Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CN(C)C=O.[CH2:6]([C:12]1[CH:27]=[CH:26][C:15]([CH2:16][S:17][C@@H:18]2[CH2:22][NH:21][C@H:20]([C:23]([OH:25])=[O:24])[CH2:19]2)=[CH:14][CH:13]=1)[CH2:7][CH2:8][CH2:9][CH2:10][CH3:11].[C:28]([S:36][CH2:37][C@@H:38]([CH3:51])[C:39](OC1C=CC([N+]([O-])=O)=CC=1)=[O:40])(=[O:35])[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>C(N(CC)CC)C>[C:28]([S:36][CH2:37][C@@H:38]([CH3:51])[C:39]([N:21]1[CH2:22][C@@H:18]([S:17][CH2:16][C:15]2[CH:26]=[CH:27][C:12]([CH:6]3[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]3)=[CH:13][CH:14]=2)[CH2:19][C@H:20]1[C:23]([OH:25])=[O:24])=[O:40])(=[O:35])[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1
Reactant: CCCCCCc1ccc(CS[C@@H]2CN[C@H](C(=O)O)C2)cc1
Reactant: C[C@H](CSC(=O)c1ccccc1)C(=O)Oc1ccc([N+](=O)[O-])cc1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: C[C@H](CSC(=O)c1ccccc1)C(=O)N1C[C@@H](SCc2ccc(C3CCCCC3)cc2)C[C@H]1C(=O)O
Temperature: 0 °C
Reaction time: 8 h
Yield: 81 %

Procedure:
Dimethylformamide (4.5 ml) is added to (4S)-4-(4-hexylbenzylthio)-L-proline (430 mg), and the mixture is cooled to 0° C. To the mixture are added successively triethylamine (0.21 ml) and 4-nitrophenyl (2S)-3-(benzoylthio)-2-methylpropionate, and the obtained mixture is stirred at room temperature overnight. To the reaction mixture is added 10% citric acid, and the whole is extracted with ethyl acetate. The organic layer is washed with water and a saturated sodium chloride aqueous solution successively and dried over sodium sulfate. The residue obtained by concentration under reduced pressure is purified by silica gel column chromatography to give 580 mg (81%) of the titled compound as an amorphous substance.
Reaction SMILES: IC.[C:3](=O)([O-])[O-].[K+].[K+].[CH3:9][O:10][C:11]([C:13]1[O:14][C:15]([CH3:36])=[C:16]([CH2:18][NH:19][C:20]2[CH:25]=[CH:24][C:23]([C:26]3[CH:31]=[CH:30][C:29]([O:32][CH:33]([F:35])[F:34])=[CH:28][CH:27]=3)=[CH:22][CH:21]=2)[CH:17]=1)=[O:12]>CN(C)C=O>[CH3:9][O:10][C:11]([C:13]1[O:14][C:15]([CH3:36])=[C:16]([CH2:18][N:19]([C:20]2[CH:21]=[CH:22][C:23]([C:26]3[CH:31]=[CH:30][C:29]([O:32][CH:33]([F:35])[F:34])=[CH:28][CH:27]=3)=[CH:24][CH:25]=2)[CH3:3])[CH:17]=1)=[O:12]
Reactant: O=C([O-])[O-]
Reactant: COC(=O)c1cc(CNc2ccc(-c3ccc(OC(F)F)cc3)cc2)c(C)o1
Agent: [K+]
Solvent: CI
Solvent: CN(C)C=O
Product: COC(=O)c1cc(CN(C)c2ccc(-c3ccc(OC(F)F)cc3)cc2)c(C)o1
Temperature: 25 °C
Reaction time: 36 h
Yield: 63.8 %

