Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([N+:12]([O-:14])=[O:13])[CH:10]=2)[CH:5]=[CH:4][N:3]=1.[CH3:15][O-:16].[Na+]>CO>[CH3:15][O:16][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([N+:12]([O-:14])=[O:13])[CH:10]=2)[CH:5]=[CH:4][N:3]=1
Reactant: O=[N+]([O-])c1ccc2ccnc(Cl)c2c1
Reactant: C[O-]
Agent: [Na+]
Solvent: CO
Product: COc1nccc2ccc([N+](=O)[O-])cc12
Yield: 81 %

Procedure:
To a suspension of 1-chloro-7-nitroisoquinoline (670 mg, 3.21 mmol) obtained in Preparation Example 1-5, Step 4 in methanol (100 ml) was added a 1M solution (6.5 ml, 6.5 mmol) of sodium methoxide. The mixture was refluxed under heating for 3 hr and concentrated under reduced pressure. The residue was dissolved in ethyl acetate, washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform:acetone=30:1) to give 1-methoxy-7-nitroisoquinoline (530 mg, 81%).
Reaction SMILES: CC(C)([O-])C.[K+].[CH3:7][C:8]1([CH2:11][OH:12])[CH2:10][CH2:9]1.Cl[C:14]1[N:19]=[CH:18][C:17]([C:20]([N:22]([O:24][CH3:25])[CH3:23])=[O:21])=[CH:16][CH:15]=1>O1CCCC1>[CH3:25][O:24][N:22]([CH3:23])[C:20]([C:17]1[CH:18]=[N:19][C:14]([O:12][CH2:11][C:8]2([CH3:7])[CH2:10][CH2:9]2)=[CH:15][CH:16]=1)=[O:21]
Reactant: CON(C)C(=O)c1ccc(Cl)nc1
Reactant: CC1(CO)CC1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: CON(C)C(=O)c1ccc(OCC2(C)CC2)nc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 54 %

Procedure:
To a solution of potassium tert-butoxide (1.68 g) in tetrahydrofuran (30 mL), a solution of 1-methylcyclopropanemethanol (1.29 g) in tetrahydrofuran (5 mL) was added and the mixture was stirred at room temperature for 10 minutes. After the reaction mixture was cooled to 0° C., a solution in tetrahydrofuran (5 mL) of the compound (3.00 g) obtained in step (1) above was added and after being brought to room temperature, the reaction mixture was stirred for an hour. The reaction mixture was then concentrated under reduced pressure and the resulting residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=95:5-50:50) to give N-methoxy-N-methyl-6-[(1-methylcyclopropyl)methoxy]pyridine-3-carboxamide as a colorless oil (2.02 g).
Reaction SMILES: [Cl:1][C:2]1[CH:18]=[CH:17][C:5]2[CH2:6][CH2:7][N:8]([C:11](=[O:16])[C:12]([F:15])([F:14])[F:13])[CH2:9][CH2:10][C:4]=2[C:3]=1OS(C(F)(F)F)(=O)=O.[NH2:27][CH2:28][C:29]1[CH:34]=[CH:33][C:32]([O:35][CH2:36][C:37]([F:40])([F:39])[F:38])=[CH:31][N:30]=1>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:18]=[CH:17][C:5]2[CH2:6][CH2:7][N:8]([C:11](=[O:16])[C:12]([F:13])([F:15])[F:14])[CH2:9][CH2:10][C:4]=2[C:3]=1[NH:27][CH2:28][C:29]1[CH:34]=[CH:33][C:32]([O:35][CH2:36][C:37]([F:40])([F:38])[F:39])=[CH:31][N:30]=1
Reactant: NCc1ccc(OCC(F)(F)F)cn1
Reactant: O=C(N1CCc2ccc(Cl)c(OS(=O)(=O)C(F)(F)F)c2CC1)C(F)(F)F
Solvent: Cc1ccccc1
Product: O=C(N1CCc2ccc(Cl)c(NCc3ccc(OCC(F)(F)F)cn3)c2CC1)C(F)(F)F

