Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[O:6][N:5]=[C:4]([NH:7][CH:8]([P:17](=[O:24])([O:21][CH2:22][CH3:23])[O:18][CH2:19][CH3:20])[P:9](=[O:16])([O:13][CH2:14][CH3:15])[O:10][CH2:11][CH3:12])[CH:3]=1.[C:25](OC(=O)C)(=[O:27])[CH3:26]>>[C:25]([N:7]([CH:8]([P:9](=[O:16])([O:10][CH2:11][CH3:12])[O:13][CH2:14][CH3:15])[P:17](=[O:24])([O:18][CH2:19][CH3:20])[O:21][CH2:22][CH3:23])[C:4]1[CH:3]=[C:2]([CH3:1])[O:6][N:5]=1)(=[O:27])[CH3:26]
Reactant: CCOP(=O)(OCC)C(Nc1cc(C)on1)P(=O)(OCC)OCC
Reactant: CC(=O)OC(C)=O
Product: CCOP(=O)(OCC)C(N(C(C)=O)c1cc(C)on1)P(=O)(OCC)OCC

Procedure:
6 g of tetraethyl [(5-methyl-3-isoxazolyl)amino]-methylene-bis(phosphonate) was dissolved in 60 ml of acetic anhydride and heated under reflux overnight. The reaction solution was concentrated under reduced pressure, and the resulting syrup was formed into a chloroform solution. This was washed with water and dried, and then the solvent was removed by distillation. The residue was purified on a silica gel column (eluent: 0.5-2% ethanolchloroform) to give 5.2 g of tetraethyl [N-acetyl(5-methyl-3-isoxazolyl)amino]methylene-bis(phosphonate) as a pale yellow syrup.
Reaction SMILES: [C:1]([N:4]([CH2:21][C@@H:22]1[O:26][C:25](=[O:27])[N:24]([C:28]2[CH:33]=[CH:32][C:31]([CH:34]3[CH2:39][CH2:38][S:37](=[O:41])(=[O:40])[CH2:36][CH2:35]3)=[C:30]([F:42])[CH:29]=2)[CH2:23]1)[C:5]([O:7][CH2:8][O:9][C:10](=[O:20])[CH2:11][NH:12]C(OC(C)(C)C)=O)=[O:6])(=[O:3])[CH3:2].C1(OC)C=CC=CC=1.C1COCC1.[ClH:56]>O1CCOCC1>[ClH:56].[C:1]([N:4]([CH2:21][C@@H:22]1[O:26][C:25](=[O:27])[N:24]([C:28]2[CH:33]=[CH:32][C:31]([CH:34]3[CH2:39][CH2:38][S:37](=[O:40])(=[O:41])[CH2:36][CH2:35]3)=[C:30]([F:42])[CH:29]=2)[CH2:23]1)[C:5]([O:7][CH2:8][O:9][C:10](=[O:20])[CH2:11][NH2:12])=[O:6])(=[O:3])[CH3:2]
Reactant: CC(=O)N(C[C@H]1CN(c2ccc(C3CCS(=O)(=O)CC3)c(F)c2)C(=O)O1)C(=O)OCOC(=O)CNC(=O)OC(C)(C)C
Agent: Cl
Solvent: C1COCCO1
Solvent: C1CCOC1
Solvent: COc1ccccc1
Product: CC(=O)N(C[C@H]1CN(c2ccc(C3CCS(=O)(=O)CC3)c(F)c2)C(=O)O1)C(=O)OCOC(=O)CN
Yield: 72 %

Procedure:
Following General procedure G, except that the entire reaction is performed at RT. (R)-Tert-butoxycarbonylamino-acetic acid (acetyl-{3-[4-(1,1-dioxo-hexahydro-1λ6-thiopyran-4-yl)-3-fluoro-phenyl]-2-oxo-oxazolidin-5-ylmethyl}-carbamoyloxy)-methyl ester (12a) (0.24 g, 0.39 mmol), anisole (0.5 mL), THF (7.3 mL), and 4 M HCl in dioxane (3 mL) gave the title compound in 72% yield (0.16 g). 1H NMR (400 MHz, DMSO): δ 8.39 (br d, 3H), 7.47 (dd, 1H), 7.39 (t, 1H), 7.28 (dd, 1H), 5.93 (m, 2H), 4.80 (m, 1H), 4.14 (m, 2H), 3.92 (m, 3H), 3.82 (m, 1H), 3.37 (m, 2H), 3.20 (m, 1H), 3.10 (m, 2H), 2.47 (s, 3H), 2.16 (m, 2H), 2.04 (m, 2H). MS-APCI (m/z+): 516, 616.
Reaction SMILES: C([NH:4][C@@H:5]([CH2:9][C:10]1[CH:15]=[CH:14][C:13]([F:16])=[C:12]([Br:17])[CH:11]=1)[C:6]([OH:8])=[O:7])(=O)C.[ClH:18]>>[ClH:18].[Br:17][C:12]1[CH:11]=[C:10]([CH:15]=[CH:14][C:13]=1[F:16])[CH2:9][C@@H:5]([C:6]([OH:8])=[O:7])[NH2:4]
Reactant: CC(=O)N[C@@H](Cc1ccc(F)c(Br)c1)C(=O)O
Agent: Cl
Product: N[C@@H](Cc1ccc(F)c(Br)c1)C(=O)O
Temperature: 100 °C
Yield: 86 %