Procedure:
Iodomethane (91 mg, 0.64 mmoles) and potassium carbonate (88 mg, 0.64 mmoles) were added to a solution of 4-(4′-difluoromethoxy-biphenyl-4-ylaminomethyl)-5-methyl-furan-2-carboxylic acid methyl ester (170) (62 mg, 0.16 mmoles) in N,N-dimethylformamide (10 ml) and the mixture stirred at room temperature for 36 hours under an argon atmosphere. The mixture was then heated at 35° C. for 21 hours. The mixture was partitioned between dichloromethane and water, the organic phase separated and dried (MgSO4). After evaporation of the solvent, the residue was purified by flash chromatography, using cyclohexane/ethyl acetate 99:1 v/v as eluent, to afford compound 175 (41 mg) as a brown oil. This was used directly in part (b).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[N:12]3[C:7](=[CH:8][CH:9]=[CH:10][C:11]=13)[C:6]([CH2:13][CH3:14])=[C:5]2[C:15]1[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=1.C([Li])(C)(C)C.CCCCC.CN(C)[C:35](=[O:42])[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1.[Cl-].[NH4+]>O1CCCC1>[C:35]([C:2]1[CH:3]=[C:4]2[N:12]3[C:7](=[CH:8][CH:9]=[CH:10][C:11]=13)[C:6]([CH2:13][CH3:14])=[C:5]2[C:15]1[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=1)(=[O:42])[C:36]1[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=1
Reactant: CCc1c(-c2ccc(OC)cc2)c2cc(Br)c3cccc1n32
Reactant: CN(C)C(=O)c1ccccc1
Agent: [Cl-]
Agent: [Li]C(C)(C)C
Agent: [NH4+]
Solvent: CCCCC
Solvent: C1CCOC1
Product: CCc1c(-c2ccc(OC)cc2)c2cc(C(=O)c3ccccc3)c3cccc1n32
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 39.5 %

Procedure:
4-Bromo-1-ethyl-2-(4-methoxyphenyl)pyrrolo[2,1,5-cd]indolizine (0.345 g, 1.0 mmol), was dissolved in 10 ml of dry tetrahydrofuran under a nitrogen atmosphere, and the solution was cooled to -78° C., while 1.35 M t-butyllithium in pentane (1.5 ml, 2.03 mmol) was added slowly. The orange solution was stirred for 30 minutes at -78° C. N,N-dimethylbenzamide (0.19 g, 1.27 mmol) dissolved in 5 ml of tetrahydrofuran was added and the reaction was stirred for 20 minutes. The reaction mixture was heated to room temperature, and stirred for 2 days. The mixture was poured into 50 ml of a saturated ammonium chloride solution and the organic material was extracted into dichloromethane (4×50 ml). The combined organic layers was washed with brine, dried overmagnesium sulfate, and evaporated to a yellow gum. The crude product was purified by column chromatography over silica gel 60, using 20% of diethyl ether in hexane as the eluent to afford 0.15 g (40%) of 4-benzoyl-1-ethyl-2-(4-methoxyphenyl)pyrrolo[2,1,5-cd]indolizine as a yellow solid. MS(SP): m/z 379 (M+). 1H--NMR (CDCl3, 200 MHz) δ: 1.47 (t, 3 H); 3.21 (q, 2 H); 3.89 (s, 3 H); 7.08 (d, 2 H); 7.46-7.60 (m,3 H); 7.69 (d, 2 H); 7.81-7.98 (m, 5 H); 8.39 (dd, 1 H).
Reaction SMILES: [N:1]#[C:2]Br.[Br:4][C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:12]2[C:13]([C:21]([NH:23][NH2:24])=[O:22])=[CH:14][N:15]([CH3:20])[C:16](=[O:19])[C:17]=2[F:18])=[C:7]([F:25])[CH:6]=1.C([O-])(O)=O.[Na+]>O1CCOCC1.O>[NH2:1][C:2]1[O:22][C:21]([C:13]2[C:12]([NH:11][C:8]3[CH:9]=[CH:10][C:5]([Br:4])=[CH:6][C:7]=3[F:25])=[C:17]([F:18])[C:16](=[O:19])[N:15]([CH3:20])[CH:14]=2)=[N:23][N:24]=1
Reactant: Cn1cc(C(=O)NN)c(Nc2ccc(Br)cc2F)c(F)c1=O
Reactant: N#CBr
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: Cn1cc(-c2nnc(N)o2)c(Nc2ccc(Br)cc2F)c(F)c1=O
Reaction time: 17 h
Yield: 89.2 %

