Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CO[C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[CH:8]([CH2:12][CH2:13][CH3:14])[CH:7]=[CH:6]2.[CH2:15]([OH:17])C>[Pd]>[CH3:15][O:17][C:11]1[CH:10]=[C:9]2[C:5]([CH2:6][CH2:7][CH:8]2[CH2:12][CH2:13][CH3:14])=[CH:4][CH:3]=1
Reactant: CCCC1C=Cc2cc(OC)ccc21
Reactant: CCO
Agent: [Pd]
Product: CCCC1CCc2ccc(OC)cc21
Reaction time: 1 h

Procedure:
The mixture of indenes from step 1 (1.24 g, approx. 6.1 mmol) was dissolved in ethanol (40 mL), treated with 10% Pd on carbon (58 mg), and hydrogenated at 40 psi and room temperature for 60 minutes. The catalyst was removed by filtration and the filtrate was evaporated under vacuum to provide a mixture (1.287 g) of 6-methoxy-1-propyl-indan and 5-methoxy-1-propyl-indan in nearly a 1:1 ratio.
Reaction SMILES: Cl[CH2:2][C:3]1[N:7]([C:8]2[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:10][CH:9]=2)[N:6]=[N:5][N:4]=1.C(N(CC)CC)C.[CH3:25][C@H:26]1[NH:31][CH2:30][CH2:29][NH:28][C:27]1=[O:32]>C(#N)C>[CH3:25][C@H:26]1[N:31]([CH2:2][C:3]2[N:7]([C:8]3[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:10][CH:9]=3)[N:6]=[N:5][N:4]=2)[CH2:30][CH2:29][NH:28][C:27]1=[O:32]
Reactant: C[C@H]1NCCNC1=O
Reactant: FC(F)(F)c1ccc(-n2nnnc2CCl)cc1
Solvent: CC#N
Solvent: CCN(CC)CC
Product: C[C@@H]1C(=O)NCCN1Cc1nnnn1-c1ccc(C(F)(F)F)cc1
Temperature: 120 °C

Procedure:
To a solution of 5-(chloromethyl)-1-[4-(trifluoromethyl)phenyl]-1H-tetrazole (500 mg, 1.90 mmol, commercially available from UkrOrgSynthesis, Kiev, Ukraine) in acetonitrile (8 mL) was added triethylamine (0.796 mL, 5.71 mmol) and (3R)-3-methyl-2-piperazinone (239 mg, 2.09 mmol, commercially available, for example from Sigma Aldrich, St Louis, USA). The reaction mixture was heated to 120° C. for 20 min.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([CH:12]3[C:21]4[C:16](=[CH:17][CH:18]=[C:19]([O:22][CH2:23][CH2:24][NH:25][S:26]([CH2:29][CH2:30][CH3:31])(=[O:28])=[O:27])[CH:20]=4)[CH2:15][CH2:14][NH:13]3)[CH2:11][CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[N:32](OC(C)(C)C)=[O:33]>O1CCCC1>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([CH:12]3[C:21]4[C:16](=[CH:17][CH:18]=[C:19]([O:22][CH2:23][CH2:24][NH:25][S:26]([CH2:29][CH2:30][CH3:31])(=[O:27])=[O:28])[CH:20]=4)[CH2:15][CH2:14][N:13]3[N:32]=[O:33])[CH2:9][CH2:10][CH2:11]2)=[CH:4][CH:3]=1
Reactant: CCCS(=O)(=O)NCCOc1ccc2c(c1)C(C1(c3ccc(F)cc3)CCC1)NCC2
Reactant: CC(C)(C)ON=O
Solvent: C1CCOC1
Product: CCCS(=O)(=O)NCCOc1ccc2c(c1)C(C1(c3ccc(F)cc3)CCC1)N(N=O)CC2
Reaction time: 2 h