Procedure:
A suspension of (S)-2-acetylamino-3-(3-bromo-4-fluoro-phenyl)-propionic acid (2.5 g, 8.2 mmol) in HCl (6.0 M in water, 5.0 mL) was heated at 100° C. for 2 h and then cooled to 0° C. The resulting solid was collected by filtration to give the title phenylalanine as a light tan solid (2.1 g, 86%). MS (ESI+): mass calcd. for C9H9BrFNO2, 261.0; m/z found, 261.8 [M+H]+. 1H NMR (400 MHz, D2O): 7.50 (dd, J=6.6, 2.1, 1H), 7.21 (ddd, J=8.4, 4.7, 2.2, 1H), 7.14 (t, J=8.7, 1H), 3.90 (dd, J=7.7, 5.5, 1H), 3.16 (dd, J=14.7, 5.4, 1H), 3.04 (dd, J=14.7, 7.7, 1H).
Reaction SMILES: [N:1]1([CH2:7][C:8]2[CH:9]=[C:10]3[C:15](=[CH:16][CH:17]=2)[N:14]([CH:18]2[CH2:23][CH2:22][O:21][CH2:20][CH2:19]2)[CH:13]=[C:12]([C:24](OCC)=[O:25])[C:11]3=[O:29])[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[Cl:30][C:31]1[CH:38]=[CH:37][C:34]([CH2:35][NH2:36])=[CH:33][CH:32]=1>>[Cl:30][C:31]1[CH:38]=[CH:37][C:34]([CH2:35][NH:36][C:24]([C:12]2[C:11](=[O:29])[C:10]3[C:15](=[CH:16][CH:17]=[C:8]([CH2:7][N:1]4[CH2:6][CH2:5][O:4][CH2:3][CH2:2]4)[CH:9]=3)[N:14]([CH:18]3[CH2:23][CH2:22][O:21][CH2:20][CH2:19]3)[CH:13]=2)=[O:25])=[CH:33][CH:32]=1
Reactant: CCOC(=O)c1cn(C2CCOCC2)c2ccc(CN3CCOCC3)cc2c1=O
Reactant: NCc1ccc(Cl)cc1
Product: O=C(NCc1ccc(Cl)cc1)c1cn(C2CCOCC2)c2ccc(CN3CCOCC3)cc2c1=O
Temperature: 190 °C

Procedure:
A flask containing ethyl 6-(4-morpholinylmethyl)-4-oxo-1-tetrahydro-2H-pyran-4-yl-1,4-dihydro-3-quinolinecarboxylate (0.21 g) is treated with 4-chlorobenzylamine (2.0 mL). The reaction is tightly capped and heated to 190° C. for 1 hour. The reaction is cooled to room temperature, adsorbed onto silica and chromatographed on silica eluting with 2% to 6% methanol in dichloromethane and then by recrystallization from ethyl acetate to afford 0.14 g of the title compound.
Reaction SMILES: CS(O[CH2:6][CH2:7][CH2:8][C:9]1[CH:10]=[CH:11][C:12]2[C:13]3[N:22]([CH2:23][C:24]([OH:27])([CH3:26])[CH3:25])[C:21]([CH2:28][O:29][CH2:30][CH3:31])=[N:20][C:14]=3[C:15]([NH2:19])=[N:16][C:17]=2[CH:18]=1)(=O)=O.[NH:32]1[CH2:37][CH2:36][O:35][CH2:34][CH2:33]1>C(#N)C>[NH2:19][C:15]1[C:14]2[N:20]=[C:21]([CH2:28][O:29][CH2:30][CH3:31])[N:22]([CH2:23][C:24]([CH3:25])([OH:27])[CH3:26])[C:13]=2[C:12]2[CH:11]=[CH:10][C:9]([CH2:8][CH2:7][CH2:6][N:32]3[CH2:37][CH2:36][O:35][CH2:34][CH2:33]3)=[CH:18][C:17]=2[N:16]=1
Reactant: C1COCCN1
Reactant: CCOCc1nc2c(N)nc3cc(CCCOS(C)(=O)=O)ccc3c2n1CC(C)(C)O
Solvent: CC#N
Product: CCOCc1nc2c(N)nc3cc(CCCN4CCOCC4)ccc3c2n1CC(C)(C)O
Temperature: 75 °C
Yield: 42.7 %