Procedure:
Cyanogen bromide (36 mg, 0.31 mmol) was added to a suspension of 4-(4-bromo-2-fluorophenylamino)-5-fluoro-1-methyl-6-oxo-1,6-dihydropyridine-3-carboxylic acid hydrazide (63 mg, 0.169 mmol) in dioxane (2 mL) followed by an aqueous NaHCO3 (2 mL of a 0.09 M solution) solution. After 17 hours, additional cyanogen bromide (14 mg) was added. After 19; hours, the reaction mixture was diluted with water and extracted with ethyl acetate. The combined organic extracts were washed with brine, dried (MgSO4) and concentrated under reduced pressure. Crystallization (MeOH:THF) followed by trituration (Et2O:MeOH 5:1) gave clean desired product as a white solid (60 mg, 89%). MS APCI (+) m/z 398, 400 (M+, Br pattern) detected; 1H NMR (400 mHz, CD3OD) δ 8.06 (s, 1H), 7.37 (d, 1H), 7.31 (d, 1H), 7.10 (td, 1H), 3.64 (s, 3H).
Reaction SMILES: C(N(C(C)C)CC)(C)C.P(Cl)(OC1C=CC=CC=1)(OC1C=CC=CC=1)=O.[OH:27][C@@H:28]([C@H:30]1[C:50](=[O:51])[N:32]2[CH:33]([C:37]([O:39][CH2:40][C:41]3[CH:46]=[CH:45][C:44]([N+:47]([O-:49])=[O:48])=[CH:43][CH:42]=3)=[O:38])[C:34](=O)[CH2:35][C@H:31]12)[CH3:29].FC(F)(F)S(O)(=O)=O.[SH:60][C@@H:61]1[CH2:65][N:64]([C:66]([O:68][CH2:69][C:70]2[CH:75]=[CH:74][C:73]([N+:76]([O-:78])=[O:77])=[CH:72][CH:71]=2)=[O:67])[C@H:63]([C:79]([N:81]2[CH2:86][CH2:85][N:84]([CH3:87])[CH2:83][CH2:82]2)=[O:80])[CH2:62]1>C(#N)C>[OH:27][C@@H:28]([C@H:30]1[C:50](=[O:51])[N:32]2[C:33]([C:37]([O:39][CH2:40][C:41]3[CH:42]=[CH:43][C:44]([N+:47]([O-:49])=[O:48])=[CH:45][CH:46]=3)=[O:38])=[C:34]([S:60][C@@H:61]3[CH2:65][N:64]([C:66]([O:68][CH2:69][C:70]4[CH:75]=[CH:74][C:73]([N+:76]([O-:78])=[O:77])=[CH:72][CH:71]=4)=[O:67])[C@H:63]([C:79]([N:81]4[CH2:82][CH2:83][N:84]([CH3:87])[CH2:85][CH2:86]4)=[O:80])[CH2:62]3)[CH2:35][C@H:31]12)[CH3:29]
Reactant: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)C(=O)C[C@H]12
Reactant: CN1CCN(C(=O)[C@@H]2C[C@H](S)CN2C(=O)OCc2ccc([N+](=O)[O-])cc2)CC1
Agent: O=P(Cl)(Oc1ccccc1)Oc1ccccc1
Agent: O=S(=O)(O)C(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(S[C@H]3C[C@@H](C(=O)N4CCN(C)CC4)N(C(=O)OCc4ccc([N+](=O)[O-])cc4)C3)C[C@H]12
Reaction time: 1 h
Yield: 61.2 %