Procedure:
N-[2-({1-[1-(4-Fluorophenyl)cyclobutyl]-1,2,3,4-tetrahydroisoquinolin-7-yl}oxy)ethyl]propane-1-sulfonamide (92 mg, 0.206 mmol, cf. example 65) was dissolved in tetrahydrofuran (1 mL) under an atmosphere of nitrogen. Tert-butyl nitrite (32 mg, 0.309 mmol) were added and the reaction mixture was stirred under reflux for 3 h. After that time additional tert-butyl nitrite (32 mg, 0.309 mmol) was added and stirring under reflux was continued for 2 h. The solvent was evaporated in vacuo and the crude product was purified by flash chromatography (silica, dichloromethane then dichloromethane:methanol=100:1). Yield: 56 mg (0.118 mmol, 57%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([O:23][CH3:24])=[C:6]([C:8]([CH3:22])([CH3:21])[CH2:9][C:10]([O:17][CH2:18][O:19][CH3:20])([C:13]([F:16])([F:15])[F:14])[CH:11]=[O:12])[CH:7]=1.[CH3:25][C:26]1[CH:27]=[C:28]([CH:32]=[C:33]([CH3:35])[CH:34]=1)[CH2:29][Mg]Br>C1COCC1>[CH3:25][C:26]1[CH:34]=[C:33]([CH2:35][CH:11]([OH:12])[C:10]([O:17][CH2:18][O:19][CH3:20])([C:13]([F:16])([F:15])[F:14])[CH2:9][C:8]([C:6]2[CH:7]=[C:2]([F:1])[CH:3]=[CH:4][C:5]=2[O:23][CH3:24])([CH3:21])[CH3:22])[CH:32]=[C:28]([CH3:29])[CH:27]=1
Reactant: COCOC(C=O)(CC(C)(C)c1cc(F)ccc1OC)C(F)(F)F
Reactant: Cc1cc(C)cc(C[Mg]Br)c1
Solvent: C1CCOC1
Product: COCOC(CC(C)(C)c1cc(F)ccc1OC)(C(O)Cc1cc(C)cc(C)c1)C(F)(F)F
Reaction time: 4 h

Procedure:
To a solution of 398 mg (1.1 mmol) of the above 4-(5-fluoro-2-methoxyphenyl)-2-methoxymethoxy-4-methyl-2-trifluoromethylpentanal in 4 mL of anhydrous THF, 10 mL (2.5 mmol) of a 0.25 M solution of 3,5-dimethylbenzylmagnesium bromide in THF was added. The mixture stirred for 4 hours and was then quenched with 10 mL of saturated ammonium chloride and extracted with three 10 mL portions of EtOAc. The combined organic layers were washed with three 5 mL portions of brine, dried over magnesium sulfate, filtered, and concentrated in vacuo. The mixture of diastereomers was purified by chromatography on silica gel eluting with dichloromethane-hexanes (0:100, then 10:90, then 15:85, then 20:80, then 25:75, then 3:7, then 4:6) to afford first 121 mg (22%) of a single diastereomer of 1-(3,5-dimethylphenyl)-5-(5-fluoro-2-methoxyphenyl)-3-methoxymethoxy-5-methyl-3-trifluoromethylhexan-2-ol, and then 137 mg (25%) of the second diastereomer.
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[C:6]([NH:9][C:10]2[CH:15]=[CH:14][C:13]([I:16])=[CH:12][C:11]=2[F:17])[C:5]([NH2:18])=[CH:4][CH:3]=1.[CH3:19][C:20]1[C:24]([S:25](Cl)(=[O:27])=[O:26])=[C:23]([CH3:29])[O:22][N:21]=1>>[F:8][C:7]1[C:6]([NH:9][C:10]2[CH:15]=[CH:14][C:13]([I:16])=[CH:12][C:11]=2[F:17])=[C:5]([NH:18][S:25]([C:24]2[C:20]([CH3:19])=[N:21][O:22][C:23]=2[CH3:29])(=[O:27])=[O:26])[CH:4]=[CH:3][C:2]=1[F:1]
Reactant: Cc1noc(C)c1S(=O)(=O)Cl
Reactant: Nc1ccc(F)c(F)c1Nc1ccc(I)cc1F
Product: Cc1noc(C)c1S(=O)(=O)Nc1ccc(F)c(F)c1Nc1ccc(I)cc1F

