Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].[NH2:3][C:4]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[Cl:17])=[CH:5][C:6]([O:8]CC)=O.[F:18][C:19]([F:34])([F:33])[O:20][C:21]1[CH:26]=[CH:25][C:24]([NH:27][C:28](=O)[O:29]CC)=[CH:23][CH:22]=1>CN(C)C=O>[F:18][C:19]([F:33])([F:34])[O:20][C:21]1[CH:22]=[CH:23][C:24]([N:27]2[C:6](=[O:8])[CH:5]=[C:4]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[Cl:17])[NH:3][C:28]2=[O:29])=[CH:25][CH:26]=1
Reactant: CCOC(=O)C=C(N)c1ccccc1Cl
Reactant: CCOC(=O)Nc1ccc(OC(F)(F)F)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=c1cc(-c2ccccc2Cl)[nH]c(=O)n1-c1ccc(OC(F)(F)F)cc1
Temperature: 0 °C
Yield: 72.6 %

Procedure:
2.0 g of sodium hydride (purity: 55%) was added to 100 ml of dimethylformamide, followed by dropwise addition of 7.9 g of ethyl 3-amino-3-(2-chlorophenyl)-2-propenoate to the solution with stirring at 0° C. The resulting solution was stirred at room temperature for 15 minutes and added with 8.7 g of ethyl 4-trifluoromethoxyphenylcarbamate. The solution was further stirred at 100° C. for 4 hours. Then the solvent was distilled away under reduced pressure and the residue was dissolved in 200 ml of water and washed twice with diethyl ether. This aqueous solution was added to a mixed solution of 100 g of ice and 50 ml of concentrated hydrochloric acid. The precipitated crystals were filtered out and dried under reduced pressure to obtain 10.7 g of a crude product. This crude product was washed with heated diisopropyl ether and dried to obtain 9.7 g of the objective compound.
Reaction SMILES: N[C:2]1[N:6]([C:7]2[CH:12]=[CH:11][N:10]=[C:9]([Cl:13])[CH:8]=2)[N:5]=[C:4]([NH:14][C:15]2[CH:20]=[CH:19][C:18]([S:21]([NH2:24])(=[O:23])=[O:22])=[CH:17][CH:16]=2)[N:3]=1.CC(O)C.N(OCCC(C)C)=O>C1COCC1>[Cl:13][C:9]1[CH:8]=[C:7]([N:6]2[CH:2]=[N:3][C:4]([NH:14][C:15]3[CH:16]=[CH:17][C:18]([S:21]([NH2:24])(=[O:22])=[O:23])=[CH:19][CH:20]=3)=[N:5]2)[CH:12]=[CH:11][N:10]=1
Reactant: Nc1nc(Nc2ccc(S(N)(=O)=O)cc2)nn1-c1ccnc(Cl)c1
Agent: CC(C)CCON=O
Solvent: CC(C)O
Solvent: C1CCOC1
Product: NS(=O)(=O)c1ccc(Nc2ncn(-c3ccnc(Cl)c3)n2)cc1
Temperature: 25 °C
Reaction time: 12 h
Yield: 49.4 %

Procedure:
To a solution of 250 mg of 4-[5-amino-1-(2-chloro-pyridin-4-yl)-1H-[1,2,4]triazol-3-ylamino]-benzenesulfonamide (0.686 mmol, 1 equiv) in 40 mL of 1:1 THF:iPrOH, 160 mg of isoamyl nitrite (1.37 mmol, 2 equiv) was added. The dark yellow solution was stirred for 12 h at 25° C. and then heated under reflux for 6 h. The reaction mixture was cooled and concentrated in vacuo. The resulting yellow solid was triturated with methanol and filtered to give the title compound as a yellow solid (118.9 mg, 50%); 1H NMR (400 MHz, (CD3)2SO) δ 10.20 (1H, s), 9.42 (1H, s), 8.55 (1H, d, J=5.6), 8.07 (1H, m), 7.95 (1H, dd, J=5.6 and 1.8), 7.77 (4H, m) and 7.18 (2H, s); MS (ES+) m/e 351.36, (ES−) m/e 349.48
Reaction SMILES: [C:1]([C:4]1[CH:5]=[N:6][C:7]2[C:12]([C:13]=1[NH:14][C:15]1[CH:16]=[CH:17][C:18]([N:21]3[CH2:26][CH2:25][CH2:24][CH:23]([NH:27]C(=O)OC(C)(C)C)[CH2:22]3)=[N:19][CH:20]=1)=[CH:11][C:10]([C:35]1[CH:40]=[C:39]([Cl:41])[C:38]([OH:42])=[C:37]([Cl:43])[CH:36]=1)=[CH:9][CH:8]=2)(=[O:3])[CH3:2].Cl>ClCCl.C(OCC)C>[NH2:27][CH:23]1[CH2:24][CH2:25][CH2:26][N:21]([C:18]2[N:19]=[CH:20][C:15]([NH:14][C:13]3[C:12]4[C:7](=[CH:8][CH:9]=[C:10]([C:35]5[CH:36]=[C:37]([Cl:43])[C:38]([OH:42])=[C:39]([Cl:41])[CH:40]=5)[CH:11]=4)[N:6]=[CH:5][C:4]=3[C:1](=[O:3])[CH3:2])=[CH:16][CH:17]=2)[CH2:22]1
Reactant: CC(=O)c1cnc2ccc(-c3cc(Cl)c(O)c(Cl)c3)cc2c1Nc1ccc(N2CCCC(NC(=O)OC(C)(C)C)C2)nc1
Agent: Cl
Solvent: CCOCC
Solvent: ClCCl
Product: CC(=O)c1cnc2ccc(-c3cc(Cl)c(O)c(Cl)c3)cc2c1Nc1ccc(N2CCCC(N)C2)nc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 95.7 %

