Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1([C:7]2[CH:17]=[CH:16][C:10]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:9][CH:8]=2)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[C:18]1([C:24]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)=[CH:25][CH:26]=O)[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCl.CO>[C:18]1([C:24]([C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=2)=[CH:25][CH2:26][N:4]2[CH2:3][CH2:2][N:1]([C:7]3[CH:8]=[CH:9][C:10]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:16][CH:17]=3)[CH2:6][CH2:5]2)[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: O=CC=C(c1ccccc1)c1ccccc1
Reactant: CCOC(=O)c1ccc(N2CCNCC2)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Solvent: ClCCl
Product: CCOC(=O)c1ccc(N2CCN(CC=C(c3ccccc3)c3ccccc3)CC2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of EXAMPLE 1B (6.27 g, 26.8 mmol) and 3,3-diphenylacrylaldehyde (7.26 g, 34.8 mmol) in dichloromethane/methanol (30 mL/30 mL) was added acetic acid (0.6 mL) followed by addition of sodium triacetoxyborohydride (8.52 g, 40.2 mmol) at room temperature. The reaction mixture was stirred overnight at room temperature. The organic solvents were concentrated in vacuo and the residue was partitioned between dichloromethane and saturated aqueous sodium bicarbonate. The organic layer was washed with water and with brine, dried over magnesium sulfate, filtered and the solvent was evaporated in vacuo. The remaining residue was crystallized from acetonitrile.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]2[N:13]=[C:12]([C:14]([F:17])([F:16])[F:15])[CH:11]=[C:10]([C:18]3[CH:23]=[CH:22][CH:21]=[C:20]([C:24]([F:27])([F:26])[F:25])[CH:19]=3)[N:9]=2)[CH:5]=[CH:4][N:3]=1.[NH2:28][C:29]1[CH:34]=[CH:33][C:32](B2OC(C)(C)C(C)(C)O2)=[CH:31][N:30]=1>>[F:15][C:14]([F:17])([F:16])[C:12]1[CH:11]=[C:10]([C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([C:24]([F:27])([F:26])[F:25])[CH:19]=2)[N:9]=[C:8]([C:6]2[CH:5]=[CH:4][N:3]=[C:2]([C:32]3[CH:31]=[N:30][C:29]([NH2:28])=[CH:34][CH:33]=3)[CH:7]=2)[N:13]=1
Reactant: FC(F)(F)c1cccc(-c2cc(C(F)(F)F)nc(-c3ccnc(Cl)c3)n2)c1
Reactant: CC1(C)OB(c2ccc(N)nc2)OC1(C)C
Product: Nc1ccc(-c2cc(-c3nc(-c4cccc(C(F)(F)F)c4)cc(C(F)(F)F)n3)ccn2)cn1

Procedure:
The title compound was prepared from 2-(2-chloro-pyridin-4-yl)-4-trifluoromethyl-6-(3-trifluoromethyl-phenyl)-pyrimidine (example E.59) (0.202 g, 0.5 mmol) and commercially available 2-amino-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (0.13 g, 0.6 mmol) according to the general procedure VI. Obtained as a light yellow solid (0.19 g, 81%). MS (ISP) 462.0 [(M+H)+]; mp 196° C.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1([C:16]#[C:17][C:18]2[CH:23]=[CH:22][C:21]([C:24]3[CH:29]=[CH:28][C:27]([OH:30])=[C:26]([C:31]45[CH2:40][CH:35]6[CH2:36][CH:37]([CH2:39][CH:33]([CH2:34]6)[CH2:32]4)[CH2:38]5)[CH:25]=3)=[CH:20][CH:19]=2)[CH2:13][O:12]C(C)(C)[O:10][CH2:9]1)(C)(C)C.C12(C3C=C(C#CC4(NC(=O)OC(C)(C)C)COC(C)(C)OC4)C=CC=3OCCCCCCCC)CC3CC(CC(C3)C1)C2>>[NH2:7][C:8]([CH2:16][CH2:17][C:18]1[CH:23]=[CH:22][C:21]([C:24]2[CH:29]=[CH:28][C:27]([OH:30])=[C:26]([C:31]34[CH2:32][CH:33]5[CH2:39][CH:37]([CH2:36][CH:35]([CH2:34]5)[CH2:40]3)[CH2:38]4)[CH:25]=2)=[CH:20][CH:19]=1)([CH2:13][OH:12])[CH2:9][OH:10]
Reactant: CC(C)(C)OC(=O)NC1(C#Cc2ccc(-c3ccc(O)c(C45CC6CC(CC(C6)C4)C5)c3)cc2)COC(C)(C)OC1
Agent: CCCCCCCCOc1ccc(C#CC2(NC(=O)OC(C)(C)C)COC(C)(C)OC2)cc1C12CC3CC(CC(C3)C1)C2
Product: NC(CO)(CO)CCc1ccc(-c2ccc(O)c(C34CC5CC(CC(C5)C3)C4)c2)cc1
Yield: 71 %