Procedure:
According to the general procedure B, 5,6-difluoro-N1-(2-fluoro-4-iodophenyl)benzene-1,2-diamine (0.182 mmol) was reacted with 3,5-dimethylisoxazole-4-sulfonyl chloride (0.5 mmol) to obtain N-(3,4-difluoro-2-(2-fluoro-4-iodophenyl amino)phenyl)-3,5dimethylisoxazole-4-sulfonamide. 1H NMR (300 MHz, CDCl3)) δ 2.2 (s, 3H), 2.4 (s, 3H), 5.8 (s, 1H), 6.0 (dt, 1H), 5.95 (s, 1H), 6.9 (s, 1H), 7.0 (q, 1H), 7.2 (m, 3H), 7.4 (dd, 1H).
Reaction SMILES: [CH2:1]([CH:4]1[CH2:9][CH2:8][N:7](C(OC(C)(C)C)=O)[CH2:6][CH2:5]1)[CH:2]=[CH2:3].Br[C:18]1[CH:25]=[CH:24][C:21]([C:22]#[N:23])=[CH:20][CH:19]=1.[ClH:26]>>[ClH:26].[C:22]([C:21]1[CH:24]=[CH:25][C:18]([CH2:3][CH2:2][CH2:1][CH:4]2[CH2:5][CH2:6][NH:7][CH2:8][CH2:9]2)=[CH:19][CH:20]=1)#[N:23]
Reactant: N#Cc1ccc(Br)cc1
Reactant: C=CCC1CCN(C(=O)OC(C)(C)C)CC1
Agent: Cl
Product: N#Cc1ccc(CCCC2CCNCC2)cc1

Procedure:
Starting with 4-(prop-2-en-1-yl)-1-t-butoxycarbonylpiperidine from Procedure 5, Step B (475 mg, 2.1 mmol) and using essentially the same methods as in Procedure 5, Step D, but substituting 4-bromobenzonitrile (382 mg, 2.1 mmol), the title compound (337 mg) was obtained as the hydrochloride.
Reaction SMILES: [Mg].Br[C:3]1[CH:8]=[CH:7][C:6]([O:9][CH3:10])=[CH:5][C:4]=1[O:11][CH3:12].Cl.Br[C:15]1[CH:20]=[CH:19][N:18]=[CH:17][CH:16]=1>C1COCC1>[CH3:12][O:11][C:4]1[CH:5]=[C:6]([O:9][CH3:10])[CH:7]=[CH:8][C:3]=1[C:15]1[CH:20]=[CH:19][N:18]=[CH:17][CH:16]=1
Reactant: COc1ccc(Br)c(OC)c1
Reactant: Brc1ccncc1
Agent: Cl
Agent: [Mg]
Solvent: C1CCOC1
Product: COc1ccc(-c2ccncc2)c(OC)c1

Procedure:
The Grignard reagent, prepared from magnesium (5 g) and 1-Bromo-2,4-dimethoxybenzene (38 g) in THF (300 ml), is added at room temperature to 4-Bromo-pyridine hydrochloride salt in THF (10 ml). The mixture is heated under reflux for 2 hours and then evaporated to dryness. The residue is taken up in ethyl acetate and extracted with 1N hydrochloric acid. The aqueous phase is neutralised with 4M sodium hydroxide solution and extracted with ethyl acetate. The organic phase is dried with magnesium sulfate, evaporated and the residue is purified by column chromatography on silica gel using n-hexane:AcOEt=1:1 (v/v). MS-APCI+ (M+H)+=216
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[CH:11][C:6]([CH2:7][N:8]=[N+:9]=[N-:10])=[CH:5][CH:4]=1.[C:13]([C:15]([O:17][CH2:18][CH3:19])=[O:16])#[N:14]>C1(C)C(C)=CC=CC=1>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:7][N:8]2[C:13]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[N:14][N:10]=[N:9]2)=[CH:11][CH:12]=1
Reactant: CCOC(=O)C#N
Reactant: COc1ccc(CN=[N+]=[N-])cc1
Solvent: Cc1ccccc1C
Product: CCOC(=O)c1nnnn1Cc1ccc(OC)cc1
Yield: 95.3 %

Procedure:
A mixture of crude 4-methoxybenzyl azide (45.3 g; prepared as described below) and ethyl cyanoformate (33 g) in xylene (300 ml) was heated at reflux for 48 hours. The mixture was evaporated at below 40° C. and under reduced pressure to leave a residue of ethyl 1-(4-methoxybenzyl)-1H-tetrazole-5-carboxylate (69.36 g), m.p. 52° C.
Reaction SMILES: [CH3:1][N:2]1[C:7](=O)[CH2:6][CH2:5][C:4]([N+:15]([O-:17])=[O:16])([C:9]2[CH:14]=[CH:13][N:12]=[CH:11][CH:10]=2)[CH2:3]1.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:27])=CC=1>C1(C)C=CC=CC=1>[CH3:1][N:2]1[C:7](=[S:27])[CH2:6][CH2:5][C:4]([N+:15]([O-:17])=[O:16])([C:9]2[CH:14]=[CH:13][N:12]=[CH:11][CH:10]=2)[CH2:3]1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: CN1CC(c2ccncc2)([N+](=O)[O-])CCC1=O
Solvent: Cc1ccccc1
Product: CN1CC(c2ccncc2)([N+](=O)[O-])CCC1=S
Temperature: 80 °C
Yield: 78.7 %