Procedure:
tert-butyl 1-(5-(3-acetyl-6-(3,5-dichloro-4-hydroxyphenyl)quinolin-4-ylamino)pyridin-2-yl)piperidin-3-ylcarbamate (52 mg, 0.080 mmol) was dissolved in dichloromethane (5 mL). To this solution was added a 2.0 M HCl solution in diethyl ether (2 mL) the mixture was stirred for 16 h at room temperature where a precipitate formed. The precipitate was filtered off, washed with dichloromethane (10 mL), dried under vacuum to obtain the desired product as the HCl salt (40 mg, 79%) as a yellow-brown solid: 1H NMR (500 MHz, DMSO-d6) δ 10.56 (s, 1H), 8.94 (s, 1H), 8.28 (s, 1H), 8.05 (s, 1H), 7.87 (s, 1H), 7.29 (s, 2H), 4.17 (s, 1H), 3.95 (s, 3H), 2.66 (s, 3H), 2.38 (s, 4H), 2.23 (s, 2H), 2.03 (s, 2H), 1.67 (s, 1H), 1.51 (s, 2H), 1.30 (s, 3H); ESI MS m/z 454, [C25H28ClN3O3+H]+; HPLC 99.5% (AUC), tR=9.99 min.
Reaction SMILES: C([O:8][C:9](=[O:62])[CH2:10][C@H:11]1[CH2:16][CH2:15][C@H:14]([CH2:17][N:18]([C:21]2[CH:26]=[CH:25][C:24]([C:27]([F:30])([F:29])[F:28])=[CH:23][C:22]=2[CH2:31][N:32]([C@H:46]([C:48]2[CH:53]=[C:52]([C:54]([F:57])([F:56])[F:55])[CH:51]=[C:50]([C:58]([F:61])([F:60])[F:59])[CH:49]=2)[CH3:47])[C:33]2[N:38]=[CH:37][C:36]([O:39][CH2:40][CH2:41][S:42]([CH3:45])(=[O:44])=[O:43])=[CH:35][N:34]=2)[CH2:19][CH3:20])[CH2:13][CH2:12]1)C1C=CC=CC=1.[H][H]>C(O)C.[Pd]>[F:61][C:58]([F:59])([F:60])[C:50]1[CH:49]=[C:48]([CH:46]([N:32]([CH2:31][C:22]2[CH:23]=[C:24]([C:27]([F:30])([F:28])[F:29])[CH:25]=[CH:26][C:21]=2[N:18]([CH2:17][C@H:14]2[CH2:15][CH2:16][C@H:11]([CH2:10][C:9]([OH:62])=[O:8])[CH2:12][CH2:13]2)[CH2:19][CH3:20])[C:33]2[N:38]=[CH:37][C:36]([O:39][CH2:40][CH2:41][S:42]([CH3:45])(=[O:43])=[O:44])=[CH:35][N:34]=2)[CH3:47])[CH:53]=[C:52]([C:54]([F:57])([F:56])[F:55])[CH:51]=1
Reactant: [H][H]
Reactant: CCN(C[C@H]1CC[C@H](CC(=O)OCc2ccccc2)CC1)c1ccc(C(F)(F)F)cc1CN(c1ncc(OCCS(C)(=O)=O)cn1)[C@@H](C)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Agent: [Pd]
Solvent: CCO
Product: CCN(C[C@H]1CC[C@H](CC(=O)O)CC1)c1ccc(C(F)(F)F)cc1CN(c1ncc(OCCS(C)(=O)=O)cn1)C(C)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Under nitrogen atmosphere, a solution of (S)-trans-{4-[({2-[({1-[3,5-bis(trifluoromethyl)phenyl]ethyl}{5-[2-(methylsulfonyl)ethoxy]pyrimidin-2-yl}amino)methyl]-4-(trifluoromethyl)phenyl}(ethyl)amino)methyl]cyclohexyl}acetic acid benzyl ester (7) (34.2 g, 37.88 mmol, >99% ee) obtained in Step 5 in ethanol (340 mL) was added with 10% Pd—C (wet, 3.4 for hydrogen substitution, and then the mixture was stirred at room temperature for 2 hours. The reaction suspension was filtered through Celite, and washed with ethanol (50 mL), and the washing solution was concentrated under reduced pressure to obtain substantially optically pure trans-{4-[({2-[({1-[3,5-bis(trifluoromethyl)phenyl]ethyl}{5-[2-(methylsulfonyl)ethoxy]pyrimidin-2-yl}amino)methyl]-4-(trifluoromethyl)phenyl}(ethyl)amino)methyl]cyclohexyl}acetic acid (III) (white amorphous, 31.78 g, yield: 100%).
Reaction SMILES: [Br:1]Br.[CH3:3][O:4][C:5]1[CH:6]=[C:7]([CH:11]=[CH:12][C:13]=1[CH3:14])[C:8]([OH:10])=[O:9]>C(O)(=O)C.O>[Br:1][C:11]1[CH:12]=[C:13]([CH3:14])[C:5]([O:4][CH3:3])=[CH:6][C:7]=1[C:8]([OH:10])=[O:9]
Reactant: BrBr
Reactant: COc1cc(C(=O)O)ccc1C
Solvent: CC(=O)O
Solvent: O
Product: COc1cc(C(=O)O)c(Br)cc1C
Temperature: 60 °C