Procedure:
When product of Step B was substitute for tert-butyl 5-((3-(1-admantyl)-4-(octyloxy)phenyl)ethynyl)-2,2-dimethyl-1,3-dioxan-5-ylcarbamate in Example 63 Step C, the similar process afforded the title compound in 71% yield, as a colourless solid. 1H-NMR (CDCl3) 1.70 (s, 6H); 1.88-1.94 (m, 2H); 2.0 (broad s, 3H); 2.1 (broad s, 6H); 2.58-2.64 (m, 2H); 3.63 (d, 2H, J=12 Hz); 3.69 (d, 2H, J=12.08 Hz); 6.69 (d, 1H, J=8.18 Hz); 7.13-7.16 (m, 3H); 7.3 (d, 1H, J=2.06 Hz); 7.37 (d, 2H, J=8.07 Hz).
Reaction SMILES: [Cl:1][C:2]1[C:3]([NH:24][CH2:25][CH2:26][CH2:27][O:28][CH3:29])=[C:4]([NH:8][C:9]([C@@H:11]2[CH2:16][CH2:15][CH2:14][N:13]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:12]2)=O)[CH:5]=[CH:6][CH:7]=1.C(O)(=O)C>C1(C)C=CC=CC=1>[Cl:1][C:2]1[C:3]2[N:24]([CH2:25][CH2:26][CH2:27][O:28][CH3:29])[C:9]([C@@H:11]3[CH2:16][CH2:15][CH2:14][N:13]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:12]3)=[N:8][C:4]=2[CH:5]=[CH:6][CH:7]=1
Reactant: COCCCNc1c(Cl)cccc1NC(=O)[C@@H]1CCCN(C(=O)OC(C)(C)C)C1
Solvent: CC(=O)O
Solvent: Cc1ccccc1
Product: COCCCn1c([C@@H]2CCCN(C(=O)OC(C)(C)C)C2)nc2cccc(Cl)c21

Procedure:
(R)-tert-Butyl 3-(3-chloro-2-(3-methoxypropylamino)phenylcarbamoyl)piperidine-1-carboxylate (30C) (crude material, 2.23 mmol max) was added to a 50 mL round-bottomed flask equipped for stirring under nitrogen. Glacial acetic acid (10 mL) was then added and the resultant solution was stirred at 70° C. under nitrogen for 16 hr. Analysis of the reaction mixture at this time by LC/MS indicated that the reaction was complete. The reaction solution was then concentrated in-vacuo to give a brownish oil. Toluene (30 mL) was added and the subsequent solution was concentrated in vacuo. This dissolution in toluene and re-concentration was repeated three times to remove any trace quantities of acetic acid affording (R)-tert-butyl 3-(7-chloro-1-(3-methoxypropyl)-1H-benzo[d]imidazol-2-yl)piperidine-1-carboxylate (30D) as a brown oil. This oil was then purified by preparative LC/MS (25-85% CH3CN in H2O) to afford the title compound 30D as a tan oil (0.233 mmol, 0.095 g, 10% yield over 3-steps). 1H NMR (400 MHz, DMSO-d6) δ ppm 1.39 (s, 9H) 1.46-1.60 (m, 1H) 1.72-1.96 (m, 2H) 1.97-2.12 (m, 3H) 2.77-2.92 (m, 1H) 3.02-3.15 (m, 2H) 3.24 (s, 3H) 3.29-3.40 (m, 2H) 3.93-4.02 (m, 1H) 4.12 (br. s., 1H) 4.51-4.59 (m, 2H) 7.20 (t, J=7.83 Hz, 1H) 7.28 (d, J=7.83 Hz, 1H) 7.58 (d, J=7.83 Hz, 1H) ESI-MS: m/z 408.2 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]3[C:12](=[O:15])[N:13]=[N:14][C:10]3=[CH:9][C:8](=[O:16])[N:7]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:6]=2[CH:23]=1.[CH3:24]I>>[CH3:24][N:13]1[C:12](=[O:15])[N:11]2[C:5]3[CH:4]=[CH:3][C:2]([Cl:1])=[CH:23][C:6]=3[N:7]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:8](=[O:16])[CH:9]=[C:10]2[NH:14]1
Reactant: O=c1cc2nnc(=O)n-2c2ccc(Cl)cc2n1-c1ccccc1
Reactant: CI
Product: CN1NC2=CC(=O)N(c3ccccc3)c3cc(Cl)ccc3N2C1=O
Temperature: 0 °C
Reaction time: 2 h