Procedure:
To a solution of 125 mg (0.531 mmol) rac-1-Methyl-3-nitro-2,3,4,5-tetrahydro-1H-[3,4]bipyridinyl-6-one in 2.5 ml toluene were added 240 mg (0.584 mmol) Lawesson reagent. The suspension was heated in a 80° C. oil bath for 30 minutes. The mixture was concentrated in vacuo. The crude oil was purified on silica gel (Eluent: Heptane/ethyl acetate 0 to 100%) to provide 105 mg (79%) of the title compound as a light yellow solid. MS (m/e): 252.1 (M+H).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]2[N:9]=[CH:8][N:7]([CH:10]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH2:11][C:12]([O:14]CC)=[O:13])[C:6]=2[CH:23]=1.[Br:24][C:25]1[C:26]([O:36][CH3:37])=[C:27]([C:31]([O:34][CH3:35])=[CH:32][CH:33]=1)[C:28]([OH:30])=O>>[Br:24][C:25]1[C:26]([O:36][CH3:37])=[C:27]([C:31]([O:34][CH3:35])=[CH:32][CH:33]=1)[C:28]([NH:1][C:2]1[CH:3]=[CH:4][C:5]2[N:9]=[CH:8][N:7]([CH:10]([C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=3)[CH2:11][C:12]([OH:14])=[O:13])[C:6]=2[CH:23]=1)=[O:30]
Reactant: CCOC(=O)CC(c1ccccc1)n1cnc2ccc(N)cc21
Reactant: COc1ccc(Br)c(OC)c1C(=O)O
Product: COc1ccc(Br)c(OC)c1C(=O)Nc1ccc2ncn(C(CC(=O)O)c3ccccc3)c2c1

Procedure:
Using the procedure of Preparation 21, the title compound (24 mg) was prepared from ethyl 3-(6-amino-1H-benzimidazol-1-yl)-3-phenylpropanoate and 3-bromo-2,6-dimethoxybenzoic acid, and purified by RP-HPLC. [LCMS (Method A, Mobile Phase I) RT=4.43 min, MH+ 526].
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Cl:14][C:15]1[CH:16]=[C:17]2[C:21](=[CH:22][CH:23]=1)[NH:20][C:19]([C:24]([NH:26][CH:27]([CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)[C:28](O)=[O:29])=[O:25])=[CH:18]2>>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:28](=[O:29])[CH:27]([NH:26][C:24]([C:19]2[NH:20][C:21]3[C:17]([CH:18]=2)=[CH:16][C:15]([Cl:14])=[CH:23][CH:22]=3)=[O:25])[CH2:31][C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: O=C(NC(Cc1ccccc1)C(=O)O)c1cc2cc(Cl)ccc2[nH]1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Product: CC(C)(C)OC(=O)N1CCN(C(=O)C(Cc2ccccc2)NC(=O)c2cc3cc(Cl)ccc3[nH]2)CC1

Procedure:
1-Piperazinecarboxylic acid t-butyl ester (1.2 mmol) and 2-[(5chloro-1H-indole-2-carbonyl)-amino]-3-phenyl-propionic acid (0.6 mmol) were coupled according to procedure A (0-25° C. reaction temperature, reaction time 4 days, extraction with acid first, then base), and the crude product purified by column chromatography on silica gel eluted with 30% ethyl acetate in hexanes to give a colorless foam: Yield 290 mg, 95%; HPLC (70/30) 6.23 min (99%); PBMS 512/514 (MH+, 100%);
Reaction SMILES: [CH2:1]([OH:6])[CH2:2][CH:3]([OH:5])[CH3:4].C(N(CC)CC)C.[F:14][C:15]([F:27])([F:26])[C:16]1[CH:21]=[CH:20][C:19]([S:22](Cl)(=[O:24])=[O:23])=[CH:18][CH:17]=1.C([O-])(O)=O.[Na+]>C(Cl)Cl>[F:27][C:15]([F:14])([F:26])[C:16]1[CH:17]=[CH:18][C:19]([S:22]([O:6][CH2:1][CH2:2][CH:3]([OH:5])[CH3:4])(=[O:24])=[O:23])=[CH:20][CH:21]=1
Reactant: CC(O)CCO
Reactant: O=S(=O)(Cl)c1ccc(C(F)(F)F)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(O)CCOS(=O)(=O)c1ccc(C(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 67.9 %