Procedure:
A round bottom flask, equipped with a stir bar, was charged with 3-[4-amino-2-(ethoxymethyl)-1-(2-hydroxy-2-methylpropyl)-1H-imidazo[4,5-c]quinolin-7-yl]propyl methanesulfonate (0.24 g, 0.53 mmol) and acetonitrile (10 mL). Morpholine (0.23 g, 2.7 mmol) was added in one portion. The reaction mixture was heated at 75° C. for 18 hours and then cooled to ambient temperature. After concentrating under reduced pressure, the resulting solid was dissolved in dichloromethane (50 mL) and washed with saturated aqueous potassium carbonate (50 mL). The fractions were separated and the organic fraction was concentrated to dryness. The solid was purified by chromatography using a HORIZON HPFC system (silica cartridge, 0-25% CMA/chloroform). The material was further purified by a second chromatography treatment using a HORIZON HPFC system (silica cartridge, 10% methanol/dichloromethane). A final recrystallization from acetonitrile provided 0.1 g of 1-[4-amino-2-(ethoxymethyl)-7-(3-morpholin-4-ylpropyl)-1H-imidazo[4,5-c]quinolin-1-yl]-2-methylpropan-2-ol as a white crystalline solid, mp 132-133° C.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][C:7]([NH:11][C:12]([C:14]3[C:18]4[N:19]=[C:20](Cl)[N:21]=[CH:22][C:17]=4[S:16][CH:15]=3)=[O:13])=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.[C@@H:24]1([NH2:31])[CH2:29][CH2:28][CH2:27][CH2:26][C@@H:25]1[NH2:30].O.ClCCl>O1CCOCC1>[N:1]1[C:10]2[C:5](=[CH:6][C:7]([NH:11][C:12]([C:14]3[C:18]4[N:19]=[C:20]([NH:30][C@@H:25]5[CH2:26][CH2:27][CH2:28][CH2:29][C@@H:24]5[NH2:31])[N:21]=[CH:22][C:17]=4[S:16][CH:15]=3)=[O:13])=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1
Reactant: O=C(Nc1ccc2ncccc2c1)c1csc2cnc(Cl)nc12
Reactant: N[C@@H]1CCCC[C@@H]1N
Solvent: ClCCl
Solvent: O
Solvent: C1COCCO1
Product: N[C@H]1CCCC[C@H]1Nc1ncc2scc(C(=O)Nc3ccc4ncccc4c3)c2n1
Yield: 55.4 %

Procedure:
To a solution of 0.0794 g (0.233 mmole) 2-chloro-thieno[3,2-d]pyrimidine-7-carboxylic acid quinolin-6-ylamide in 2.33 mL of dioxane was added 0.168 mL (1.4 mmole) of cis-cyclohexane-1,2-diamine. The mixture was heated at 100 degrees for 2 hours. Water and dichloromethane were added, separated. The aqueous layer was washed with dichloromethane twice. The organic layer was washed with aqueous sodium carbonate, brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. Purification by silica gel chromatography, eluting with dichloromethane-0.7 N ammonia solution in methanol (gradient 100:0-90:10) gave 0.054 g of 2-(cis-2-amino-cyclohexylamino)-thieno[3,2-d]pyrimidine-7-carboxylic acid quinolin-6-ylamide as a light yellow solid. MH+/Z=419.
Reaction SMILES: Cl.[F:2][C:3]1[C:12]([F:13])=[C:11]2[C:6]([CH2:7][CH2:8][CH:9]([CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])[O:10]2)=[C:5]([I:19])[C:4]=1[O:20]COC>C1COCC1.CC(OC)(C)C>[F:2][C:3]1[C:12]([F:13])=[C:11]2[C:6]([CH2:7][CH2:8][CH:9]([CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])[O:10]2)=[C:5]([I:19])[C:4]=1[OH:20]
Reactant: CCCCCC1CCc2c(I)c(OCOC)c(F)c(F)c2O1
Agent: Cl
Solvent: C1CCOC1
Solvent: COC(C)(C)C
Product: CCCCCC1CCc2c(I)c(O)c(F)c(F)c2O1
Temperature: 25 °C
Reaction time: 17 h