Procedure:
To an ice-cooled, stirred solution of 3.7 g of 8-chloro-6-phenyl-1H-s-triazolo[4,3-a][1,5]benzodiazepine-1,5-dione in 100 ml of dried and distilled 1,2-dimethoxyethane is added, in a portionwise manner, 0.57 g of a 57% dispersion of sodium hydride in mineral oil. After the evolution of hydrogen has ceased (15 min), a solution of 1.79 g (0.014 mole) of methyl iodide is added, the ice bath removed and stirring continued at room temperature for 2 hours, followed by heating under reflux for 1 hour. The solvent is then removed by distillation. The residue is dissolved in 100 ml of chloroform, washed twice with 100 ml portions of water, dried and concentrated. Treatment of the residue with a small amount of ether precipitates the title compound which is filtered off, dried and recrystallized from ethyl acetate.
Reaction SMILES: [C:1]([NH2:10])(=[O:9])[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[OH:4].[CH:11](O)([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C1(C)C=CC(S(O)(=O)=O)=CC=1>C(O)(=O)C>[C:12]1([CH:11]([C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)[C:7]2[CH:8]=[C:2]([C:1]([NH2:10])=[O:9])[C:3]([OH:4])=[CH:5][CH:6]=2)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: OC(c1ccccc1)c1ccccc1
Reactant: NC(=O)c1ccccc1O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CC(=O)O
Product: NC(=O)c1cc(C(c2ccccc2)c2ccccc2)ccc1O

Procedure:
A mixture of 25 g (0.182 mol) of salicylamide, 30 g (0.163 mol) of benzhydrol, 30 g (0.158 mol) of p-toluenesulfonic acid and 200 ml of acetic acid was refluxed for 3 hours with heating. After cooling, the precipitated white crystals were separated by filtration and washed with water to obtain 5-diphenylmethylsalicylamide. Thereafter 40 g of sodium hydroxide in 100 ml of water were added and the mixture was heated on a steam bath for 6 hours with stirring. After being allowed to cool, the mixture was acidified using diluted hydrochloric acid to obtain 40 g of a crude product comprising 5-diphenylmethylsalicylic acid, Compound (2). When the crude product was recrystallized using diluted methanol, it had a melting point of 190° to 191.5° C. The resulting Compound (2) was converted into the zinc salt by the same process as that described in Synthesis Example 2.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]([C:11]([OH:13])=O)=[CH:5]2.[NH2:14][CH:15]([CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[F:30])[C:16]([N:18]1[CH2:22][CH2:21][S:20][CH2:19]1)=[O:17]>>[F:30][C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=1[CH2:23][CH:15]([NH:14][C:11]([C:6]1[NH:7][C:8]2[C:4]([CH:5]=1)=[CH:3][C:2]([Cl:1])=[CH:10][CH:9]=2)=[O:13])[C:16](=[O:17])[N:18]1[CH2:22][CH2:21][S:20][CH2:19]1
Reactant: NC(Cc1ccccc1F)C(=O)N1CCSC1
Reactant: O=C(O)c1cc2cc(Cl)ccc2[nH]1
Product: O=C(NC(Cc1ccccc1F)C(=O)N1CCSC1)c1cc2cc(Cl)ccc2[nH]1