Procedure:
A solution of 1,3-butanediol (2.00 g, 22.193 mmol) and triethylamine (2.695 g, 26.631 mmol) in 10 mL of methylene chloride was stirred at −20° C. under nitrogen. (4-trifluoromethyl)benzene sulfonyl chloride (5.429 g, 22.193 mmol) in 10 mL of methylene chloride was added drop wise to the solution, over 1 hr. The reaction was kept at −20° C. for an additional 3 hours and then stirred at room temperature for 24 hours. The reaction was quenched with water and then washed with 10% aqueous HCl (5×30 mL), sat. NaHCO3 (3×20 mL), H2O (2×20 mL) and brine (1×20 mL). The organic layer was dried over Na2SO4 and the solvent was evaporated under reduced pressure. The product obtained was purified by column chromatography to get a white solid. (1.541 g, 23% yield). 1H NMR (400 MHz, CDCl3) δ1.19 (d, J=6.29, 3H, CH3), 1.66-1.76 (m, 1H, CH2), 1.80-1.91 (m, 1H, CH2), 3.93 (br. s, 1H, CH—OH), 4.14-4.23 (m, 1H, CH2O—SO2), 4.25-4.36 (m, 1H, CH2O—SO2), 7.81 (d, J=8.08, 2H, aromatic), 8.04 (d, J=8.71, 2H, aromatic). Repeat synthesis: To a solution of 1,3-butane diol (4.34 g, 48 mmol) and TEA (3.19 g, 31.5 mmol) in CH2Cl2 (20 mL) at 0° C. was added p-(trifluoromethyl)benzene-sulfonyl chloride (3.97 g, 16.2 mmol) dissolved in CH2Cl2 (20 mL). The solution was stirred at 0° C. for 2 h. Saturated aqueous NaHCO3 (15 mL) was added to the solution and mixture was stirred at rt for 40 min. The organics were extracted with CH2Cl2 (50 mL) and washed with 1 M HCl (3×25 mL) and saturated aqueous NaCl (1×25 mL). The organics were dried over Na2SO4 and concentrated to give the desired product (3.28 g, 65%). 1H NMR (400 MHz CDCl3) δ 8.02 (d, 2H, J=8.2 Hz), 7.80 (d, 2H, J=8.3), 4.29 (m, 1H), 4.17 (m, 1H), 3.91 (m, 1H), 1.83 (m, 1H), 1.70 (m, 1H), 1.17 (d, 3H, J=6.2 Hz); Anal. Calcd. For C11H13F3O4S: C, 44.29; H, 4.39. Found: C, 44.16; H, 4.17.
Reaction SMILES: [CH:1]1([N:6]2[CH2:12][C:11]([F:14])([F:13])[C:10](=[O:15])[N:9]([CH3:16])[C:8]3[CH:17]=[N:18][C:19]([NH:21][C:22]4[CH:30]=[CH:29][C:25]([C:26]([OH:28])=O)=[CH:24][C:23]=4[O:31][CH3:32])=[N:20][C:7]2=3)[CH2:5][CH2:4][CH2:3][CH2:2]1.C(N(C(C)C)C(C)C)C.[NH2:42][CH2:43][CH2:44][CH2:45][OH:46]>CN(C)C=O>[CH:1]1([N:6]2[CH2:12][C:11]([F:13])([F:14])[C:10](=[O:15])[N:9]([CH3:16])[C:8]3[CH:17]=[N:18][C:19]([NH:21][C:22]4[CH:30]=[CH:29][C:25]([C:26]([NH:42][CH2:43][CH2:44][CH2:45][OH:46])=[O:28])=[CH:24][C:23]=4[O:31][CH3:32])=[N:20][C:7]2=3)[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: NCCCO
Reactant: COc1cc(C(=O)O)ccc1Nc1ncc2c(n1)N(C1CCCC1)CC(F)(F)C(=O)N2C
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COc1cc(C(=O)NCCCO)ccc1Nc1ncc2c(n1)N(C1CCCC1)CC(F)(F)C(=O)N2C
Temperature: 25 °C
Reaction time: 1 h
Yield: 88.1 %