Procedure:
9.2 ml of conc. HCl are added to a solution of 21.4 g (50.2 mmol) of 7,8-difluoro-5-iodo-6-methoxymethoxy-2-pentylchroman in 90 ml of THF, and the mixture is stirred at room temperature for 17 h. The batch is diluted with MTBE, and the solution is washed with water. The aqueous phase is extracted with MTBE, and the combined organic phases are washed with water and sat. sodium chloride soln. The solution is dried using sodium sulfate and concentrated to dryness. The crude product is purified by column chromatography (SiO2, n-heptane:MTBE=1:1), giving 7,8-difluoro-5-iodo-2-pentylchroman-6-ol as a beige solid.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([C:12](O)=[O:13])[CH2:11][CH2:10][CH2:9]2)=[C:4]([O:15][CH3:16])[CH:3]=1.B.O1CCCC1>O1CCCC1>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([CH2:12][OH:13])[CH2:9][CH2:10][CH2:11]2)=[C:4]([O:15][CH3:16])[CH:3]=1
Reactant: COc1cc(Br)ccc1C1(C(=O)O)CCC1
Agent: B
Solvent: C1CCOC1
Product: COc1cc(Br)ccc1C1(CO)CCC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 92.2 %

Procedure:
To a mixture of 1-(4-bromo-2-methoxyphenyl)cyclobutanecarboxylic acid (320 mg, 1.12 mmol) in dry tetrahydrofuran (10 mL) was added borane-tetrahydrofuran (0.67 mL, 6.7 mmol) dropwise. The mixture was stirred at room temperature for 3 hours. The reaction mixture was quenched by water and extracted with dichloromethane. The organic layers were combined, dried over sodium sulfate, and concentrated to give the title compound (280 mg, 92%) as a colorless oil. 1H NMR (500 MHz, DMSO-d6) δ 7.05 (m, 2H), 6.86 (d, 1H), 4.57 (t, 1H), 3.73 (s, 3H), 3.55 (d, 2H), 2.05-2.17 (m, 4H), 1.95 (m, 1H), 1.69 (m, 1H).
Reaction SMILES: [C:1]([N:5]1[CH2:10][CH2:9][N:8]([C:11]([O:13]C(C)(C)C)=O)[CH2:7][CH2:6]1)(=[O:4])[CH:2]=[CH2:3].Cl.CO.[Cl:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[C:28]1[CH:29]=[C:30]([CH:34]=[C:35]([O:37][CH3:38])[CH:36]=1)C(O)=O.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl.CCN(CC)CC>C(Cl)Cl.CN(C=O)C>[Cl:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[C:28]1[CH:36]=[C:35]([O:37][CH3:38])[CH:34]=[C:30]([C:11]([N:8]2[CH2:7][CH2:6][N:5]([C:1](=[O:4])[CH:2]=[CH2:3])[CH2:10][CH2:9]2)=[O:13])[CH:29]=1
Reactant: C=CC(=O)N1CCN(C(=O)OC(C)(C)C)CC1
Reactant: COc1cc(C(=O)O)cc(-c2ccccc2Cl)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CO
Solvent: CN(C)C=O
Solvent: ClCCl
Product: C=CC(=O)N1CCN(C(=O)c2cc(OC)cc(-c3ccccc3Cl)c2)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 48.6 %