Procedure:
85 μl of diisopropylethylamine and 86 μl of diphenyl chlorophosphate were simultaneously added, whilst ice-cooling, to a solution of 161 mg of 4-nitrobenzyl (5R,6S)-6-[(1R)-1-hydroxyethyl]-2-oxo-1-carbapenam-3-carboxylate in 2 ml of anhydrous acetonitrile, and the resulting mixture was stirred at the same temperature for 1 hour. At the end of this time, 232 μof diisopropylethylamine and a solution of 310 mg of (2S,4S)-4-mercapto-2-(4-methyl-1-piperazinylcarbonyl)-1-(4-nitrobenzyloxycarbonyl)pyrrolidine trifluoromethanesulfonate [prepared as described in Example 1(1)] in 2 ml of anhydrous acetonitrile were added dropwise to the mixture, whilst ice-cooling, and the resulting mixture was stirred at the same temperature for 2 hours, after which it was allowed to stand overnight, whilst ice-cooling. At the end of this time, the solvent was removed by distillation under reduced pressure, and the resulting residue was worked up and purified in a similar manner to that described in Example 29(1), to afford 209 mg of the title compound as a powder.
Reaction SMILES: O[C@@H]1CCCC[C@H]1NC(C1C(C(F)(F)F)=N[C:14]([O:21]CC2CC2)=[C:13]([C:26]2[CH:31]=[CH:30][C:29](Cl)=CC=2)[N:12]=1)=O.[OH:33][C@@H:34]1[CH2:39][CH2:38][CH2:37][CH2:36][C@H:35]1[NH:40][C:41]([C:43]1[C:48]([C:49]([F:52])([F:51])[F:50])=[N:47][C:46](Br)=[C:45]([C:54]2[CH:59]=[CH:58][CH:57]=[C:56]([Cl:60])[CH:55]=2)[N:44]=1)=[O:42].C1(CO)CC1.N1C=CC=CC=1CO>>[OH:33][C@@H:34]1[CH2:39][CH2:38][CH2:37][CH2:36][C@H:35]1[NH:40][C:41]([C:43]1[C:48]([C:49]([F:52])([F:51])[F:50])=[N:47][C:46]([O:21][CH2:14][C:13]2[CH:26]=[CH:31][CH:30]=[CH:29][N:12]=2)=[C:45]([C:54]2[CH:59]=[CH:58][CH:57]=[C:56]([Cl:60])[CH:55]=2)[N:44]=1)=[O:42]
Reactant: O=C(N[C@@H]1CCCC[C@H]1O)c1nc(-c2ccc(Cl)cc2)c(OCC2CC2)nc1C(F)(F)F
Reactant: O=C(N[C@@H]1CCCC[C@H]1O)c1nc(-c2cccc(Cl)c2)c(Br)nc1C(F)(F)F
Agent: OCC1CC1
Agent: OCc1ccccn1
Product: O=C(N[C@@H]1CCCC[C@H]1O)c1nc(-c2cccc(Cl)c2)c(OCc2ccccn2)nc1C(F)(F)F

Procedure:
In analogy to example 1 (6-(4-chloro-phenyl)-5-cyclopropylmethoxy-3-trifluoromethyl-pyrazine-2-carboxylic acid ((1R,2R)-2-hydroxy-cyclohexyl)-amide) this compound was prepared by substituting 5-bromo-6-(4-chloro-phenyl)-3-trifluoromethyl-pyrazine-2-carboxylic acid ((1R,2R)-2-hydroxy-cyclohexyl)-amide with 5-bromo-6-(3-chloro-phenyl)-3-trifluoromethyl-pyrazine-2-carboxylic acid ((1R,2R)-2-hydroxy-cyclohexyl)-amide and cyclopropylmethanol with pyridin-2-yl-methanol.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([CH2:8]O)[CH:3]=1.S(Cl)([Cl:12])=O>C(Cl)Cl>[Cl:12][CH2:8][C:4]1[CH:3]=[C:2]([CH3:1])[CH:7]=[CH:6][N:5]=1
Reactant: Cc1ccnc(CO)c1
Reactant: O=S(Cl)Cl
Solvent: ClCCl
Product: Cc1ccnc(CCl)c1
Yield: 72.1 %

Procedure:
A mixture solution of (4-methyl-pyridine-2-yl)-methanol (410 mg, 3.33 mmol) described in Manufacturing Example 11-1-3, thionyl chloride (0.49 mL, 6.66 mmol) and methylene chloride (10 mL) was stirred under reflux for 5 minutes. The reaction solution was allowed to room temperature and concentrated under a reduced pressure. The resulting residue was partitioned into diethyl ether and saturated sodium bicarbonate solution. The organic layer was purified by silica gel column chromatography (ethyl acetate) to obtain the title compound (340 mg, 72.1%).
Reaction SMILES: [O:1]=[C:2]1[CH2:9][C:6]([CH3:8])([CH3:7])[CH2:5][C:4]([CH3:10])=[CH:3]1.[O-]CC.[Na+].[CH2:15]([N:19]([CH2:30][CH2:31][CH2:32][CH3:33])[C:20]1[CH:27]=[CH:26][C:23]([CH:24]=O)=[C:22]([O:28][CH3:29])[CH:21]=1)[CH2:16][CH2:17][CH3:18].C(OCC)(=O)C>O1CCCC1>[CH2:15]([N:19]([CH2:30][CH2:31][CH2:32][CH3:33])[C:20]1[CH:27]=[CH:26][C:23]([CH:24]=[CH:10][C:4]2[CH2:5][C:6]([CH3:8])([CH3:7])[CH2:9][C:2](=[O:1])[CH:3]=2)=[C:22]([O:28][CH3:29])[CH:21]=1)[CH2:16][CH2:17][CH3:18]
Reactant: CC1=CC(=O)CC(C)(C)C1
Reactant: CCCCN(CCCC)c1ccc(C=O)c(OC)c1
Agent: CC[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCCCN(CCCC)c1ccc(C=CC2=CC(=O)CC(C)(C)C2)c(OC)c1
Temperature: 50 °C
Reaction time: 4.5 h
Yield: 45 %

