMILES: [CH3:1][O:2][C:3]([N:5]1[C@@H:13]2[C@@H:8]([C@@:9]([OH:23])([C:14]#[C:15][C:16]3[CH:17]=[C:18]([CH3:22])[CH:19]=[CH:20][CH:21]=3)[CH2:10][CH2:11][CH2:12]2)[CH2:7][CH2:6]1)=[O:4].[Br:24][C:25]1[CH:33]=[CH:32][C:28]([C:29](O)=[O:30])=[CH:27][CH:26]=1>>[Br:24][C:25]1[CH:33]=[CH:32][C:28]([C:29]([O:23][C@@:9]2([C:14]#[C:15][C:16]3[CH:17]=[C:18]([CH3:22])[CH:19]=[CH:20][CH:21]=3)[CH2:10][CH2:11][CH2:12][C@@H:13]3[C@H:8]2[CH2:7][CH2:6][N:5]3[C:3]([O:2][CH3:1])=[O:4])=[O:30])=[CH:27][CH:26]=1
Reactant: COC(=O)N1CC[C@H]2[C@@H]1CCC[C@]2(O)C#Cc1cccc(C)c1
Reactant: O=C(O)c1ccc(Br)cc1
Product: COC(=O)N1CC[C@@H]2[C@H]1CCC[C@]2(C#Cc1cccc(C)c1)OC(=O)c1ccc(Br)cc1

Procedure:
Synthesis in analogy to the General Method 1 starting from (3aS,4R,7aS)-4-hydroxy-4-m-tolylethynyl-octahydro-indole-1-carboxylic acid methyl ester and 4-brom-benzoic acid to yield (3aR,4S,7aR)-methyl 4-(4-bromobenzoyloxy)-4-(m-tolylethynyl)octahydro-1H-indole-1-carboxylate. MS [M+H]=296 (ester elimination ion); RT=7.705 min; LC-MS Method II
Reaction SMILES: [CH2:1]1[CH:6]2[CH2:7][N:8]3[C:13](=[O:14])[C:12]([OH:15])=[C:11]([C:16]([NH:18][CH2:19][C:20]4[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=4)=[O:17])[N:10]=[C:9]3[C:3]([NH2:27])([CH2:4][O:5]2)[CH2:2]1.CCN(CC)CC.[C:35](Cl)(=[O:37])[CH3:36]>C(Cl)Cl>[CH3:36][C:35]([NH:27][C:3]12[CH2:4][O:5][CH:6]([CH2:7][N:8]3[C:13](=[O:14])[C:12]([OH:15])=[C:11]([C:16]([NH:18][CH2:19][C:20]4[CH:21]=[CH:22][C:23]([F:26])=[CH:24][CH:25]=4)=[O:17])[N:10]=[C:9]31)[CH2:1][CH2:2]2)=[O:37]
Reactant: CC(=O)Cl
Reactant: NC12CCC(Cn3c1nc(C(=O)NCc1ccc(F)cc1)c(O)c3=O)OC2
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)NC12CCC(Cn3c1nc(C(=O)NCc1ccc(F)cc1)c(O)c3=O)OC2
Temperature: 25 °C
Reaction time: 16 h
Yield: 27 %

Procedure:
To a solution of 10-amino-N-(4-fluorobenzyl)-3-hydroxy-4-oxo-4,6,7,8,9,10-hexahydro-7,10-(epoxymethano)pyrimido[1,2-a]azepine-2-carboxamide (30 mg, 0.080 mmol) in CH2Cl2 (2 mL) was added Et3N (0.056 mL, 0.401 mmol) followed by acetyl chloride (0.05 mL, 0.401 mmol) and the resulting mixture stirred at room temperature for 16 h. The reaction mixture was concentrated and the resulting residue dissolved in methanol (2 mL) and treated with 2M dimethylamine in methanol (0.5 mL). The resulting reaction mixture was stirred at 60° C. for 2 h, cooled and purified by preparative HPLC to afford the title compound as a white solid (9 mg, 27% yield). 1H NMR (500 MHz, CDCl3) δ: 11.92 (s, 1H), 7.39 (brs, 1H), 7.29-7.33 (m, 2H), 7.05-7.09 (m, 2H), 6.13 (s, 1H), 4.59-4.65 (m, 2H), 4.48-4.55 (m, 3H), 4.30 (d, 1H, J=11.9 Hz), 4.10 (d, 1H, J=16.17 Hz), 2.52-2.58 (m, 1H), 2.30-2.36 (m, 1H), 1.82 (s, 3H), 1.75-1.82 (m, 1H), 1.50-1.55 (m, 1H). LCMS (M+H)=417.25. HPLC purity>95%.
Reaction SMILES: [Cl:1][C:2]1[CH:15]=[CH:14][C:13]([N+:16]([O-:18])=[O:17])=[CH:12][C:3]=1[O:4][CH2:5][CH:6]1[CH2:11][CH2:10][NH:9][CH2:8][CH2:7]1.[CH3:19][C:20]([CH3:22])=O.[BH3-]C#N.[Na+]>CC#N>[Cl:1][C:2]1[CH:15]=[CH:14][C:13]([N+:16]([O-:18])=[O:17])=[CH:12][C:3]=1[O:4][CH2:5][CH:6]1[CH2:7][CH2:8][N:9]([CH:20]([CH3:22])[CH3:19])[CH2:10][CH2:11]1
Reactant: CC(C)=O
Reactant: O=[N+]([O-])c1ccc(Cl)c(OCC2CCNCC2)c1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC#N
Product: CC(C)N1CCC(COc2cc([N+](=O)[O-])ccc2Cl)CC1
Reaction time: 14 h