Procedure:
From 5-chloro-1H-indole-2-carboxylic acid and (±)-2-amino-3-(2-fluoro-phenyl)-1-thiazolidin-3-yl-propan-1-one. mp 216-217° C.
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[N:11]=[C:10]([C:12]([OH:14])=O)[CH:9]=[CH:8][C:7]=2[CH:15]2[CH2:19][CH2:18][O:17][CH2:16]2)[CH2:3][CH2:2]1.C1(COC2N=C(C(O)=O)C=CC=2C2CCCO2)CC1.[NH2:39][C:40]([CH3:44])([CH3:43])[CH2:41][OH:42]>>[OH:42][CH2:41][C:40]([NH:39][C:12]([C:10]1[CH:9]=[CH:8][C:7]([CH:15]2[CH2:19][CH2:18][O:17][CH2:16]2)=[C:6]([O:5][CH2:4][CH:1]2[CH2:2][CH2:3]2)[N:11]=1)=[O:14])([CH3:44])[CH3:43]
Reactant: O=C(O)c1ccc(C2CCOC2)c(OCC2CC2)n1
Reactant: CC(C)(N)CO
Agent: O=C(O)c1ccc(C2CCCO2)c(OCC2CC2)n1
Product: CC(C)(CO)NC(=O)c1ccc(C2CCOC2)c(OCC2CC2)n1

Procedure:
The title compound was synthesized in analogy to Example 1, using the mixture of 6-(cyclopropylmethoxy)-5-(tetrahydrofuran-3-yl)-pyridine-2-carboxylic acid and 6-(cyclopropylmethoxy)-5-(tetrahydrofuran-2-yl)-pyridine-2-carboxylic acid (mixture from Example 114 d), and 2-amino-2-methyl-1-propanol (CAN 124-68-5) as starting materials, MS (EI): m/e=335.1 [M+H]+.
Reaction SMILES: F[C:2]1[CH:7]=[C:6]([C:8]2[C:16]([C:17]3[CH:22]=[CH:21][N:20]=[C:19]([NH:23][CH:24]([CH3:26])[CH3:25])[N:18]=3)=[C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][N:10]3[N:9]=2)[CH:5]=[CH:4][N:3]=1>C(N)(C)C>[CH:24]([NH:23][C:19]1[N:18]=[C:17]([C:16]2[C:8]([C:6]3[CH:5]=[CH:4][N:3]=[C:2]([NH:9][CH:8]([CH3:16])[CH3:6])[CH:7]=3)=[N:9][N:10]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=23)[CH:22]=[CH:21][N:20]=1)([CH3:26])[CH3:25]
Reactant: CC(C)Nc1nccc(-c2c(-c3ccnc(F)c3)nn3ccccc23)n1
Solvent: CC(C)N
Product: CC(C)Nc1cc(-c2nn3ccccc3c2-c2ccnc(NC(C)C)n2)ccn1
Temperature: 120 °C
Yield: 112.2 %

Procedure:
4-[2-(2-Fluoro-4-pyridinyl)pyrazolo[1,5-a]pyridin-3-yl]-N-isopropyl-2-pyrimidinamine (80 mg, 0.23 mmol) was dissolved in isopropylamine (10 mL) in a pressure vessel and the resulting solution heated at 120° C. for 4 days. The resulting mixture was concentrated to a solid that was purified by by silica gel chromatography (1:1 ethyl acetate:hexane) to give 50 mg (56%) of the title compound as a solid. 1H NMR (CDCl3): δ 8.53 (d, 1H), 8.43 (d, 1H), 8.1.5 (two d, 2H), 7.35 (t, 1H), 6.96 (t, 1H), 6.82 (d, 1H), 6.65 (s, 1H), 6.50 (d, 1H), 5.08 (d, 1H), 4.60 (d, 1H), 4.25 (m, 1H), 3.94 (m, 1H), 1.33 (d, 6H), 1.25 (d, 6H); MS m/388 (M+1).
Reaction SMILES: [OH-].[K+].Cl.CN.[CH2:6]([N:13]1[CH2:18][CH2:17][C:16](=O)[C:15]([CH2:21][CH3:22])([CH3:20])[CH2:14]1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[C:23]([BH3-])#[N:24].[Na+]>CO>[CH2:6]([N:13]1[CH2:18][CH2:17][CH:16]([NH:24][CH3:23])[C:15]([CH2:21][CH3:22])([CH3:20])[CH2:14]1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: CCC1(C)CN(Cc2ccccc2)CCC1=O
Reactant: [BH3-]C#N
Agent: CN
Agent: Cl
Agent: [K+]
Solvent: CO
Product: CCC1(C)CN(Cc2ccccc2)CCC1NC
Reaction time: 0.5 h