Procedure:
Br2 (0.74 mL, 14.4 mmol) was added to a rt suspension of 3-methoxy-4-methylbenzoic acid (2.00 g, 12 mmol) in acetic acid (15 mL) and water (15 mL), then the mixture was heated to 60° C. for 2 h. The mixture was allowed to reach rt and the solids were filtered off and rinsed with cold water (40 mL) to yield 2-bromo-5-methoxy-4-methylbenzoic acid as a white solid which was used further without purification. LC-MS A: tR=0.76 min, [M+H]+=no ionization. 1H NMR (DMSO) δH: 7.49 (s, 1H), 7.29 (s, 1H), 3.82 (s, 3H), 2.17 (s, 3H).
Reaction SMILES: [O-]S(C(F)(F)F)(=O)=O.[CH2:9]([O:16][C:17]1[CH:18]=[C:19]([C:27]2[N:32]=[C:31]([C:33]([O:35][CH3:36])=[O:34])[CH:30]=[CH:29][C:28]=2O)[CH:20]=[CH:21][C:22]=1[C:23]([F:26])([F:25])[F:24])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.[CH3:38][C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][C:40]=1B(O)O>>[CH2:9]([O:16][C:17]1[CH:18]=[C:19]([C:27]2[N:32]=[C:31]([C:33]([O:35][CH3:36])=[O:34])[CH:30]=[CH:29][C:28]=2[C:40]2[CH:41]=[CH:42][CH:43]=[CH:44][C:39]=2[CH3:38])[CH:20]=[CH:21][C:22]=1[C:23]([F:24])([F:26])[F:25])[C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1
Reactant: Cc1ccccc1B(O)O
Reactant: COC(=O)c1ccc(O)c(-c2ccc(C(F)(F)F)c(OCc3ccccc3)c2)n1
Agent: O=S(=O)([O-])C(F)(F)F
Product: COC(=O)c1ccc(-c2ccccc2C)c(-c2ccc(C(F)(F)F)c(OCc3ccccc3)c2)n1
Yield: 89 %