Procedure:
4-(2-Chloro-5-nitro-phenoxymethyl)-piperidine (7 g, 25.9 mmol) was dissolved in CH3CN (50 mL) and acetone (9.48 ml, 129 mmol) was added. NaBH3CN (2.6 g, 41.4 mmol) was added. After 14 h, the mixture was concentrated in vacuo and the residue was dissolved in EtOAc, washed with brine. The EtOAc portion was dried with Na2SO4, and evaporated. The title compound was purified by column chromatography using 0-75% of a 90:10:1 (CH2Cl2:MeOH: NH4OH) solution as the eluent to yield a yellow solid. MS(MH+)=NA; Calc'd 312.12 for C15H21ClN2O3.
Reaction SMILES: Br[C:2]1[N:6](CC2C=CC(OC)=CC=2)[N:5]=[C:4]([C:16]2[S:17][C:18]([Cl:21])=[CH:19][CH:20]=2)[C:3]=1[C:22]1[CH:27]=[CH:26][N:25]=[CH:24][CH:23]=1.Br[C:29]1C(C2C=CN=CC=2)=C(C2SC(Cl)=CC=2)N(CC2C=CC(OC)=CC=2)[N:30]=1>CN(C)C=O.O.C(OCC)(=O)C.[C-]#N.[Zn+2].[C-]#N.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>[Cl:21][C:18]1[S:17][C:16]([C:4]2[C:3]([C:22]3[CH:23]=[CH:24][N:25]=[CH:26][CH:27]=3)=[C:2]([C:29]#[N:30])[NH:6][N:5]=2)=[CH:20][CH:19]=1
Reactant: COc1ccc(Cn2nc(-c3ccc(Cl)s3)c(-c3ccncc3)c2Br)cc1
Reactant: COc1ccc(Cn2nc(Br)c(-c3ccncc3)c2-c2ccc(Cl)s2)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [C-]#N
Agent: [Zn+2]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: O
Product: N#Cc1[nH]nc(-c2ccc(Cl)s2)c1-c1ccncc1
Temperature: 160 °C
Reaction time: 0.08 h
Yield: 15 %

Procedure:
To 4-[5-bromo-3-(5-chloro-2-thienyl)-1-(4-methoxybenzyl)-1H-pyrazol-4-yl]pyridine and 4-[3-bromo-5-(5-chloro-2-thienyl)-1-(4-methoxybenzyl)-1H-pyrazol-4-yl]pyridine (mixture of isomers 2:1, 1 eq, 0.435 mmol) in 1 mL of N,N-dimethylformamide, were added zinc cyanide (0.65 mmol) and Tetrakis(triphenylphosphine)palladium(0) (0.09 mmol). The mixture was stirred for 5 mins at 160° C. in the microwave. After cooling to room temperature, the reaction mixture was diluted with water and ethyl acetate was added. The aqueous layer was extracted with ethyl acetate and the combined organic extracts were dried over MgSO4, filtered and concentrated. The residue was dissolved in 1 mL of trifluoroacetic acid and stirred at 65° C. for 2 h. Water and ethyl acetate were added. And the aqueous layer was extracted with ethyl acetate. The combined organic extracts were washed with a saturated solution of sodium hydrogen carbonate, dried over MgSO4, filtered and concentrated. The residue was purified by chromatography on silica gel (dichloromethane/methanol 20:1 to 10:1) to afford 19 mg of 3-(5-chloro-2-thienyl)-4-(pyridin-4-yl)-1H-pyrazole-5-carbonitrile (15% yield).
Reaction SMILES: [CH3:1][C:2]1[C:10]([C:11](=O)[CH2:12][C:13]([O:15]C(C)(C)C)=O)=[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][N:4]2[N:3]=1.[SH:21][CH2:22][C:23]([O:25][CH3:26])=[O:24].[CH3:27]CO>>[OH:15][C:13]1[CH:12]=[C:11]([C:10]2[C:2]([CH3:1])=[N:3][N:4]3[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=23)[S:21][C:22]=1[C:23]([O:25][CH2:26][CH3:27])=[O:24]
Reactant: Cc1nn2ccccc2c1C(=O)CC(=O)OC(C)(C)C
Reactant: CCO
Reactant: COC(=O)CS
Product: CCOC(=O)c1sc(-c2c(C)nn3ccccc23)cc1O
Temperature: 25 °C
Reaction time: 24 h
Yield: 23 %