Procedure:
Potassium hydroxide (15.45 g, 276 mmol) was added to the stirred solution of methylamine hydrochloride (18.54 g, 276 mmol) in methanol (100 ml) and stirring was continued for 30 min at 30° C. 1-benzyl-3-ethyl-3-methyl-4-piperidinone (8 g, 34.6 mmol) was added to the resulting mixture and stirred for 6 hr. Sodium cyanoborohydride (2.18 g, 34.6 mmol) was added to it and reaction mixture was stirred for 15 hr. The reaction mixture was concentrated to dryness, triturated with water, extracted with chloroform, dried (Na2SO4) and concentrated to give 1-benzyl-4-methylamino-3-ethyl-3-methylpiperidine. Yield 6 g (67%), C16H26N2, m/z 247 (M+1).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][C:9]([S:12]([NH:15][C@@H:16]([CH:20]([CH3:22])[CH3:21])[C:17]([NH2:19])=[O:18])(=[O:14])=[O:13])=[CH:8][CH:7]=1.C(N(C(C)C)CC)(C)C.I.[NH2:33][C:34]1[C:35]([C:42]([NH:44][C:45](=[NH:48])SC)=[O:43])=[N:36][C:37]([Cl:41])=[C:38]([NH2:40])[N:39]=1>C(O)C>[NH2:33][C:34]1[C:35]([C:42]([N:44]=[C:45]([NH2:48])[NH:1][CH2:2][CH2:3][CH2:4][CH2:5][C:6]2[CH:7]=[CH:8][C:9]([S:12]([NH:15][C@@H:16]([CH:20]([CH3:22])[CH3:21])[C:17]([NH2:19])=[O:18])(=[O:14])=[O:13])=[CH:10][CH:11]=2)=[O:43])=[N:36][C:37]([Cl:41])=[C:38]([NH2:40])[N:39]=1
Reactant: CSC(=N)NC(=O)c1nc(Cl)c(N)nc1N
Reactant: CC(C)[C@H](NS(=O)(=O)c1ccc(CCCCN)cc1)C(N)=O
Agent: I
Solvent: CCO
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)[C@H](NS(=O)(=O)c1ccc(CCCCNC(N)=NC(=O)c2nc(Cl)c(N)nc2N)cc1)C(N)=O
Temperature: 25 °C
Yield: 54 %

Procedure:
A solution of (2S)-[4-(4-aminobutyl)benzenesulfonylamino]-3-methylbutyramide 15 (156 mg, 0.47 mmol), diisopropylethylamine (0.60 mL, 3.0 mmol), and 1-(3,5-diamino-6-chloropyrazine-2-carbonyl)-2-methylisothiourea hydriodide (230 mg, 0.61 mmol) in absolute ethanol (8 mL) was stirred at 70° C. for 5 h and then cooled to room temperature. The reaction mixture was concentrated by rotary evaporation. The crude residue was washed with water, filtered and the crude solid product was purified by flash silica gel column chromatography eluting with chloroform/methanol/concentrated ammonium hydroxide (5:1:0.1, v/v) to give the desired product as a yellow solid (137 mg, 54% yield). Part of the solid (86 mg) was further purified by semi-preparative HPLC (acetonitrile/water/0.1% TFA) to give the analytical pure sample which was then co-evaporated with 5% aqueous HCl to give the hydrochloride salt 16. mp 154–156° C. (decomposed). 1H NMR (300 MHz, CD3OD) δ 0.85 (d, 3H), 0.86 (d, 3H), 1.70 (m, 4H), 1.90 (m, 1H), 2.75 (m, 2H), 3.32 (m, 2H), 3.52 (d, 1H), 7.35 (d, 2H), 7.75 (d, 2H). m/z (ESI): 540 [C21H30ClN9O4S+H]+. [α]D25+5.2° (c 0.50, MeOH).
Reaction SMILES: [C:1]([O:5][C:6]([O:8]C([O-])=O)=O)([CH3:4])([CH3:3])[CH3:2].C(=O)(O)[O-].[Na+].[NH:17]1[CH2:32][C@H:30]([OH:31])[CH2:29][C@H:18]1[C:19]([O:21][CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)=[O:20]>C1COCC1.C(OCC)(=O)C>[N:17]1([C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:8])[CH2:32][C@H:30]([OH:31])[CH2:29][C@H:18]1[C:19]([O:21][CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)=[O:20]
Reactant: O=C(OCc1ccccc1)[C@@H]1C[C@@H](O)CN1
Reactant: CC(C)(C)OC(=O)OC(=O)[O-]
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1C[C@H](O)C[C@H]1C(=O)OCc1ccccc1
Reaction time: 0.5 h
Yield: 73.9 %