Procedure:
According to the triflate/Suzuki coupling steps described in examples 4.4 and 4.5 respectively, starting from 4.38 g (10.9 mmol) of methyl 6-[3-(benzyloxy)-4-(trifluoromethyl)phenyl]-5-hydroxypyridine-2-carboxylate and 1.8 g (13.1 mmol) of 2-methylphenylboronic acid, we obtain 4.63 g of methyl 6-[3-(benzyloxy)-4-(trifluoromethyl)phenyl]-5-(2-methylphenyl)pyridine-2-carboxylate in the form of a white solid.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][OH:5].Cl[C:7]([O:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:8]>C(Cl)Cl>[CH2:10]([O:9][C:7]([NH:1][CH2:2][CH2:3][CH2:4][OH:5])=[O:8])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: NCCCO
Solvent: ClCCl
Product: O=C(NCCCO)OCc1ccccc1
Temperature: 0 °C
Reaction time: 3 h
Yield: 96.8 %

Procedure:
To a solution of 3-amino-1-propanol (3.75 g, 50 mmol) in methylene chloride (40 mL) was slowly added benzyl chloroformate (3.4 g, 20 mmol) in methylene chloride (10 mL) at 0° C. and the mixture was stirred at 0° C. for 3 h. Additional methylene chloride (50 mL) was added, the solution washed with 10% citric acid (3×50 mL) and brine (50 mL), and dried over Na2SO4. After evaporating the solvent in vacuo, the residue was purified by filtration through silica gel (1:1 ethyl acetate:hexane) to give the title compound as a white solid (4.05 g, 97%). 1H-NMR (300 MHz, CDCl3) δ7.34 (m, 5H), 5.17 (br s, 1H), 5.10 (s, 2H), 3.66 (t, J=5.8 Hz, 2H), 3.33 (t, J=6.1 Hz, 2H), 2.63 (br s, 1H), 1.69 (pentet, J=6.1 Hz, 2H).
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH2:5][OH:6].[O:10]1[CH:15]=[CH:14][CH2:13][CH2:12][CH2:11]1>ClCCl.C1(C)C=CC(S(O)(=O)=O)=CC=1>[I:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH2:5][O:6][CH:11]1[CH2:12][CH2:13][CH2:14][CH2:15][O:10]1
Reactant: C1=COCCC1
Reactant: OCc1cccc(I)c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: ClCCl
Product: Ic1cccc(COC2CCCCO2)c1
Temperature: 25 °C
Yield: 103.6 %

Procedure:
para-Toluenesulfonic acid (100 mg, cat.) was added in one portion to a cooled solution (0 C) of 3-iodobenzyl alcohol (4.71 g, 0.02 mol) and dihydropyran (1.86 g, 0.022 mol) in dichloromethane (50 mL) under a nitrogen atmosphere. The cooling bath was removed and the reaction mixture was allowed to warm to room temperature over 1 hr. Diethyl ether (100 mL) was then added followed by saturated sodium hydrogen carbonate solution (100 mL). The organic layer was separated, dried (MgSO4) and evaporated in vacuo to yield the crude product (6.59 g) A332.1, which was used immediately without further purification. HPLC YMC S-5 4.6×33 mm (2 min grad): retention time 2.16 min, no M+H+ observed.
Reaction SMILES: C(O[C:4]([C:6]1[CH:11]=[C:10]([C:12]2[CH:17]=[C:16]([F:18])[CH:15]=[C:14]([F:19])[CH:13]=2)[CH:9]=[C:8]([CH3:20])[N:7]=1)=[O:5])C.[CH3:21][O:22][CH2:23][C:24]1[N:25]=[C:26]([NH2:29])[S:27][CH:28]=1>>[CH3:21][O:22][CH2:23][C:24]1[N:25]=[C:26]([NH:29][C:4]([C:6]2[CH:11]=[C:10]([C:12]3[CH:13]=[C:14]([F:19])[CH:15]=[C:16]([F:18])[CH:17]=3)[CH:9]=[C:8]([CH3:20])[N:7]=2)=[O:5])[S:27][CH:28]=1
Reactant: CCOC(=O)c1cc(-c2cc(F)cc(F)c2)cc(C)n1
Reactant: COCc1csc(N)n1
Product: COCc1csc(NC(=O)c2cc(-c3cc(F)cc(F)c3)cc(C)n2)n1