Procedure:
To a mixture of 0.08 g (0.18 mmole) of 4-(9-cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-3-methoxy-benzoic acid (I-100), 0.16 mL (0.90 mmole) of ethyldiisopropyl amine and 0.016 mL (0.20 mmole) of 3-amino-propan-1-ol in 2.0 mL of dimethylformamide was added 0.085 g (0.20 mmole) of 1-(di-1-pyrrolidinylmethylene)-1H-benzotriazolium 3-oxide hexafluorophosphate. The mixture was stirred at room temperature for 1 hour, then diluted with 10 mL of ice water. The resulting solid was collected by filtration, washed with saturated sodium carbonate and water, and dried under vacuum. Purification by silica gel chromatography, eluting with dichloromethane-methanol (gradient, 100:0-90:10) gave 0.080 g of 4-(9-cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-N-(3-hydroxy-propyl)-3-methoxy-benzamide (I-41) as a white solid.
Reaction SMILES: [CH2:1]([C:13]1[CH:18]=[CH:17][C:16]([S:19](Cl)(=[O:21])=[O:20])=[CH:15][CH:14]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].[NH2:23][C:24]1[S:28][C:27]([CH2:29][C:30]([O:32][CH2:33][CH3:34])=[O:31])=[N:26][N:25]=1.Cl>N1C=CC=CC=1>[CH2:1]([C:13]1[CH:18]=[CH:17][C:16]([S:19]([NH:23][C:24]2[S:28][C:27]([CH2:29][C:30]([O:32][CH2:33][CH3:34])=[O:31])=[N:26][N:25]=2)(=[O:21])=[O:20])=[CH:15][CH:14]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12]
Reactant: CCOC(=O)Cc1nnc(N)s1
Reactant: CCCCCCCCCCCCc1ccc(S(=O)(=O)Cl)cc1
Agent: Cl
Solvent: c1ccncc1
Product: CCCCCCCCCCCCc1ccc(S(=O)(=O)Nc2nnc(CC(=O)OCC)s2)cc1
Temperature: 25 °C
Reaction time: 4.5 h
Yield: 43 %

Procedure:
To a solution of p-dodecylbenzenesulfonyl chloride (1.01 g, 2.94 mmol) in pyridine (10 mL) was added ethyl 2-(5-amino-1,3,4-thiadiazol-2-yl)acetate (500 mg, 2.67 mmol). The reaction mixture was stirred at room temperature for 4.5 h, then 2 M HCl (20 mL) was added to quench the reaction. The mixture was extracted with ethyl acetate (3×50 mL). The organic extracts were washed with water (20 mL), brine (20 mL), dried over Na2SO4, filtered, and concentrated. The residue was purified by chromatography over silica gel (70-230 mesh) eluted with CH2Cl2:methanol 19:1 to give the product as a solid, mp 108-109° C., in 43% yield (570 mg, 1.15 mmol); 1H NMR (300 MHz, CDCl3) δ 0.87 (t, 3H, J=7.2 Hz), 1.24-1.34 (m, 21H), 1.55-1.66 (m, 2H), 2.63 (t, 2H, J=7.2 Hz), 3.88 (s, 2H), 4.25 (q, 2H, J=7.5 Hz), 7.25 (d, 2H, J=8.1 Hz), 7.81 (d, 2H, J=7.8 Hz); 13C NMR (75 MHz, CDCl3) δ 14.0, 14.1, 22.7, 29.3, 29.5, 29.6, 29.7, 31.2, 31.9, 35.9, 38.1, 61.9, 126.7, 128.4, 138.8, 147.2, 152.1, 168.3, 170.3; MS (LCQ, ESI+) Calcd for C24H38N3O4S2 496.2. found 496.2 (M+H)+; HRMS (ESI+, m/z) Calcd for C24H38N3O4S2 496.2304. found 496.2295 (M+H)+.
Reaction SMILES: [C:1]1([CH3:11])[CH:6]=[CH:5][C:4]([S:7](Cl)(=[O:9])=[O:8])=[CH:3][CH:2]=1.[Cl:12][C:13]1[C:14](=[O:28])[N:15]([C:24]([CH3:27])([CH3:26])[CH3:25])[N:16]=[CH:17][C:18]=1[NH:19][CH2:20][CH2:21][CH2:22][OH:23].ClCCl>N1C=CC=CC=1>[Cl:12][C:13]1[C:14](=[O:28])[N:15]([C:24]([CH3:25])([CH3:27])[CH3:26])[N:16]=[CH:17][C:18]=1[NH:19][CH2:20][CH2:21][CH2:22][O:23][S:7]([C:4]1[CH:5]=[CH:6][C:1]([CH3:11])=[CH:2][CH:3]=1)(=[O:9])=[O:8]
Reactant: CC(C)(C)n1ncc(NCCCO)c(Cl)c1=O
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: c1ccncc1
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)OCCCNc2cnn(C(C)(C)C)c(=O)c2Cl)cc1
Temperature: 0 °C