Procedure:
t-Butyldicarbonate (1.1 g) and then sat. sodium bicarbonate (20 ml) were added to a suspension of trans-Hyp-OBn (1.1 g) in THF (25 ml) and the mixture stirred for 30 min. The mixture was diluted with ethyl acetate and washed with water, dried (MgSO4) and evaporated. Flash chromatography (SiO2 DCM then ether) gave Boc-Hyp-OBn 1.18 g
Reaction SMILES: [C:1]([O:5][C:6](=[O:30])[NH:7][CH2:8][C:9]1[N:10]([CH2:26][CH:27]([CH3:29])[CH3:28])[C:11](=[O:25])[C:12]2[C:17]([C:18]=1[O:19][CH2:20][CH2:21][CH2:22][CH3:23])=[CH:16][C:15](Br)=[CH:14][CH:13]=2)([CH3:4])([CH3:3])[CH3:2].C([Sn](CCCC)(CCCC)[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][N:37]=1)CCC.O>CN(C)C=O.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]([O:5][C:6](=[O:30])[NH:7][CH2:8][C:9]1[N:10]([CH2:26][CH:27]([CH3:29])[CH3:28])[C:11](=[O:25])[C:12]2[C:17]([C:18]=1[O:19][CH2:20][CH2:21][CH2:22][CH3:23])=[CH:16][C:15]([C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][N:37]=1)=[CH:14][CH:13]=2)([CH3:4])([CH3:3])[CH3:2]
Reactant: CCCCOc1c(CNC(=O)OC(C)(C)C)n(CC(C)C)c(=O)c2ccc(Br)cc12
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccccn1
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
Product: CCCCOc1c(CNC(=O)OC(C)(C)C)n(CC(C)C)c(=O)c2ccc(-c3ccccn3)cc12
Yield: 75.1 %

Procedure:
A solution of tert-butyl(6-bromo-4-butoxy-2-isobutyl-1-oxo-1,2-dihydro-3-isoquinolinyl)methylcarbamate (0.48 g, 1 mmol), tri-n-butyl(2-pyridyl)tin (0.37 g, 1 mmol) and tetrakis(triphenylphosphine)palladium (58 mg, 0.05 mmol) in N,N-dimethylformamide (10 ml) was stirred at 100° C. for 10 h. The reaction mixture was poured into water and extracted with ethyl acetate. The extract was washed with brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give tert-butyl[4-butoxy-2-isobutyl-1-oxo-6-(2-pyridyl)-1,2-dihydro-3-isoquinolinyl]methylcarbamate (0.36 g, 75.0%) as crystals.
Reaction SMILES: [NH:1]1[C:5]([C:6]([O:8]CC)=[O:7])=[CH:4][C:3]([C:11]([O:13]CC)=[O:12])=[N:2]1.C([O-])([O-])=O.[K+].[K+].[CH3:22][O:23][C:24]1[CH:31]=[CH:30][C:27]([CH2:28]Cl)=[CH:26][CH:25]=1.[OH-].[Na+].Cl>CN(C=O)C.C1COCC1.O.CCOC(C)=O>[CH3:22][O:23][C:24]1[CH:31]=[CH:30][C:27]([CH2:28][N:1]2[C:5]([C:6]([OH:8])=[O:7])=[CH:4][C:3]([C:11]([OH:13])=[O:12])=[N:2]2)=[CH:26][CH:25]=1
Reactant: COc1ccc(CCl)cc1
Reactant: CCOC(=O)c1cc(C(=O)OCC)[nH]n1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccc(Cn2nc(C(=O)O)cc2C(=O)O)cc1