Procedure:
To a solution of tert-butyl 4-acryloylpiperazine-1-carboxylate (260 mg, 1.07 mmol) in DCM (2 mL), a solution of HCl in MeOH (10 mL, 28.6 mmol) was added and the resulting mixture was stirred at room temperature for 1 h. The mixture was concentrated in vacuo. The residue was added to the solution of 3-(2-chlorophenyl)-5-methoxybenzoic acid (280 mg, 1.07 mmol), HOBt (290 mg, 2.17 mmol), EDCI.HCl (410 mg, 2.17 mmol) and Et3N (324 mg, 3.21 mmol) in DMF (10 mL). The resulting mixture was stirred at room temperature for 16 h and partitioned between DCM and saturated NaHCO3 solution. The organic layer was dried over MgSO4, filtered and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel (dichloromethane/methanol=50:1) to afford the desired product (200 mg, 52% yield). ESI-MS m/z: 385.2[M+H]+.
Reaction SMILES: [ClH:1].[Cl:2]C1C=CC(OC2C=CC(NC3SC=C([C:20]4([C:27]([NH2:29])=[NH:28])[CH2:24][CH:23]=[C:22]([S:25][CH3:26])[S:21]4)N=3)=CC=2)=CC=1.Br.Cl[C:34]1[CH:62]=[CH:61][C:37]([O:38][C:39]2[CH:44]=[CH:43][C:42]([NH:45][C:46]3[S:47][CH:48]=[C:49](C4C=C(C(OC)=S)SC=4C)[N:50]=3)=[CH:41][CH:40]=2)=[CH:36][CH:35]=1>>[ClH:2].[Cl:1][C:34]1[CH:62]=[CH:61][C:37]([O:38][C:39]2[CH:40]=[CH:41][C:42]([NH:45][C:46]3[S:47][CH:48]=[C:49]([C:23]4[CH:24]=[C:20]([C:27]([NH2:29])=[NH:28])[S:21][C:22]=4[S:25][CH3:26])[N:50]=3)=[CH:43][CH:44]=2)=[CH:36][CH:35]=1
Reactant: COC(=S)c1cc(-c2csc(Nc3ccc(Oc4ccc(Cl)cc4)cc3)n2)c(C)s1
Reactant: CSC1=CCC(C(=N)N)(c2csc(Nc3ccc(Oc4ccc(Cl)cc4)cc3)n2)S1
Agent: Br
Agent: Cl
Product: CSc1sc(C(=N)N)cc1-c1csc(Nc2ccc(Oc3ccc(Cl)cc3)cc2)n1
Yield: 49 %

Procedure:
4-(2-{[4-(4-Chlorophenoxy)phenyl]amino(1,3-thiazol-4-yl)}-5-methylthiothiophene-2-carboxamidine hydrochloride: Methyl 4-(2-{[4-(4-chlorophenoxy)phenyl]amino}(1,3-thiazol-4-yl))-5-methylthiothiophene-2-carboxylate hydrobromide (300 mg, 0.52 mmol) was treated as described in Example 154, step (b) to give 129.9 mg (49% yield) of 4-(2-{[4-(4-chlorophenoxy)phenyl]amino}(1,3-thiazol-4-yl))-5-methylthiothiophene-2-carboxamidine hydrochloride. 1H NMR (DMSO-d6, 300 MHz) δ 2.72 (s, 3H), 6.97 (m, 2H), 7.07 (m, 2H), 7.15 (s, 1H), 7.40 (m, 2H), 7.85 (m, 2H), 8.46 (s, 1H), 8.82 (bs, 2H), 9.27 (bs, 2H), 10.43 (bss, 1H); Mass Spectrum (ESI) m/z calcd. for C21H17ClN4OS3, 473.1 (M+H), found 473.2, 475.1.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[O:10][C:11]3[C:17]([CH3:18])=[CH:16][C:15]([CH3:19])=[CH:14][C:12]=3[N:13]=2)=[C:4]([F:20])[CH:3]=1.FC1C=C([B:28]2[O:32][C:31]([CH3:34])([CH3:33])[C:30]([CH3:36])([CH3:35])[O:29]2)C=CC=1NC1OC2C=CC=CC=2N=1>>[F:20][C:4]1[CH:3]=[C:2]([B:28]2[O:32][C:31]([CH3:34])([CH3:33])[C:30]([CH3:36])([CH3:35])[O:29]2)[CH:7]=[CH:6][C:5]=1[NH:8][C:9]1[O:10][C:11]2[C:17]([CH3:18])=[CH:16][C:15]([CH3:19])=[CH:14][C:12]=2[N:13]=1
Reactant: Cc1cc(C)c2oc(Nc3ccc(Br)cc3F)nc2c1
Reactant: CC1(C)OB(c2ccc(Nc3nc4ccccc4o3)c(F)c2)OC1(C)C
Product: Cc1cc(C)c2oc(Nc3ccc(B4OC(C)(C)C(C)(C)O4)cc3F)nc2c1