Procedure:
The title compound, was prepared from 4-(3,5-Difluorophenyl)-6-methyl-pyridine-2-carboxylic acid ethyl ester in accordance with the general method of example 26, step 6 using 4-Methoxymethyl-thiazol-2-ylamine (CAS: [640768-40-7]) instead of 3-chloro-aniline to yield the final compound as a light brown solid, MS (ISP): m/e=376.3 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:25]([OH:27])=O)[CH:5]=[N:6][C:7]=1[N:8]1[CH2:13][CH2:12][CH:11]([N:14]2[C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=3[CH2:17][O:16][C:15]2=[O:24])[CH2:10][CH2:9]1.C(N1C=CN=C1)(N1C=CN=C1)=O.Cl.[NH2:41][C@@H:42]([C:46]([NH2:48])=[O:47])[CH:43]([CH3:45])[CH3:44].C(N(CC)C(C)C)(C)C>CN1CCCC1=O>[NH2:48][C:46]([C@H:42]([NH:41][C:25]([C:4]1[CH:5]=[N:6][C:7]([N:8]2[CH2:9][CH2:10][CH:11]([N:14]3[C:19]4[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=4[CH2:17][O:16][C:15]3=[O:24])[CH2:12][CH2:13]2)=[C:2]([Cl:1])[CH:3]=1)=[O:27])[CH:43]([CH3:45])[CH3:44])=[O:47]
Reactant: CC(C)[C@@H](N)C(N)=O
Reactant: O=C(O)c1cnc(N2CCC(N3C(=O)OCc4ccccc43)CC2)c(Cl)c1
Agent: Cl
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CN1CCCC1=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)[C@@H](NC(=O)c1cnc(N2CCC(N3C(=O)OCc4ccccc43)CC2)c(Cl)c1)C(N)=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 34.2 %

Procedure:
The product of step (i) (0.14 g) was dissolved in 1-methyl-2-pyrrolidinone (4 ml) and to this solution was added carbonyldiimidazole (0.064 g) the mixture was stirred at room temperature for 1 h and then treated with D-valinamide hydrochloride (0.11 g) and N,N-diisopropylethylamine (0.10 g). After stirring for 18 h at room temperature the mixture was partitioned between aqueous sodium bicarbonate and ethyl acetate, the organic layer was washed with water, dried and evaporated under reduced pressure. The resultant solid was washed with ethyl acetate to yield 0.06 g of product.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH:11][C:12](=[O:14])[CH3:13])[CH:6]=[C:7]([O:9][CH3:10])[CH:8]=1.C1C(=O)N([Br:22])C(=O)C1>C(Cl)(Cl)(Cl)Cl>[Br:22][C:8]1[C:3]([O:2][CH3:1])=[CH:4][C:5]([NH:11][C:12](=[O:14])[CH3:13])=[CH:6][C:7]=1[O:9][CH3:10]
Reactant: O=C1CCC(=O)N1Br
Reactant: COc1cc(NC(C)=O)cc(OC)c1
Solvent: ClC(Cl)(Cl)Cl
Product: COc1cc(NC(C)=O)cc(OC)c1Br
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 25.4 %

Procedure:
N-(3,5-Dimethoxyphenyl)acetamide (500 mg, 2.56 mmol) was suspended in CCl4 (3 mL) followed by the addition of NBS (456 mg, 2.56 mmol) at room temperature. The reaction mixture was stirred at room temperature for 0.5 hour, heated at 80° C. for 2 hours and then concentrated under reduced pressure. The crude material was purified by silica gel chromatography (80 g ISCO column, eluting with 0% to 20% EtOAc in CH2Cl2) to provide Intermediate 9A (178 mg, 0.649 mmol, 25.4% yield) as a white solid. MS (ES): m/z=276.0 [M+H]+. 1H NMR (400 MHz, MeOD) δ ppm 2.14 (s, 3 H) 3.85 (s, 6 H) 7.01 (s, 2 H).
Reaction SMILES: [CH:1]1([CH:7]([N:11]2[C:15]3[CH:16]=[C:17]([F:21])[C:18]([F:20])=[CH:19][C:14]=3[N:13]=[C:12]2[C:22]2[C:23]([O:30][CH3:31])=[N:24][C:25]([O:28][CH3:29])=[CH:26][CH:27]=2)[C:8](O)=[O:9])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(N(CC)CC)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.Cl.[NH2:64][C@H:65]1[CH2:70][CH2:69][C@H:68]([OH:71])[CH2:67][CH2:66]1>C(Cl)Cl>[CH:1]1([CH:7]([N:11]2[C:15]3[CH:16]=[C:17]([F:21])[C:18]([F:20])=[CH:19][C:14]=3[N:13]=[C:12]2[C:22]2[C:23]([O:30][CH3:31])=[N:24][C:25]([O:28][CH3:29])=[CH:26][CH:27]=2)[C:8]([NH:64][C@H:65]2[CH2:70][CH2:69][C@H:68]([OH:71])[CH2:67][CH2:66]2)=[O:9])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: COc1ccc(-c2nc3cc(F)c(F)cc3n2C(C(=O)O)C2CCCCC2)c(OC)n1
Reactant: N[C@H]1CC[C@H](O)CC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1ccc(-c2nc3cc(F)c(F)cc3n2C(C(=O)N[C@H]2CC[C@H](O)CC2)C2CCCCC2)c(OC)n1
Temperature: 40 °C
Reaction time: 0.25 h