Procedure:
To a stirred solution of tert-butyl 3-(2-methylpyrazolo[1,5-a]pyridin-3-yl)-3-oxopropanoate (1.5 g, 5.47 mmol) prepared above and methyl 2-mercaptoacetate (4 mL, 40 mmol) in EtOH (4 mL), a stream of hydrogen chloride gas was bubbled at 0° C. for 2 h. After bubbling of hydrogen chloride gas was stopped, the mixture was stirred for 24 h at rt. The solvent was removed by evaporation. To the residue, were added a saturated aqueous solution of NaHCO3 (100 mL) and EtOAc (300 mL). The resulting biphasic mixture was vigorously stirred for 30 min and then aqueous phase was discarded. The organic phase was washed with brine and then dried over anhydrous magnesium sulfate. Insoluble materials were removed by filtration and the filtrate was concentrated under reduced pressure. To the residue was added a 20% solution of sodium ethylate in ethanol (50 mL) and the mixture was stirred for 16 h at rt. To the mixture, were added EtOAc (400 mL), a saturated aqueous solution of ammonium chloride and a 1N aqueous solution of hydrogen chloride to adjust ca pH 4-5. After being stirred for 30 min, the organic phase was washed with brine and then dried over anhydrous magnesium sulfate. Insoluble materials were removed by filtration and the filtrate was concentrated under reduced pressure. Column chromatography was performed to yield the title compound (381 mg, 23%) as a pale yellow solid. 1H NMR (300 MHz, d6-DMSO) δ: 10.31 (br s, 1H), 8.69 (d, J=6.8 Hz, 1H), 7.88 (d, J=9.1 Hz, 1H), 7.48-7.38 (m, 1H), 7.04-6.92 (m, 2H), 4.32-4.21 (m, 2H), 2.56 (s, 3H), 1.38-1.18 (m, 3H).
Reaction SMILES: [Cl:1][C:2]1[C:3]2[C:10](I)=[CH:9][N:8]([CH2:12][O:13][CH2:14][CH2:15][Si:16]([CH3:19])([CH3:18])[CH3:17])[C:4]=2[N:5]=[CH:6][N:7]=1.[NH2:20][C:21]1[CH:22]=[C:23]([SH:27])[CH:24]=[CH:25][CH:26]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O.[Cu]I>[Cl:1][C:2]1[C:3]2[C:10]([S:27][C:23]3[CH:22]=[C:21]([CH:26]=[CH:25][CH:24]=3)[NH2:20])=[CH:9][N:8]([CH2:12][O:13][CH2:14][CH2:15][Si:16]([CH3:19])([CH3:18])[CH3:17])[C:4]=2[N:5]=[CH:6][N:7]=1
Reactant: C[Si](C)(C)CCOCn1cc(I)c2c(Cl)ncnc21
Reactant: Nc1cccc(S)c1
Agent: [Cu]I
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: C[Si](C)(C)CCOCn1cc(Sc2cccc(N)c2)c2c(Cl)ncnc21
Yield: 25.6 %

Procedure:
4-Chloro-5-iodo-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidine (400 mg, 0.98 mmol) was treated with 3-aminobenzenethiol (120 mg, 0.96 mmol), copper(I) iodide (300 mg, 1.58 mmol), potassium carbonate (300 mg, 2.17 mmol) and 8 ml N,N-dimethylformamide as solvent according to Preparation 86. The residue was purified using SP1® Purification System (hexane-ethyl acetate) to obtain 100 mg (25% yield) of the title compound. Purity 98%.
Reaction SMILES: [BH4-].[Na+].[CH3:3][N:4]1[CH2:9][CH2:8][CH:7]([C:10]2[C:15]([O:16][CH3:17])=[CH:14][C:13]([O:18][CH3:19])=[CH:12][C:11]=2[O:20][CH3:21])[C:6](=[O:22])[CH2:5]1>C(O)C.O>[OH:22][C@H:6]1[C@@H:7]([C:10]2[C:11]([O:20][CH3:21])=[CH:12][C:13]([O:18][CH3:19])=[CH:14][C:15]=2[O:16][CH3:17])[CH2:8][CH2:9][N:4]([CH3:3])[CH2:5]1
Reactant: COc1cc(OC)c(C2CCN(C)CC2=O)c(OC)c1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: COc1cc(OC)c([C@H]2CCN(C)C[C@H]2O)c(OC)c1