Procedure:
In 15 ml of tetrahydrofuran, 1.5 g (10.85 mmol) of isophorone was dissolved, and 3.4 g of sodium ethoxide (20% solution in ethanol) (10.0 mmol) was added thereto. To this mixture, 2.6 g (9.87 mmol) of 4-dibutylamino-2-methoxybenzaldehyde in tetrahydrofuran was added dropwise with heating at 50° C., and the mixture was stirred for 4.5 hours. To the mixture, 100 ml of ethyl acetate was added. Washing with a saturated saline solution, drying over anhydrous sodium sulfate, and concentration were performed. The residue was purified by silica gel column chromatography to give 1.7 g of a reddish orange oily matter (yield: 45.0%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([N:9]2[C:13](=[O:14])[O:12][N:11]=[C:10]2[C:15]2[C:19]([NH:20][CH2:21][CH2:22][OH:23])=[N:18][O:17][N:16]=2)[CH:5]=[CH:6][C:7]=1[F:8].[CH3:24][S:25](Cl)(=[O:27])=[O:26].C(N(CC)CC)C>C(OCC)(=O)C>[CH3:24][S:25]([O:23][CH2:22][CH2:21][NH:20][C:19]1[C:15]([C:10]2[N:9]([C:4]3[CH:5]=[CH:6][C:7]([F:8])=[C:2]([Br:1])[CH:3]=3)[C:13](=[O:14])[O:12][N:11]=2)=[N:16][O:17][N:18]=1)(=[O:27])=[O:26]
Reactant: CS(=O)(=O)Cl
Reactant: O=c1onc(-c2nonc2NCCO)n1-c1ccc(F)c(Br)c1
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: CS(=O)(=O)OCCNc1nonc1-c1noc(=O)n1-c1ccc(F)c(Br)c1
Temperature: 35 °C
Reaction time: 2 h