Procedure:
2.55 g of p-toluenesulfonyl chloride was added to a mixture comprising 3.16 g of 4-chloro-5-(3-hydroxypropylamino)-2-t-butyl-3(2H) pyridazinone prepared in Reference Example 4, 1.44 g of pyridine and 50 ml of dichloromethane under stirring and cooling with ice, and the mixture was stirred at the same temperature for 2 hours. Then, 2.0 g of pyridine and 2.5 g of p-toluenesulfonyl chloride were added to the reaction mixture in this order. The mixture was stirred for further 2 hours under cooling with ice, and left to stand overnight in an ice chamber. The solvent was distilled off, and the pale yellow oily substance thereby obtained was extracted with benzene. The extract was washed sequentially with dilute hydrochloric acid, water (twice) and a saturated sodium chloride aqueous solution, and dried over sodium sulfate. Then, solvent was distilled off to obtain a pale yellow oily substance. The oily substance was purified by silica gel column chromatography by using benzene-ethyl acetate (1:1, v/v) as the developer, to obtain 4.67 g of the above identified compound as a pale yellow viscous oily substance.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:10]([O:24][CH3:25])=[CH:11][C:12]([C:18]2[N:22]=[C:21]([CH3:23])[O:20][N:19]=2)=[C:13]([CH:17]=1)[C:14](O)=[O:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.S(Cl)([Cl:28])=O>CN(C)C=O.C1(C)C=CC=CC=1>[CH2:1]([O:8][C:9]1[C:10]([O:24][CH3:25])=[CH:11][C:12]([C:18]2[N:22]=[C:21]([CH3:23])[O:20][N:19]=2)=[C:13]([CH:17]=1)[C:14]([Cl:28])=[O:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=S(Cl)Cl
Reactant: COc1cc(-c2noc(C)n2)c(C(=O)O)cc1OCc1ccccc1
Solvent: CN(C)C=O
Solvent: Cc1ccccc1
Product: COc1cc(-c2noc(C)n2)c(C(=O)Cl)cc1OCc1ccccc1
Temperature: 80 °C
Reaction time: 0.5 h

Procedure:
A mixture of 5-benzyloxy-4-methoxy-2-(5-methyl-[1,2,4]oxadiazol-3-yl)benzoic acid (reference example 5-1) (817 mg), thionyl chloride (0.53 mL), N,N-dimethylformamide (1 drop) and toluene (10 mL) was stirred at 80° C. for 30 minutes. The mixture was concentrated under reduced pressure. Toluene was added to the residue, and the mixture was concentrated under reduced pressure to give 5-benzyloxy-4-methoxy-2-(5-methyl-[1,2,4]oxadiazol-3-yl)benzoyl chloride.
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]#[N:9])=[C:6](Cl)[N:5]=[CH:4][N:3]=1.CCN(C(C)C)C(C)C.[F:20][C:21]1[CH:22]=[CH:23][C:24]2[N:28]=[C:27]([CH:29]([NH2:31])[CH3:30])[N:26]([C:32]3[CH:33]=[N:34][CH:35]=[C:36]([F:38])[CH:37]=3)[C:25]=2[CH:39]=1>C(O)CCC>[NH2:1][C:2]1[C:7]([C:8]#[N:9])=[C:6]([NH:31][CH:29]([C:27]2[N:26]([C:32]3[CH:33]=[N:34][CH:35]=[C:36]([F:38])[CH:37]=3)[C:25]3[CH:39]=[C:21]([F:20])[CH:22]=[CH:23][C:24]=3[N:28]=2)[CH3:30])[N:5]=[CH:4][N:3]=1
Reactant: N#Cc1c(N)ncnc1Cl
Reactant: CC(N)c1nc2ccc(F)cc2n1-c1cncc(F)c1
Solvent: CCN(C(C)C)C(C)C
Solvent: CCCCO
Product: CC(Nc1ncnc(N)c1C#N)c1nc2ccc(F)cc2n1-c1cncc(F)c1
Temperature: 120 °C
Reaction time: 4 h