Procedure:
N2-[2-Fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-5,7-dimethyl-1,3-benzoxazol-2-amine was prepared from N2-(4-bromo-2-fluorophenyl)-5,7-dimethyl-1,3-benzoxazol-2-amine (6.500 g, 19.39 mmol) in a manner similar to that used for the preparation of N2-[2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-1,3-benzoxazol-2-amine. The compound was formed as a pink solid (3.549 g, 48%). RP-HPLC (25 to 100% CH3CN in 0.1 N aqueous ammonium acetate over 10 min at 1 mL/min using a Hypersil HS C18, 250×4.6 mm column) Rt=15.50 min, 78%; m/z 383 (MH+).
Reaction SMILES: [CH3:1][NH:2][NH:3][C:4]1[CH2:5][N:6]=[C:7]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[Cl:22])[C:8]2[CH:13]=[C:12]([CH2:14][CH3:15])[S:11][C:9]=2[N:10]=1.[C:23](Cl)(=[O:27])[O:24][CH2:25][CH3:26]>C(Cl)(Cl)Cl>[CH2:25]([O:24][C:23]([N:2]([CH3:1])[NH:3][C:4]1[CH2:5][N:6]=[C:7]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[Cl:22])[C:8]2[CH:13]=[C:12]([CH2:14][CH3:15])[S:11][C:9]=2[N:10]=1)=[O:27])[CH3:26]
Reactant: CCOC(=O)Cl
Reactant: CCc1cc2c(s1)N=C(NNC)CN=C2c1ccccc1Cl
Solvent: ClC(Cl)Cl
Product: CCOC(=O)N(C)NC1=Nc2sc(CC)cc2C(c2ccccc2Cl)=NC1
Reaction time: 8 h

Procedure:
5 g of 2-(2-methylhydrazino)-5-o-chlorophenyl-7-ethyl-3H-thieno-[2,3-e][1,4]diazepine is dissolved in 30 ml of chloroform and a solution of 1.8 g of ethyl chlorocarbonate in 10 ml of chloroform is added dropwise with stirring, and the resulting mixture is stirred at room temperature for 2 hours. Then the reaction mixture is washed successively with water, an aqueous sodium hydrogen carbonate solution and water, and dried over anhydrous magnesium sulfate, and the chloroform is removed under reduced pressure. The residue is dissolved in ligroin, and the solution is allowed to stand overnight in a refrigerator to give 2-(2-ethoxycarbonyl-2-methylhydrazino)-5-o-chlorophenyl-7-ethyl-3H-thieno[2,3-e][1,4]diazepine appearing as pale yellow crystals, melting at 172°-174° C.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([S:8]([CH:11]2[CH2:16][CH2:15][N:14]([CH2:17][CH2:18][C:19]3[CH:24]=[CH:23][C:22]([F:25])=[CH:21][C:20]=3[F:26])[CH2:13][CH2:12]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[CH3:27][N:28]1[N:32]=[N:31][C:30]([Sn](CCCC)(CCCC)CCCC)=[N:29]1.O.CCOC(C)=O>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:26][C:20]1[CH:21]=[C:22]([F:25])[CH:23]=[CH:24][C:19]=1[CH2:18][CH2:17][N:14]1[CH2:15][CH2:16][CH:11]([S:8]([C:5]2[CH:6]=[CH:7][C:2]([C:30]3[N:31]=[N:32][N:28]([CH3:27])[N:29]=3)=[CH:3][CH:4]=2)(=[O:10])=[O:9])[CH2:12][CH2:13]1
Reactant: O=S(=O)(c1ccc(Br)cc1)C1CCN(CCc2ccc(F)cc2F)CC1
Reactant: CCCC[Sn](CCCC)(CCCC)c1nnn(C)n1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Solvent: O
Solvent: CCOC(C)=O
Product: Cn1nnc(-c2ccc(S(=O)(=O)C3CCN(CCc4ccc(F)cc4F)CC3)cc2)n1
Temperature: 110 °C
Yield: 57.2 %