Procedure:
Use a method similar to the General Procedure 5-2 to couple 7-chloro-6-trifluoromethanesulfonyloxy-3-(2,2,2-trifluoroacetyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepine (370 mg, 0.9 mmol) with 2-aminomethyl-5-(2,2,2-trifluoroethoxy)-pyridine (180 mg, 0.9 mmol) in toluene (8 mL). Purify by chromatography on silica gel eluting with hexane/EtOAc (10:1, 5:1 and 3:1) followed by SCX chromatography [pre-wash column with methanol followed by DCM, load material dissolved in DCM, then elute with DCM/2M ammonia in methanol (1:1) and concentrate in vacuo] to obtain 7-chloro-6-{[5-(2,2,2-trifluoro-ethoxy)-pyridin-2-ylmethyl]-amino}-3-(2,2,2-trifluoroacetyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepine.
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([NH:12][N:13]([CH3:15])[CH3:14])[C:5]2[S:10][CH:9]=[C:8]([CH3:11])[C:6]=2[N:7]=1.[CH2:16]([NH2:19])[CH:17]=[CH2:18].C(=O)([O-])O.[Na+]>>[CH2:16]([NH:19][C:2]1[N:3]=[C:4]([NH:12][N:13]([CH3:15])[CH3:14])[C:5]2[S:10][CH:9]=[C:8]([CH3:11])[C:6]=2[N:7]=1)[CH:17]=[CH2:18]
Reactant: C=CCN
Reactant: Cc1csc2c(NN(C)C)nc(Cl)nc12
Agent: O=C([O-])O
Agent: [Na+]
Product: C=CCNc1nc(NN(C)C)c2scc(C)c2n1
Yield: 92.5 %

Procedure:
150 mg (0.62 mmol) of 2-chloro-7-methyl-4-(2,2-dimethylhydrazino)thieno[3,2-d]pyrimidine and 564 mg (9.89 mmol) of allylamine were heated in a sealed tube at 160° C. for 16 hours. After completion of the reaction, the reaction mixture was allowed to resume room temperature, followed by adding a saturated aqueous sodium hydrogen carbonate solution thereto and extraction with ethyl acetate (50 ml×2). After the organic layer was washed with brine and dried over anhydrous sodium sulfate, the solvent was distilled off. The residue was purified by a silica gel chromatography (eluent: ethyl acetate-hexane=1/2) to give 151 mg (yield: 92.6%) of the title compound.
Reaction SMILES: C(=O)(OC(C)(C)C)N.[F:9][CH:10]1[CH2:15][CH2:14][N:13](C(OC(C)(C)C)=O)[C@@H:12]([C:23](=[O:37])[NH:24][C@H:25]([C:27]2[CH:32]=[CH:31][C:30]([C:33]([O:35][CH3:36])=[O:34])=[CH:29][CH:28]=2)[CH3:26])[CH2:11]1>>[F:9][CH:10]1[CH2:15][CH2:14][NH:13][C@@H:12]([C:23]([NH:24][C@H:25]([C:27]2[CH:28]=[CH:29][C:30]([C:33]([O:35][CH3:36])=[O:34])=[CH:31][CH:32]=2)[CH3:26])=[O:37])[CH2:11]1
Reactant: COC(=O)c1ccc([C@H](C)NC(=O)[C@H]2CC(F)CCN2C(=O)OC(C)(C)C)cc1
Agent: CC(C)(C)OC(N)=O
Product: COC(=O)c1ccc([C@H](C)NC(=O)[C@H]2CC(F)CCN2)cc1
Yield: 111.6 %