Procedure:
To a microwave vessel was added 4-amino-6-chloropyrimidine-5-carbonitrile (0.075 g, 0.486 mmol), DIEA (0.162 mL, 0.926 mmol), and 1-(6-fluoro-1-(5-fluoropyridin-3-yl)-1H-benzo[d]imidazol-2-yl)ethanamine (0.127 g, 0.463 mmol) in n-butanol (2.315 mL). The solution was stirred at 120° C. for 4 h under microwave irradiation and then purified by column chromatography on a silica gel column using 0 to 10% gradient of MeOH in DCM as eluent to give 4-amino-6-((1-(6-fluoro-1-(5-fluoro-3-pyridinyl)-1H-benzimidazol-2-yl)ethyl)amino)-5-pyrimidinecarbonitrile: 1H NMR (400 MHz, DMSO-d6) δ ppm 1.59 (d, J=6.85 Hz, 3H) 5.60 (qd, J=7.04, 6.85 Hz, 1H) 7.08 (dd, J=9.00, 2.35 Hz, 1H) 7.15 (td, J=9.78, 8.90, 2.45 Hz, 1H) 7.25 (br. s., 2H) 7.69-7.81 (m, 2H) 7.84 (s, 1H) 8.08 (d, J=9.00 Hz, 1H) 8.63 (s, 1H) 8.67 (d, J=2.54 Hz, 1H); LC-MS (ESI) m/z 393.0 [M+H]+.
Reaction SMILES: Cl.Cl[CH2:3][C:4]1[C:9]([CH3:10])=[C:8]([S:11][CH2:12][C:13]2[O:14][CH:15]=[CH:16][CH:17]=2)[CH:7]=[CH:6][N:5]=1.[SH:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=1>C(O)C.[OH-].[Na+]>[O:14]1[CH:15]=[CH:16][CH:17]=[C:13]1[CH2:12][S:11][C:8]1[CH:7]=[CH:6][N:5]=[C:4]([CH2:3][S:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=2)[C:9]=1[CH3:10]
Reactant: Cc1c(SCc2ccco2)ccnc1CCl
Reactant: Sc1ccccn1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Cc1c(SCc2ccco2)ccnc1CSc1ccccn1
Temperature: 55 °C
Reaction time: 3.5 h

Procedure:
One equivalent (2.92 g) of 2-chloromethyl-4-(2-furylmethylthio)-3-methylpyridine hydrochloride (dissolved in 10 ml of water) is added dropwise at 40° C. in the course of 20 min. to a solution of 2-mercaptopyridine (1.12 g/10 mmol) in 40 ml of ethanol and 21 ml of 1 N sodium hydroxide solution. The mixture is then stirred for 2-3 h at 50-60° C. and for a further 3-4 h at RT.
Reaction SMILES: [C@@H:1]12[CH2:9][CH2:8][C:7](=[O:10])[C@@H:6]1[CH2:5][CH2:4][C:3](=[O:11])[NH:2]2.[CH3:12][C:13]1[CH:21]=[CH:20][C:16]([C:17](Cl)=[O:18])=[CH:15][CH:14]=1.C(N(CC)CC)C>ClCCl>[C:13]1([CH3:12])[CH:21]=[CH:20][C:16]([C:17]([N:2]2[C:3](=[O:11])[CH2:4][CH2:5][C@@H:6]3[C@H:1]2[CH2:9][CH2:8][C:7]3=[O:10])=[O:18])=[CH:15][CH:14]=1
Reactant: O=C1CC[C@H]2C(=O)CC[C@H]2N1
Reactant: Cc1ccc(C(=O)Cl)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1ccc(C(=O)N2C(=O)CC[C@H]3C(=O)CC[C@H]32)cc1
Yield: 65.9 %

Procedure:
In 20 ml of dichloromethane were dissolved 0.3 g of Compound 6b obtained in Example 11 and 0.39 g of 4-methylbenzoyl chloride. Thereto was added dropwise 0.38 ml of triethylamine with ice cooling. The mixture was reacted at room temperature for 12 hours. The reaction mixture was washed with 0.1N hydrochloric acid, with 0.1N aqueous solution of NaOH and then with water, and dried over anhydrous sodium sulfate. After dried, the solvent was removed and the residue was recrystallized to obtain 0.35 g of Compound mentioned above (yield: 66 % ). Table 6 shows analytical data,