Procedure:
A mixture of 4-(4-bromophenylsulphonyl)-1-[2-(2,4-difluorophenyl)ethyl]piperidine (0.38 g, 0.86 mmol), 2-methyl-5-(tributylstannyl)tetrazole (0.64 g, 1.72 mmol) and tetrakis(triphenylphosphine)palladium (100 mg, 0.02 mmol) in DMF was heated at 110° C. for 16 hours while stirring under nitrogen. The solution was poured into water/EtOAc (5/20 ml) and further extracted into EtOAc. The combined organic phase was washed with water, dried (Na2SO4) and evaporated to yield a syrup. Column chromatography (silica, EtOAc) followed by recrystallisation from EtOAc yielded 220 mg of crystalline material. δH (400 MHz, CDCl3) 1.73-1.80 (2H, m), 1.98-2.06 (4H, m), 2.50-2.54 (2H, m), 2.71-2.75 (2H, m), 2.92-2.98 (1H, m), 3.05-3.08 (2H, m), 4.45 (3H, s), 6.71-6.80 (2H, m), 7.09-7.14 (1H, m), 7.99 (1H, d, J 5.2 Hz), 8.34 (1H, d, J 5.2 Hz).
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH2:4][CH2:5][C:6]2=O.[CH3:12][C:13]([S@:16]([NH2:18])=[O:17])([CH3:15])[CH3:14].C1COCC1.[BH4-].[Na+]>C1(C)C=CC=CC=1.[O-]CC.[O-]CC.[O-]CC.[O-]CC.[Ti+4]>[Br:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH2:4][CH2:5][C@H:6]2[NH:18][S@@:16]([C:13]([CH3:15])([CH3:14])[CH3:12])=[O:17]
Reactant: CC(C)(C)[S@](N)=O
Reactant: O=C1CCc2c(Br)cccc21
Agent: [Ti+4]
Agent: CC[O-]
Agent: [BH4-]
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: CC(C)(C)[S@@](=O)N[C@@H]1CCc2c(Br)cccc21
Temperature: 60 °C
Reaction time: 0.25 h

Procedure:
To a stirring solution of 4-bromo-2,3-dihydro-1H-inden-1-one (5.0 g, 23.6 mmol) and (R)-2-methylpropane-2-sulfinamide (3.15 g, 26.0 mmol) in toluene (40 mL) was added titanium tetraethoxide (8.1 g, 35.5 mmol) and the reaction mixture was heated at 60° C. for 18 h under N2. To this mixture was added THF (40 mL) and the resulting solution was cooled to −78° C. Sodium borohydride (3.5 g, 94.7 mmol) was added in one portion. The reaction mixture was stirred at −78° C. for 15 min, and then warmed to room temperature and stirred at this temperature for 2 h. The reaction mixture was cooled to 0° C. before quenching with brine and sodium potassium-tartrate. EA was added and the mixture was stirred at room temperature overnight during which time Ti salts precipitated. The organic layers were decanted, and washed successively with saturated NH4Cl, water, and brine. The organic layers were dried over MgSO4, filtered through a pad of MgSO4, and concentrated to produce (R)-N-((R)-4-bromo-2,3-dihydro-1H-inden-1-yl)-2-methylpropane-2-sulfinamide INT-34 as a solid (3.14 g, 42%) which was used in the next step without purification. LCMS-ESI (m/z) calculated C13H18BrNOS: 317.3; found 318.0 [M+H]+, tR=3.59 min. 1H NMR (400 MHz, CDCl3) δ 7.46 (d, J=7.5, 1H), 7.34 (d, J=7.9, 1H), 7.05 (t, J=7.7, 1H), 4.96-4.77 (m, 1H), 3.39 (d, J=6.8, 1H), 3.06-2.86 (m, 1H), 2.82-2.60 (m, 1H), 2.50-2.29 (m, 1H), 2.05-1.81 (m, 1H), 1.16 (s, 9H).
Reaction SMILES: [C:1]1([N:7]([CH2:30][CH2:31][CH2:32][C:33]([O:35][C:36]([CH3:39])(C)C)=[O:34])[C:8]([C:10]2[CH:29]=[CH:28][C:13]3[N:14]([CH3:27])[C:15]([CH2:17][NH:18][C:19]4[CH:24]=[CH:23][C:22]([C:25]#[N:26])=[CH:21][CH:20]=4)=[N:16][C:12]=3[CH:11]=2)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[ClH:40].C(O)C.C(=O)([O-])[O-].[NH4+:48].[NH4+]>ClCCl.C(O)C>[ClH:40].[ClH:40].[C:1]1([N:7]([CH2:30][CH2:31][CH2:32][C:33]([O:35][CH2:36][CH3:39])=[O:34])[C:8]([C:10]2[CH:29]=[CH:28][C:13]3[N:14]([CH3:27])[C:15]([CH2:17][NH:18][C:19]4[CH:20]=[CH:21][C:22]([C:25](=[NH:26])[NH2:48])=[CH:23][CH:24]=4)=[N:16][C:12]=3[CH:11]=2)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: Cn1c(CNc2ccc(C#N)cc2)nc2cc(C(=O)N(CCCC(=O)OC(C)(C)C)c3ccccc3)ccc21
Reactant: [NH4+]
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: CCO
Solvent: ClCCl
Product: CCOC(=O)CCCN(C(=O)c1ccc2c(c1)nc(CNc1ccc(C(=N)N)cc1)n2C)c1ccccc1
Yield: 68 %