Procedure:
The title compound (D95) (75 mg) was prepared according to the general procedure for t-Butyl carbamate (Boc) cleavage starting from (2R)-tert-butyl 4-fluoro-2-(((S)-1-(4-(methoxycarbonyl)phenyl)ethyl)carbamoyl)piperidine-1-carboxylate (D62) (89 mg).
Reaction SMILES: [CH3:1][C:2]1[CH:15]=[CH:14][C:5]([C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[O:7])=[CH:4][CH:3]=1.[Br:16]Br.C1C=CC=CC=1>C(OCC)C>[Br:16][CH2:1][C:2]1[CH:15]=[CH:14][C:5]([C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[O:7])=[CH:4][CH:3]=1
Reactant: BrBr
Reactant: Cc1ccc(C(=O)c2ccccc2)cc1
Solvent: CCOCC
Solvent: c1ccccc1
Product: O=C(c1ccccc1)c1ccc(CBr)cc1
Temperature: 70 °C

Procedure:
30 g (0.153 mol) of 4-methylbenzophenone are introduced into a 250 ml three-necked flask equipped with a reflux condenser and a dropping funnel containing 8.7 ml (0.168 mol) of bromine. In a first step, the reaction medium is heated to 70° C. and then, after complete dissolution of the solid, to 150° C. The bromine is then added dropwise over a period of 3 hours. The reaction is exothermic. The initially colorless solution becomes orange-yellow. Heating is maintained at 150° C. for 15 hours. At the end of the reaction, the temperature of the reaction medium is allowed to return to room temperature. The solution is brown in color. 75 ml of benzene and 35 ml of diethyl ether are added. Washing is carried out with a saturated Na2CO3 solution, then with a saturated Na2S2O3 solution and finally with a saturated NaCl solution, in order to remove the salts formed and to bring the solution to a pH of the order of 6-7. The organic phase is recovered and the solvents are evaporated. A caramel-colored paste is obtained. It is recrystallized from 100 ml of ethanol. The cream-colored crystals are collected and dried under vacuum. The mother liquors are collected and a second crystallization is carried out. The crystals obtained are dried under vacuum. The yield of expected product is 50%, m=20.81 g.
Reaction SMILES: Br[CH2:2][CH:3]=[C:4]([F:15])[C:5]([C:8]1[CH:13]=[CH:12][C:11]([Cl:14])=[CH:10][CH:9]=1)([CH3:7])[CH3:6].C(=O)([O-])[O-].[K+].[K+].[F:22][C:23]1[CH:28]=[CH:27][C:26](B(O)O)=[CH:25][C:24]=1[O:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1.C(Cl)Cl.CCCCCC>C1(C)C=CC=CC=1.C(O)C.C(OCC)(=O)C>[Cl:14][C:11]1[CH:12]=[CH:13][C:8]([C:5]([CH3:7])([CH3:6])[C:4]([F:15])=[CH:3][CH2:2][C:26]2[CH:27]=[CH:28][C:23]([F:22])=[C:24]([O:32][C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)[CH:25]=2)=[CH:9][CH:10]=1
Reactant: CC(C)(C(F)=CCBr)c1ccc(Cl)cc1
Reactant: OB(O)c1ccc(F)c(Oc2ccccc2)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CCO
Solvent: CCCCCC
Product: CC(C)(C(F)=CCc1ccc(F)c(Oc2ccccc2)c1)c1ccc(Cl)cc1
Temperature: 25 °C
Yield: 85.6 %