Procedure:
Diethyl 3,5-pyrazoledicarboxylate (400 mg, 1.9 mmol, 1.0 eq.) and K2CO3 (391 mg, 2.8 mmol, 1.5 eq.) were dissolved in DMF (1.50 mL) with stirring. p-Methoxybenzyl chloride (295 mg, 1.9 mmol, 1.0 eq.) was added and the mixture was stirred at room temperature overnight. EtOAc (20 mL) and water (20 mL) were added. The organic fractions were separated and washed with water (20 mL) and saturated aqueous NaCl (20 mL), dried over Na2SO4, The solvent was removed to yield a clear oil, which was purified by flash chromatography (0-40% EtOAc/hexanes over 20 minutes). The fractions were combined and the solvent evaporated. THF (7 mL) and 2M aqueous NaOH (3.8 mL, 4.0 eq.) was added and the mixture stirred at room temperature overnight. The mixture was acidified with 1N HCl to pH˜4. The precipitate was filtered off and dried under vacuum to yield the title compound as a white solid. (440 mg).
Reaction SMILES: [C:1]([NH:4][C:5]1[N:10]=[CH:9][C:8]([C:11]#[C:12][C:13]2[CH:14]=[C:15]([CH:19]=[CH:20][C:21]=2[CH3:22])[C:16]([OH:18])=O)=[CH:7][CH:6]=1)(=[O:3])[CH3:2].[CH3:23][N:24]1[CH2:29][CH2:28][N:27]([CH2:30][C:31]2[CH:37]=[CH:36][C:34]([NH2:35])=[CH:33][C:32]=2[Si:38]([CH3:41])([CH3:40])[CH3:39])[CH2:26][CH2:25]1>>[C:1]([NH:4][C:5]1[N:10]=[CH:9][C:8]([C:11]#[C:12][C:13]2[CH:14]=[C:15]([CH:19]=[CH:20][C:21]=2[CH3:22])[C:16]([NH:35][C:34]2[CH:36]=[CH:37][C:31]([CH2:30][N:27]3[CH2:26][CH2:25][N:24]([CH3:23])[CH2:29][CH2:28]3)=[C:32]([Si:38]([CH3:39])([CH3:41])[CH3:40])[CH:33]=2)=[O:18])=[CH:7][CH:6]=1)(=[O:3])[CH3:2]
Reactant: CN1CCN(Cc2ccc(N)cc2[Si](C)(C)C)CC1
Reactant: CC(=O)Nc1ccc(C#Cc2cc(C(=O)O)ccc2C)cn1
Product: CC(=O)Nc1ccc(C#Cc2cc(C(=O)Nc3ccc(CN4CCN(C)CC4)c([Si](C)(C)C)c3)ccc2C)cn1

Procedure:
This compound can be made in a similar way described in alternative synthesis of example 1 using 3-{[6-(acetylamino)pyridin-3-yl]ethynyl}-4-methylbenzoic acid and 4-[(4-methylpiperazin-1-yl)methyl]-3-(trimethylsilyl)aniline.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([F:11])[C:3]=1[C:4](=[S:6])[NH2:5].[CH3:12]OS(OC)(=O)=O>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([F:11])[C:3]=1[C:4]([S:6][CH3:12])=[NH:5]
Reactant: NC(=S)c1c(F)cccc1Cl
Reactant: COS(=O)(=O)OC
Solvent: Cc1ccccc1
Product: CSC(=N)c1c(F)cccc1Cl
Yield: 87 %