Procedure:
To a solution of 4-(3-bromo-4-fluorophenyl)-3-{4-[(2-hydroxyethyl)amino]-1,2,5-oxadiazol-3-yl}-1,2,4-oxadiazol-5(4H)-one (1.5 kg, 3.9 mol, containing also some of the corresponding bromo-compound) in ethyl acetate (12 L) was added methanesulfonyl chloride (185 mL, 2.4 mol) dropwise over 1 h at room temperature. Triethylamine (325 mL, 2.3 mol) was added dropwise over 45 min, during which time the reaction temperature increased to 35° C. After 2 h, the reaction mixture was washed with water (5 L), brine (1 L), dried over sodium sulfate, combined with 3 more reactions of the same size, and the solvents removed in vacuo to afford the desired product (7600 g, quantitative yield) as a tan solid. LCMS for C13H11BrFN5O6SNa (M+Na)+: m/z=485.9, 487.9. 1H NMR (400 MHz, DMSO-d6): δ 8.08 (dd, J=6.2, 2.5 Hz, 1H), 7.72 (m, 1H), 7.58 (t, J=8.7 Hz, 1H), 6.75 (t, J=5.9 Hz, 1H), 4.36 (t, J=5.3 Hz, 2H), 3.58 (dd, J=11.2, 5.6 Hz, 2H), 3.18 (s, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([NH:8][CH:9]2[CH2:14][CH2:13][N:12]([CH:15]3[CH2:20][CH2:19][O:18][CH2:17][CH2:16]3)[CH2:11][CH2:10]2)[C:5]([NH2:21])=[CH:4][C:3]=1[C:22]([F:25])([F:24])[F:23].[C:26](C1NC=CN=1)(C1NC=CN=1)=[O:27].C(OCC)(=O)C>O1CCCC1>[Cl:1][C:2]1[C:3]([C:22]([F:23])([F:25])[F:24])=[CH:4][C:5]2[NH:21][C:26](=[O:27])[N:8]([CH:9]3[CH2:10][CH2:11][N:12]([CH:15]4[CH2:20][CH2:19][O:18][CH2:17][CH2:16]4)[CH2:13][CH2:14]3)[C:6]=2[CH:7]=1
Reactant: Nc1cc(C(F)(F)F)c(Cl)cc1NC1CCN(C2CCOCC2)CC1
Reactant: O=C(c1ncc[nH]1)c1ncc[nH]1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: O=c1[nH]c2cc(C(F)(F)F)c(Cl)cc2n1C1CCN(C2CCOCC2)CC1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
A stirred solution of 5-chloro-N-[1-(tetrahydro-2H-pyran-4-yl)-4-piperidinyl]-4-trifluoromethyl-1,2-benzenediamine (D52) (0.34 g, 0.9 mmol) in anhydrous tetrahydrofuran (40 ml) was treated with carbonyl diimidazole (0.29 g, 1.80 mmol)—added in portion over 5 minutes. The mixture was stirred at room temperature under argon for 4 hours. The mixture was warmed to a gentle reflux. After 18 hours, a further 0.29 g, 1.8 mmole of carbonyl diimidazole was added and the mixture maintained at reflux for another 24 hours. The mixture was cooled to room temperature and was treated with ethyl acetate (40 ml) and washed with water and brine then dried over MgSO4 and concentrated to dryness. The residue was purified by silica gel chromatography eluting with 1 to 10% methanol in dichloromethane to afford 6-chloro-5-trifluoromethyl-1-[1-(tetrahydro-2H-pyran-4-yl)-4-piperidinyl]-1,3-dihydro-2H-benzimidazol-2-one, which was subsequently converted to the hydrochloride salt and isolated as a cream powder. 0.25 g, 73%. MH+=404 and 406
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7](=[O:12])[CH2:6][CH2:5]2.[CH3:13][C:14]([O-])(C)[CH3:15].[K+].C(Br)(C)C>CN(C=O)C.Cl>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]([CH:14]([CH3:15])[CH3:13])[C:7](=[O:12])[CH2:6][CH2:5]2
Reactant: CC(C)(C)[O-]
Reactant: O=C1CCc2cc(Br)ccc2N1
Agent: Cl
Agent: [K+]
Solvent: CC(C)Br
Solvent: CN(C)C=O
Product: CC(C)N1C(=O)CCc2cc(Br)ccc21
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 38.9 %

Procedure:
To a solution of 6-bromo-3,4-dihydro-1H-quinolin-2-one (750 mg, 3.32 mmol) in 20 ml dry DMF was added potassium tert-butylate (804 mg, 6.64 mmol). After the mixture was stirred for 30 min at room temperature, a solution of isopropyl bromide (814 mg, 6.64 mmol) in 10 ml dry DMF was added and the mixture heated to 80° C. After stirring for additional 48 h, the mixture was cooled to room temperature and diluted with 150 ml 1 N HCl. Extraction with ethyl acetate (2×100 mL) followed by washing of the organic extracts with water and brine, drying over MgSO4 and removal of the solvent in vacuo gave a light yellow solid. Purification by flash chromatography (hexanes/ethyl acetate, 4/1, Rf=0.21) gave 6-bromo-1-isopropyl-3,4-dihydro-1H-quinolin-2-one (347 mg, 1.29 mmol, 33%) as pale yellow solid.
Reaction SMILES: [CH3:1][CH:2]1[N:7]([CH2:8][C:9]2[N:13]([C:14]3[CH:19]=[CH:18][CH:17]=[C:16]([C:20]([F:23])([F:22])[F:21])[CH:15]=3)[N:12]=[N:11][N:10]=2)[CH2:6][CH2:5][NH:4][C:3]1=[O:24].I[CH:26]([CH3:28])[CH3:27].[H-].[Na+]>CN(C)C=O.C(OCC)(=O)C>[CH3:1][CH:2]1[N:7]([CH2:8][C:9]2[N:13]([C:14]3[CH:19]=[CH:18][CH:17]=[C:16]([C:20]([F:23])([F:22])[F:21])[CH:15]=3)[N:12]=[N:11][N:10]=2)[CH2:6][CH2:5][N:4]([CH:26]([CH3:28])[CH3:27])[C:3]1=[O:24]
Reactant: CC(C)I
Reactant: CC1C(=O)NCCN1Cc1nnnn1-c1cccc(C(F)(F)F)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC1C(=O)N(C(C)C)CCN1Cc1nnnn1-c1cccc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 24 h
Yield: 9.5 %