Procedure:
A mixture of 1-bromo-4-(p-chlorophenyl)-3-fluoro-4-methyl-2-pentene, (Z)- (1.02 g, 3.5 mmol), and bis(di-benzylideneacetone)palladium(0) (Pd(dba)2, 0.1 g, 0.17 mmol) in toluene (20 mL) under nitrogen is stirred for one minute, treated with potassium carbonate (1.94 g, 0.014 mol), degassed, treated with a solution of 4-fluoro-3-phenoxybenzeneboronic acid (1.05 g, 4.55 mmol) in ethanol (5 mL), refluxed for 50 minutes, cooled to room temperature, diluted with ethyl acetate and filtered through diatomaceous earth. The filtrate is washed sequentially with water and brine, dried over anhydrous sodium sulfate and concentrated in vacuo to obtain a residue. Flash chromatography of the residue using silica gel and a 15:100 methylene chloride/hexane solution gives the title compound as a colorless oil (1.19 g, 85.6% yield) which is identified by NMR spectral analyses.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[N:6][C:5](Br)=[CH:4][N:3]=1.[F:9][C:10]1[CH:15]=[C:14]([S:16]([CH3:19])(=[O:18])=[O:17])[CH:13]=[CH:12][C:11]=1B(O)O.C([O-])([O-])=O.[Na+].[Na+]>O1CCOCC1.CO.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[F:9][C:10]1[CH:15]=[C:14]([S:16]([CH3:19])(=[O:18])=[O:17])[CH:13]=[CH:12][C:11]=1[C:5]1[N:6]=[CH:7][C:2]([NH2:1])=[N:3][CH:4]=1
Reactant: Nc1cnc(Br)cn1
Reactant: CS(=O)(=O)c1ccc(B(O)O)c(F)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CO
Solvent: C1COCCO1
Product: CS(=O)(=O)c1ccc(-c2cnc(N)cn2)c(F)c1

Procedure:
5-[2-Fluoro-4-(methylsulfonyl)phenyl]-2-pyrazinamine (0.30 g, 50%) was prepared as a yellowish brown solid from 2-amino-5-bromopyrazine (0.4 g, 2.23 mmol), [2-fluoro-4-(methylsulfonyl)phenyl]boronic acid (0.50 g, 2.23 mmol), 2M Na2CO3 (4 mL), Pd(PPh3)4 (52 mg, 0.05 mmol) in 1,4-dioxane (8 mL) and MeOH (4 mL) in a manner similar to Example 145, Step 1. The crude product was triturated with CH2Cl2 to give 5-[2-fluoro-4-(methylsulfonyl)phenyl]-2-pyrazinamine as a yellowish brown solid. 1H NMR (400 MHz, DMSO-d6): δ 8.41 (s, 1H), 8.11 (t, 1H, J=8.0 Hz), 8.01 (s, 1H), 7.85-7.75 (m, 2H), 6.91 (s, 2H), 3.26 (s, 3H); LRMS (ESI), m/z 268 (M+H).
Reaction SMILES: [ClH:1].[CH2:2]([C:6]1[N:7]=[C:8]([NH2:11])[NH:9][CH:10]=1)[CH2:3][C:4]#[CH:5].[N:12]([CH2:15][CH:16]=[CH:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=[N+:13]=[N-:14]>>[ClH:1].[C:18]1([CH:17]=[CH:16][CH2:15][N:12]2[CH:5]=[C:4]([CH2:3][CH2:2][C:6]3[N:7]=[C:8]([NH2:11])[NH:9][CH:10]=3)[N:14]=[N:13]2)[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: [N-]=[N+]=NCC=Cc1ccccc1
Reactant: C#CCCc1c[nH]c(N)n1
Agent: Cl
Product: Nc1nc(CCc2cn(CC=Cc3ccccc3)nn2)c[nH]1
Yield: 39 %