Procedure:
To a solution of cyclohexyl-[2-(2,6-dimethoxy-pyridin-3-yl)-5,6-difluoro-benzoimidazol-1-yl]-acetic acid (300 mg, 0.70 mmol, 1.0 equiv) in DCM (5 mL) was added triethylamine (142.1 mg, 194.7 μL, 1.39 mmol, 2.0 equiv) and HATU (341.6 mg, 0.90 mmol, 1.3 equiv) and the mixture stirred at 40° C. After 15 min, trans-4-amino-cyclohexanol hydrochloride (137.04 mg, 0.90 mmol, 1.3 equiv; [CAS RN 50910-54-8]) was added and stirring continued at 50° C. for 2 h. Removal of the solvent mixture under reduced pressure and purification by silica column chromatography using a MPLC system (CombiFlash Companion, Isco Inc.) eluting with a gradient of heptane/ethyl acetate yielded 0.33 g (90%) of the title compound. MS (ES+): 529 (M+H).
Reaction SMILES: [CH2:1]([C:3]1[CH:12]=[C:11]([CH3:13])[C:10]2[C:9](=[O:14])[NH:8][C@H:7]3[CH2:15][N:16]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:17][C@@H:6]3[C:5]=2[CH:4]=1)[CH3:2].Cl>C(OCC)C>[CH2:1]([C:3]1[CH:12]=[C:11]([CH3:13])[C:10]2[C:9](=[O:14])[NH:8][C@@H:7]3[CH2:15][N:16]([C:18]([O:20][C:21]([CH3:22])([CH3:24])[CH3:23])=[O:19])[CH2:17][C@H:6]3[C:5]=2[CH:4]=1)[CH3:2]
Reactant: CCc1cc(C)c2c(c1)[C@H]1CN(C(=O)OC(C)(C)C)C[C@@H]1NC2=O
Agent: Cl
Solvent: CCOCC
Product: CCc1cc(C)c2c(c1)[C@@H]1CN(C(=O)OC(C)(C)C)C[C@H]1NC2=O
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 79 %

Procedure:
To a solution of (3aR,9bS)-tert-butyl 8-ethyl-6-methyl-5-oxo-3,3a,4,5-tetrahydro-1H-pyrrolo[3,4-c]isoquinoline-2(9bH)-carboxylate, the first eluting compound from Part B above, (48 mg, 0.15 mmol) in 2 mL of diethyl ether was added 1 mL of 12 N HCl. The resulting mixture was stirred vigorously for 5 min at ambient temperature and then was concentrated and dried in vacuo. The resulting white solid was triturated twice with diethyl ether and dried in vacuo. The residue was dissolved in 1 mL distilled water, filtered, and lyophilized to afford 30 mg (79%) of the title compound of Example 74 as a white powder. 1H NMR (DMSO-d6): δ 9.40 (broad s, 2H), 8.47 (s, 1H), 7.07 (s, 1H), 6.89 (s, 1H), 3.87-3.82 (m, 1H), 3.52-3.46 (m, 1H), 3.45-3.40 (m, 1H), 3.21-3.10 (overlapping m, 2H), 3.07-3.01 (m, 1H), 2.58 (q, 2H, J=7.5 Hz), 2.54 (s, 3H), 1.18 (t, 3H, J=7.7 Hz). LRMS (ESI): 231.2 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:4]=1[CH2:5][CH2:6][CH2:7][CH:8]2[C:13]([OH:15])=O.[CH2:16]([N:18]1[CH:22]=[C:21]([CH2:23][NH:24][C:25]2[CH:30]=[CH:29][C:28]([CH:31]([CH3:33])[CH3:32])=[CH:27][CH:26]=2)[CH:20]=[N:19]1)[CH3:17]>>[CH2:16]([N:18]1[CH:22]=[C:21]([CH2:23][N:24]([C:25]2[CH:26]=[CH:27][C:28]([CH:31]([CH3:32])[CH3:33])=[CH:29][CH:30]=2)[C:13]([CH:8]2[C:9]3[C:4](=[C:3]([O:2][CH3:1])[CH:12]=[CH:11][CH:10]=3)[CH2:5][CH2:6][CH2:7]2)=[O:15])[CH:20]=[N:19]1)[CH3:17]
Reactant: COc1cccc2c1CCCC2C(=O)O
Reactant: CCn1cc(CNc2ccc(C(C)C)cc2)cn1
Product: CCn1cc(CN(C(=O)C2CCCc3c(OC)cccc32)c2ccc(C(C)C)cc2)cn1
Yield: 80.2 %