Procedure:
Sodium borohydride (10 g) is added with stirring to a solution, boiling under reflux, of 1-methyl-4-(2,4,6-trimethoxyphenyl)-piperidin-3-one in absolute ethanol. Stirring and heating under reflux is then continued for a further hour. On cooling, the reaction mixture is diluted with water, then concentrated in order to remove the ethanol and extracted with chloroform. The chloroform extract is washed with water, dried over anhydrous sodium sulfate and concentrated to give a solid residue which, on crystallization from acetone, gives the desired product (29.2 g) of melting point 124°-125° C.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:11]([N:13]3[CH2:18][CH2:17][C:16]4([C:22]5[CH:23]=[CH:24][C:25]([F:27])=[CH:26][C:21]=5[C:20](=[O:28])[O:19]4)[CH2:15][CH2:14]3)=[O:12])=[CH:7][NH:8]2)=[CH:4][CH:3]=1.[CH3:29][C:30]1[O:34][N:33]=[C:32]([CH2:35]OS(C)(=O)=O)[CH:31]=1>>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:11]([N:13]3[CH2:18][CH2:17][C:16]4([C:22]5[CH:23]=[CH:24][C:25]([F:27])=[CH:26][C:21]=5[C:20](=[O:28])[O:19]4)[CH2:15][CH2:14]3)=[O:12])=[CH:7][N:8]2[CH2:35][C:32]2[CH:31]=[C:30]([CH3:29])[O:34][N:33]=2)=[CH:4][CH:3]=1
Reactant: Cc1cc(COS(C)(=O)=O)no1
Reactant: O=C1OC2(CCN(C(=O)c3c[nH]c4cc(Cl)ccc34)CC2)c2ccc(F)cc21
Product: Cc1cc(Cn2cc(C(=O)N3CCC4(CC3)OC(=O)c3cc(F)ccc34)c3ccc(Cl)cc32)no1

Procedure:
Following the general procedure III as described above, the alkylation of 1′-[(6-chloro-1H-indol-3-yl)carbonyl]-5-fluoro-3H-spiro[2-benzofuran-1,4′-piperidin]-3-one (prepared according to example 19) with methanesulfonic acid 5-methyl-isoxazol-3-ylmethyl ester (described in WO 2004092172) gave the title compound.
Reaction SMILES: [Cl:1]N1C(=O)CCC1=O.CSC.[F:12][C:13]([F:35])([F:34])[O:14][C:15]1[CH:20]=[CH:19][C:18]([NH:21]/[N:22]=[CH:23]/[C:24]2[CH:33]=[CH:32][C:27]([C:28]([O:30][CH3:31])=[O:29])=[CH:26][CH:25]=2)=[CH:17][CH:16]=1>C(Cl)Cl>[Cl:1][C:23](=[N:22][NH:21][C:18]1[CH:19]=[CH:20][C:15]([O:14][C:13]([F:34])([F:35])[F:12])=[CH:16][CH:17]=1)[C:24]1[CH:33]=[CH:32][C:27]([C:28]([O:30][CH3:31])=[O:29])=[CH:26][CH:25]=1
Reactant: O=C1CCC(=O)N1Cl
Reactant: COC(=O)c1ccc(/C=N/Nc2ccc(OC(F)(F)F)cc2)cc1
Solvent: CSC
Solvent: ClCCl
Product: COC(=O)c1ccc(C(Cl)=NNc2ccc(OC(F)(F)F)cc2)cc1
Temperature: -78 °C
Reaction time: 0.25 h

Procedure:
To a magnetically stirred solution of N-chlorosuccinimide (0.59 g, 4.43 mmoL) in CH2Cl2 (8 mL) at 0° C. was added dimethyl sulfide (0.85 mL, 8.87 mmoL) and the reaction mixture was stirred for 15 minutes (min) and then cooled to −78° C. To this solution was added (E)-methyl 4-((2-(4-(trifluoromethoxy)-phenyl)hydrazono) methyl)benzoate dissolved in 8 mL of CH2Cl2 and the reaction mixture was stirred at this temperature for 1 hour (h), warmed to room temperature and stirred for 2 h. The solution was concentrated under reduced pressure. The residue was dissolved in CH2Cl2 (15 mL) and added to a silica gel (SiO2) loading cartridge and purified via flash column chromatography (Gradient EtOAc/hexanes). The title compound was obtained as a yellow solid as a mixture of E and Z isomers: mp 159-162° C.; 1H NMR (400 MHz, CDCl3) δ 8.18 (s, 1H), 8.07 (d, J=8.8 Hz, 2H), 7.98 (d, J=8.8 Hz, 2H), 7.20 (s, 4H), 3.95 (s, 3H); 19F NMR (376 MHz, CDCl3) δ−58.32; ESIMS m/z 372 ([M+H])+.