Procedure:
Prepared analogously to Example 25d from 1-methyl-2-[N-(4-cyanophenyl)aminomethyl]benzimidazol-5-yl-carboxylic acid-N-phenyl-N-(3-tert-butyloxycarbonylpropyl)amide and ethanolic hydrochloric acid, ethanol, and ammonium carbonate. Yield: 68% of theory, C29H32N6O3 (512.6); Rf value: 0.12 (silica gel; dichloromethane/ethanol=4:1); EKA mass spectrum: (M+H)+=513; (M+H+Na)++=268.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:29])[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][CH:15]=[CH2:16])=[CH:9][C:8]=1[C:17](=[O:28])[NH:18][CH2:19][C:20]1[CH:25]=[CH:24][C:23](Br)=[CH:22][C:21]=1[F:27])[CH3:2]>C(O)C.C(OCC)(=O)C.[Pd]>[CH2:1]([O:3][C:4](=[O:29])[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][CH2:15][CH3:16])=[CH:9][C:8]=1[C:17](=[O:28])[NH:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[F:27])[CH3:2]
Reactant: C=CCOc1ccc(OCC(=O)OCC)c(C(=O)NCc2ccc(Br)cc2F)c1
Agent: [Pd]
Solvent: CCO
Solvent: CCOC(C)=O
Product: CCCOc1ccc(OCC(=O)OCC)c(C(=O)NCc2ccccc2F)c1
Reaction time: 8 h

Procedure:
A solution of [4-allyloxy-2-(4-bromo-2-fluoro-benzylcarbamoyl)-phenoxy]-acetic acid ethyl ester (0.998 g, 2.35 mmol) in ethanol (150 mL) and ethyl acetate (5 mL) was degassed and put under a nitrogen atmosphere. Palladium catalyst (10% Pd-c, Degussa) was added and the flask was evacuated and treated with hydrogen (balloon). After stirring overnight, the solution was filtered through a pad of silica gel and washed with methanol. After concentrating the solution, the crude product was purified by flash collumn chromatography (30% hepatane in ethyl acetate) to give [4-propyloxy-2-(2-fluoro-benzylcarbamoyl)-phenoxy]-acetic acid ethyl ester.
Reaction SMILES: [C:1]1([CH2:7][C:8]#[N:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:10]([O:15][CH2:16][CH3:17])(=[O:14])[C:11]([O-])=[O:12].[O-]CC.[Na+]>C(O)C>[C:8]([CH:7]([C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)[C:11](=[O:12])[C:10]([O:15][CH2:16][CH3:17])=[O:14])#[N:9]
Reactant: N#CCc1ccccc1
Reactant: CCOC(=O)C(=O)[O-]
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Product: CCOC(=O)C(=O)C(C#N)c1ccccc1

Procedure:
A mixture of 117.1 g. (1.0m.) of phenylacetonitrile and 326 ml. (2.4m.) of ethyl oxalate is added to an ethanol solution of sodium ethoxide (prepared by dissolving 23.8 g., 1.08m. of sodium in 500 ml. of absolute ethanol) and refluxed two hours. After cooling, diluting with 2500 ml. of water and extracting with ether, the solution is acidified with acetic acid. The solid is removed and washed with water to give ethyl 3-cyano-3-phenylpyruvate, m.p. 127°-129° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:15]2[C:23](C(OCC)=O)=[C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][N:17]3[N:16]=2)[CH:6]=[CH:7][C:8]=1[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=1.S(=O)(=O)(O)O>C(=O)([O-])[O-].[Na+].[Na+]>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:15]2[CH:23]=[C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][N:17]3[N:16]=2)[CH:6]=[CH:7][C:8]=1[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=1
Reactant: CCOC(=O)c1c(-c2ccc(-c3ccccn3)c(OC)c2)nn2ccccc12
Agent: O=C([O-])[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Product: COc1cc(-c2cc3ccccn3n2)ccc1-c1ccccn1
Temperature: 100 °C

Procedure:
Ethyl 2-(3-methoxy-4-pyridin-2-ylphenyl)pyrazolo[1,5-a]pyridin-3-carboxylate (25 mg, 0.013 mmol) was treated with 40% sulfuric acid (1 mL), and the reaction mixture was heated to 100° C. for 12 h. The cooled reaction mixture was diluted with a solution of saturated aqueous sodium carbonate (25 mL), and the product was extracted into CH2Cl2 (3×20 mL), dried (MgSO4) and concentrated to afford 2-(3-methoxy-4-pyridin-2-ylphenyl)pyrazolo[1,5-a]pyridine.