Procedure:
By the reaction and treatment in the same manner as in Example 12 using 5-methoxy-1,2,3,4-tetrahydronaphthalene-1-carboxylic acid (0.31 g) and [(1-ethylpyrazol-4-yl)methyl] (4-isopropylphenyl)amine (0.37 g) as starting materials, N-[(1-ethylpyrazol-4-yl)methyl]-N-(4-isopropylphenyl)-5-methoxy-1,2,3,4-tetrahydronaphthalene-1-carboxamide (0.52 g) was obtained.
Reaction SMILES: [NH2:1][C:2]1[NH:6][N:5]=[C:4]([NH:7][CH2:8][CH2:9][NH:10][C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[C:3]=1[C:18]#[N:19].C(O[CH:23](OCC)[N:24]([CH3:26])[CH3:25])C.C1(C)C=CC=CC=1>C(O)C>[C:11]([NH:10][CH2:9][CH2:8][NH:7][C:4]1[C:3]([C:18]#[N:19])=[C:2]([N:1]=[CH:23][N:24]([CH3:26])[CH3:25])[NH:6][N:5]=1)([O:13][C:14]([CH3:15])([CH3:16])[CH3:17])=[O:12]
Reactant: CCOC(OCC)N(C)C
Reactant: CC(C)(C)OC(=O)NCCNc1n[nH]c(N)c1C#N
Solvent: Cc1ccccc1
Solvent: CCO
Product: CN(C)C=Nc1[nH]nc(NCCNC(=O)OC(C)(C)C)c1C#N
Temperature: 100 °C
Reaction time: 5 h

Procedure:
A mixture of 76.3 9 (286.1 mmol) of 5-amino-3-[2-(Boc-amino)-ethylamino]-4cyano-pyrazole, 54 ml (315.1 mmol) of N,N-dimethylformamide diethyl acetal, 850 ml of toluene and 85 ml of ethanol is stirred at 100° C. for 5 hours. A further 24.5 ml (143 mmol) of N,N-dimethylformamide diethyl acetal are then added to the reaction mixture and stirring is continued for a further 3 hours at 100° C. After cooling to about 10° C., filtration and washing the filter residue with toluene and diethyl ether, 3-[2-(Boc-amino)-ethylamino]-4-cyano-5-(dimethylamino-methyleneamino)-pyrazole is obtained; m.p. 158-160° C.; ESI-MS: (M−H)−=320.
Reaction SMILES: C([O:5][C:6]([C:8]1[C:9]2[CH2:33][CH2:32][CH2:31][CH2:30][C:10]=2[S:11][C:12]=1[NH:13][C:14](=[O:29])[CH2:15][N:16]1[C:24]2[CH2:23][CH2:22][CH2:21][CH2:20][C:19]=2[C:18]([C:25]([F:28])([F:27])[F:26])=[N:17]1)=[O:7])(C)(C)C>C(Cl)Cl.C(O)(C(F)(F)F)=O>[F:28][C:25]([F:26])([F:27])[C:18]1[C:19]2[CH2:20][CH2:21][CH2:22][CH2:23][C:24]=2[N:16]([CH2:15][C:14]([NH:13][C:12]2[S:11][C:10]3[CH2:30][CH2:31][CH2:32][CH2:33][C:9]=3[C:8]=2[C:6]([OH:7])=[O:5])=[O:29])[N:17]=1
Reactant: CC(C)(C)OC(=O)c1c(NC(=O)Cn2nc(C(F)(F)F)c3c2CCCC3)sc2c1CCCC2
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(Cn1nc(C(F)(F)F)c2c1CCCC2)Nc1sc2c(c1C(=O)O)CCCC2
Temperature: 25 °C
Reaction time: 3 h