Procedure:
To a solution of 3-methyl-4-({1-[3-(trifluoromethyl)phenyl]-1H-tetrazol-5-yl}methyl)-2-piperazinone (75 mg, 0.220 mmol, Compound 32), in N,N-Dimethylformamide (DMF) (1 mL) was added 2-iodopropane (0.024 mL, 0.242 mmol) and sodium hydride (8.81 mg, 0.220 mmol). The resulting reaction mixture was stirred at room temperature for 24 hours. To the reaction mixture was added 1 equivalent of 2-iodopropane and 0.5 equivalent of sodium hydride and stirred for an additional 24 h at room temperature. The reaction mixture was diluted with ethyl acetate (20 mL) and washed with 2N NaOH solution (10 mL). The aqueous phase was extracted with ethyl acetate (2×10 mL). All of the organic phases were combined, dried over magnesium sulphate, filtered and concentrated. The crude product was purified by MDAP. The relevant fractions were combined, concentrated and dried to give the title compound as a colourless oil (8 mg).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[NH2:11])[C:5]([OH:7])=[O:6].[C:12](O)(=O)[CH3:13]>Cl>[CH3:12][C:13]1[NH:11][C:10]2[CH:9]=[CH:8][C:4]([C:5]([OH:7])=[O:6])=[CH:3][C:2]=2[N:1]=1
Reactant: CC(=O)O
Reactant: Nc1ccc(C(=O)O)cc1N
Agent: Cl
Product: Cc1nc2cc(C(=O)O)ccc2[nH]1

Procedure:
100 g (0.657 mol) of 3,4-diaminobenzoic acid are boiled under reflux with 47.3 g (0.788 mol) of glacial acetic acid and 600 ml of 4N HCl in analogy to Example 14a.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:17]3[C:12](=[CH:13][C:14]([S:18]([N:21](CC4C=CC(OC)=CC=4)[C:22]4[CH:27]=[CH:26][N:25]=[CH:24][N:23]=4)(=[O:20])=[O:19])=[CH:15][CH:16]=3)[CH:11]=[CH:10][N:9]=2)=[C:4]([O:37][CH3:38])[CH:3]=1.C(=O)([O-])[O-].[Cs+].[Cs+].CN(C=O)C.FC(F)(F)S(O[CH2:56][C:57]([F:60])([F:59])[F:58])(=O)=O>O>[CH3:38][O:37][C:4]1[CH:3]=[C:2]([O:1][CH2:56][C:57]([F:60])([F:59])[F:58])[CH:7]=[CH:6][C:5]=1[C:8]1[C:17]2[C:12](=[CH:13][C:14]([S:18]([NH:21][C:22]3[CH:27]=[CH:26][N:25]=[CH:24][N:23]=3)(=[O:20])=[O:19])=[CH:15][CH:16]=2)[CH:11]=[CH:10][N:9]=1
Reactant: O=S(=O)(OCC(F)(F)F)C(F)(F)F
Reactant: COc1ccc(CN(c2ccncn2)S(=O)(=O)c2ccc3c(-c4ccc(O)cc4OC)nccc3c2)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1cc(OCC(F)(F)F)ccc1-c1nccc2cc(S(=O)(=O)Nc3ccncn3)ccc12
Temperature: 50 °C
Reaction time: 8 h
Yield: 65.7 %