Procedure:
Into a 25-mL three-necked round bottom flask equipped with a magnetic stirrer was added 2-chloro-6-fluorobenzthioamide (1.89 g, 10.0 mmol) and toluene (10 mL). Dimethylsulfate was added dropwise and the mixture was allowed to stir at reflux using a Dean Stark trap. The solids were removed via filtration and washed with small portions of toluene to give methyl 2-chloro-6-fluorobenzthioimidate as a light yellow solid: 2.7 g (87% yield): 1H NMR (DMSO-d6) δ7.7 (m, 1H), 7.5 (m, 2H), 3.3 (s, 3H), 2.7 (s, 3H); 98% pure by HPLC analysis.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[C:12]([CH3:14])[C:11]([C:15]([F:18])([F:17])[F:16])=[CH:10][C:9]=1[NH:19][C:20](=[O:39])[CH2:21][C:22]([C:24]1[CH:29]=[CH:28][CH:27]=[C:26]([C:30]2[CH:31]=[N:32][C:33]([CH:36]([CH3:38])[CH3:37])=[CH:34][CH:35]=2)[CH:25]=1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH:36]([C:33]1[N:32]=[CH:31][C:30]([C:26]2[CH:25]=[C:24]([C:22]3[CH2:21][C:20](=[O:39])[NH:19][C:9]4[CH:10]=[C:11]([C:15]([F:18])([F:17])[F:16])[C:12]([CH3:14])=[CH:13][C:8]=4[N:7]=3)[CH:29]=[CH:28][CH:27]=2)=[CH:35][CH:34]=1)([CH3:38])[CH3:37]
Reactant: Cc1cc(NC(=O)OC(C)(C)C)c(NC(=O)CC(=O)c2cccc(-c3ccc(C(C)C)nc3)c2)cc1C(F)(F)F
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1cc2c(cc1C(F)(F)F)NC(=O)CC(c1cccc(-c3ccc(C(C)C)nc3)c1)=N2

Procedure:
The title compound was prepared from (2-{3-[3-(6-isopropyl-pyridin-3-yl)-phenyl]-3-oxo-propionylamino}-5-methyl-4-trifluoromethyl-phenyl)-carbamic acid tert-butyl ester (Example M162) (167 mg, 0.30 mmol) by treatment with TFA in CH2Cl2 according to the general procedure N. Obtained as an off-white solid (91 mg, 69%).
Reaction SMILES: [C:1]([C:4]1[S:27][C:7]2[S:8](=[O:26])(=[O:25])[CH2:9][CH2:10][C:11]3[C:12](=[N:13][N:14]([C:18]4[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=4)[C:15](=[O:17])[CH:16]=3)[C:6]=2[CH:5]=1)(=[O:3])[CH3:2].CO.C(Cl)(Cl)Cl.[BH4-].[Na+]>O>[Cl:24][C:21]1[CH:22]=[CH:23][C:18]([N:14]2[C:15](=[O:17])[CH:16]=[C:11]3[CH2:10][CH2:9][S:8](=[O:26])(=[O:25])[C:7]4[S:27][C:4]([CH:1]([OH:3])[CH3:2])=[CH:5][C:6]=4[C:12]3=[N:13]2)=[CH:19][CH:20]=1
Reactant: CC(=O)c1cc2c(s1)S(=O)(=O)CCc1cc(=O)n(-c3ccc(Cl)cc3)nc1-2
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: ClC(Cl)Cl
Solvent: CO
Product: CC(O)c1cc2c(s1)S(=O)(=O)CCc1cc(=O)n(-c3ccc(Cl)cc3)nc1-2
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 49.8 %

Procedure:
To a solution of 0.5 g of 9-acetyl-2-(4-chlorophenyl)-5,6-dihydrothieno[2',3':2,3]thiepino[4,5-c]pyridazin-3(2H)-one 7,7-dioxide obtained in Example 48 in a mixed solvent of 40 ml of methanol and 30 ml of chloroform is added 0.1 g of sodium borohydride under ice-cooling and the mixture is stirred for 30 minutes at room temperature. After the completion of reaction, to the mixture is added water and the solution is extracted with chloroform. The extract is washed with water, dried and concentrated under reduced pressure. The resulting crystals are recrystallized with ethanol to give 0.25 g of 2-(4-chlorophenyl)-9-(1-hydroxyethyl)-5,6-dihydrothieno[2',3':2,3]thiepino[4,5-c]pyridazin-3(2H)-one 7,7-dioxide as white crystals, melting at 233°-235° C.