Procedure:
2-[2-(3-Trifluoromethyl-4,5,6,7-tetrahydroindazol-1-yl)-acetylamino]-4,5,6,7-tetrahydrobenzo[b]thiophene-3-carboxylic acid tert-butyl ester was dissolved in a solution of DCM (5 mL) and TFA (5 mL), and the resulting mixture stirred at RT for 3 h, before concentration in vacuo to afford the title compound as a pale yellow solid (870 mg). This was used directly in the next step without any further purification.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[NH:10][C:9](=O)[NH:8][C:7]2=O)([O-:3])=[O:2].[CH2:16]([NH2:20])[CH2:17][CH2:18][CH3:19]>O>[CH2:16]([NH:20][C:9]1[N:8]=[C:7]([NH:1][CH2:4][CH:5]=[C:6]([CH3:11])[CH3:7])[C:6]2[C:11](=[CH:12][CH:13]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=2)[N:10]=1)[CH2:17][CH2:18][CH3:19]
Reactant: O=c1[nH]c(=O)c2cc([N+](=O)[O-])ccc2[nH]1
Reactant: CCCCN
Solvent: O
Product: CCCCNc1nc(NCC=C(C)C)c2cc([N+](=O)[O-])ccc2n1
Temperature: 25 °C
Reaction time: 3 h
Yield: 20.9 %

Procedure:
2-chloro-4-(3-methyl-2-butenylamino)-6-nitroquinazoline was obtained in accordance with the process described in Example 59, starting from 278 mg (1.45 mmol) of 6-nitroquinazoline-2,4(1H,3H)-dione. After 1.00 ml (10.12 mmol) of butylamine was added to the compound thus obtained and the reaction mixture was stirred at room temperature for 3 hours, water was added to the reaction solution, followed by extraction with ethyl acetate, washing with brine and drying over anhydrous sodium sulfate. After the solvent was distilled off, the residue was purified by a silica gel column to give 50 mg (11.9%) of the title compound.
Reaction SMILES: [CH2:1]([NH:8][C:9]1[C:10]([NH2:26])=[CH:11][CH:12]=[C:13]([S:15][C:16]2[CH:25]=[CH:24][CH:23]=[C:22]3[C:17]=2[CH:18]=[CH:19][N:20]=[CH:21]3)[CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:27](O)(=O)[CH3:28].[Cl-].[Na+]>Cl>[CH2:1]([N:8]1[C:9]2[CH:14]=[C:13]([S:15][C:16]3[CH:25]=[CH:24][CH:23]=[C:22]4[C:17]=3[CH:18]=[CH:19][N:20]=[CH:21]4)[CH:12]=[CH:11][C:10]=2[N:26]=[C:27]1[CH3:28])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(=O)O
Reactant: Nc1ccc(Sc2cccc3cnccc23)cc1NCc1ccccc1
Agent: Cl
Agent: [Cl-]
Agent: [Na+]
Product: Cc1nc2ccc(Sc3cccc4cnccc34)cc2n1Cc1ccccc1
Yield: 43.3 %

Procedure:
N2-Benzyl-4-(5-isoquinolylsulfanyl)-1,2-benzenediamine 730 mg (2.0 mmol) was dissolved in 4N hydrochloric acid 20 ml, acetic acid 0.3 ml was added, and the mixture was heated and refluxed overnight. 40% sodium chloride was added to obtain an alkaline solution, and the solution was extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (chloroform: acetone=5:1), and 1-benzyl-6-(5-isoquinolylsulfanyl)-2-methyl-1H-benzo[d]imidazole 330 mg (43.3%) was obtained.
Reaction SMILES: [OH-].[Na+].Cl[C:4]1[N:5]=[CH:6][C:7]([C:10]([O:12]C)=[O:11])=[N:8][CH:9]=1.[C:14](OCC)(=[O:16])[CH3:15].O>C(O)C>[CH2:14]([O:16][C:4]1[N:5]=[CH:6][C:7]([C:10]([OH:12])=[O:11])=[N:8][CH:9]=1)[CH3:15]
Reactant: COC(=O)c1cnc(Cl)cn1
Reactant: CCOC(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CCOc1cnc(C(=O)O)cn1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
A 5 N sodium hydroxide solution (2 mL) was added to a solution of methyl 5-chloropyrazine-2-carboxylate (150 mg) in ethanol (4 mL), and the mixture was stirred at room temperature for five hours. Ethyl acetate and water were added to the reaction solution, and the aqueous layer was separated. The aqueous layer was made acidic with concentrated hydrochloric acid. Brine and ethyl acetate were added to the mixture, and the organic layer was separated. The organic layer was dried over anhydrous magnesium sulfate. The organic layer was concentrated to obtain the title compound (135 mg).