Procedure:
A vial was charged with 1-(4-hydroxy-2-methoxyphenyl)-N-(4-methoxybenzyl)-N-(pyrimidin-4-yl)isoquinoline-6-sulfonamide (from EXAMPLE 361, STEP 1; 54 mg, 0.102 mmol), cesium carbonate (100 mg, 0.306 mmol), and DMF (511 μl). 2,2,2-Trifluoroethyl trifluoromethanesulfonate (28.0 μl, 0.204 mmol) was added and the vial was heated to 50° C. for 1 h. The mixture was diluted with water and extracted with EtOAc (3×). The combined organic extracts were concentrated. The residue was dissolved in DCM (1 mL) and TFA (1 mL), and the resulting solution was stirred overnight. The mixture was diluted with MeOH and concentrated. The residue was dissolved in EtOAc and washed with saturated aq. sodium bicarbonate solution. The aq. wash was extracted with EtOAc (2×). The combined organic extracts were dried over sodium sulfate, filtered, and concentrated. The residue was purified by chromatography on silica gel (3.5% MeOH/DCM) to give 1-(2-methoxy-4-(2,2,2-trifluoroethoxy)phenyl)-N-(pyrimidin-4-yl)isoquinoline-6-sulfonamide (32.7 mg, 0.067 mmol, 65.3% yield) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ=13.06 (br. s., 1H), 8.70-8.61 (m, 2H), 8.57 (s, 1H), 8.25 (d, J=5.6 Hz, 1H), 8.06 (d, J=5.8 Hz, 1H), 7.94 (dd, J=1.9, 8.9 Hz, 1H), 7.72 (d, J=8.9 Hz, 1H), 7.30 (d, J=8.3 Hz, 1H), 7.03 (d, J=5.1 Hz, 1H), 6.90 (d, J=2.3 Hz, 1H), 6.82 (dd, J=2.3, 8.4 Hz, 1H), 4.89 (q, J=8.9 Hz, 2H), 3.65 (s, 3H). m/z (ESI) 491.2 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1[C:6]([CH2:7][N:8]2[CH:12]=[C:11]([NH2:13])[CH:10]=[N:9]2)=[C:5]([CH3:14])[O:4][N:3]=1.[CH2:15]([N:23]=[C:24]=[O:25])[CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>>[CH3:1][C:2]1[C:6]([CH2:7][N:8]2[CH:12]=[C:11]([NH:13][C:24]([NH:23][CH2:15][CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)=[O:25])[CH:10]=[N:9]2)=[C:5]([CH3:14])[O:4][N:3]=1
Reactant: O=C=NCCc1ccccc1
Reactant: Cc1noc(C)c1Cn1cc(N)cn1
Product: Cc1noc(C)c1Cn1cc(NC(=O)NCCc2ccccc2)cn1
Yield: 29 %

Procedure:
Prepared as in example 9-6b from 1-((3,5-dimethylisoxazol-4-yl)methyl)-1H-pyrazol-4-amine and phenethyl isocyanate. Yield: 29%. 1H NMR (DMSO-d6, 400 MHz): δ2.10 (s, 3H), 2.36 (s, 3H), 2.69 (t, J=7.2 Hz, 2H), 3.25 (q, J=7.4 Hz, 2H), 5.02 (s, 2H), 6.00 (t, J=5.8 Hz, 1H), 7.16-7.30 (m, 6H), 7.68 (s, 1H), 8.13 (s, 1H). LC/MS; [M+H] calculated for C18H21N5O2; expected 340.17; found 340.20.
Reaction SMILES: FC(F)(F)S(O[C:7]1[CH:8]=[CH:9][CH:10]=[C:11]2[C:16]=1[N:15]=[C:14]([CH3:17])[CH:13]=[CH:12]2)(=O)=O.[C-:20]#[N:21].[Na+]>C(#N)C.C(OCC)(=O)C.[Cu]I.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>[CH3:17][C:14]1[CH:13]=[CH:12][C:11]2[C:16](=[C:7]([C:20]#[N:21])[CH:8]=[CH:9][CH:10]=2)[N:15]=1
Reactant: Cc1ccc2cccc(OS(=O)(=O)C(F)(F)F)c2n1
Reactant: [C-]#N
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Na+]
Solvent: CC#N
Solvent: CCOC(C)=O
Product: Cc1ccc2cccc(C#N)c2n1
Yield: 98.1 %

Procedure:
To a solution of 2-methylquinolin-8-yl trifluoromethanesulfonate (3.0 g, 10.3 mmol) in acetonitrile (26 mL) was added sodium cyanide (1.0 g, 20.6 mmol). The solution was degassed under nitrogen for 10 minutes, followed by addition of copper (I) iodide (0.20 g, 1.03 mmol) and Pd(PPh3)4 (0.60 g, 0.52 mmol) under nitrogen. The mixture was heated at reflux for 2 hours. After cooling the mixture was diluted with ethyl acetate (50 mL) and filtered through Celite and washed with ethyl acetate (50 mL). The filtrate was washed with water and brine, dried (MgSO4), filtered and concentrated under reduced pressure. The residue was purified by column chromatography (Biotage, 40 M; 20% ethyl acetate:hexanes) to afford 2-methylquinoline-8-carbonitrile (1.70 g, 98%).