Procedure:
4-But-3-ynyl-1H-imidazol-2-ylamine hydrochloride (0.066 g, 0.383 mmol) was reacted with (3-azido-propenyl)-benzene, which was synthesized using previously reported methods (Rad et al., Tetrahedron Letters 2007, 48, 3445-3449), (0.079 g, 0.460 mmol) following the general procedure for click reactions outlined above to produce 4-{2-[1-(3-Phenyl-allyl)-1H-[1,2,3]triazol-4-yl]-ethyl}-1H-imidazol-2-ylamine hydrochloride (0.049 g, 39%) of a pale yellow oil. 1H NMR (300 MHz, CD3OD) δ 8.19 (s, 1H), δ 7.44 (d, 2H), δ 7.29 (m, 3H), δ 6.73 (d, 1H), δ 6.53 (s, 1H), δ 6.42 (m, 2H), δ 5.24 (d, 2H), δ 3.07 (t, 2H), δ 2.88 (t, 2H) ppm; 13C 148.6, 145.3, 139.4, 139.2, 129.8, 129.7, 129.6, 128.5, 128.4, 127.6, 54.6, 47.3, 45.9, 26.3, 22.6 ppm; HRMS (ESI) calcd for C16H19N6(M+) 295.1665, found 295.1670.
Reaction SMILES: C[O:2][C:3](=[O:29])/[CH:4]=[CH:5]/[C:6]1[CH:27]=[C:26]2[C:9]([C:10](=[O:28])[CH2:11][C:12]3([O:25]2)[CH2:17][CH2:16][N:15]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:14][CH2:13]3)=[CH:8][CH:7]=1.[OH-].[Na+]>>[C:21]([O:20][C:18]([N:15]1[CH2:16][CH2:17][C:12]2([CH2:11][C:10](=[O:28])[C:9]3[C:26](=[CH:27][C:6](/[CH:5]=[CH:4]/[C:3]([OH:29])=[O:2])=[CH:7][CH:8]=3)[O:25]2)[CH2:13][CH2:14]1)=[O:19])([CH3:24])([CH3:22])[CH3:23]
Reactant: COC(=O)/C=C/c1ccc2c(c1)OC1(CCN(C(=O)OC(C)(C)C)CC1)CC2=O
Agent: [Na+]
Agent: [OH-]
Product: CC(C)(C)OC(=O)N1CCC2(CC1)CC(=O)c1ccc(/C=C/C(=O)O)cc1O2
Yield: 96.4 %

Procedure:
(E)-3-{1′-Tert-butoxycarbonyl-4-oxo-spiro[chromane-2,4′-piperidine]-7-yl}-acrylic acid methyl ester (602 mg, 1.5 mmol, Intermediate 2, Step B) was treated with NaOH following the procedure described in Example 1, Step A, giving (E)-3-{1′-tert-butoxycarbonyl-4-oxo-spiro[chromane-2,4′-piperidine]-7-yl}-acrylic acid as a white solid (560 mg, 96%). The resulting product was treated with NH2OTHP according to the procedure described in Example 1, Step B, giving (E)-3-{1′-tert-butoxycarbonyl-4-oxo-spiro[chromane-2,4′-piperidine]-7-yl}-N-(tetrahydro-pyran-2-yloxy)-acrylamide as a yellow solid (572 mg, 81%). Finally, removal of the THP and the BOc protecting groups following the procedure described in Example 1, Step C gave (E)-3-{4-oxo-spiro[chromane-2,4′-piperidine]-7-yl}-N-hydroxy-acrylamide (280 mg, 70%) as a yellow solid (hydrochloride salt).
Reaction SMILES: FC1C(C)=NC2C(N=1)=C([C:12]1[NH:20][C:19]3[CH2:18][CH2:17][NH:16][C:15](=[O:21])[C:14]=3[CH:13]=1)C=CC=2.Cl.FC1(F)CC(N)C1.CCN(C(C)C)C(C)C.CO.C(Cl)Cl>CS(C)=O>[NH:20]1[C:19]2[CH2:18][CH2:17][NH:16][C:15](=[O:21])[C:14]=2[CH:13]=[CH:12]1
Reactant: Cc1nc2cccc(-c3cc4c([nH]3)CCNC4=O)c2nc1F
Agent: Cl
Agent: NC1CC(F)(F)C1
Solvent: CS(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CO
Product: O=C1NCCc2[nH]ccc21
Temperature: 80 °C
Yield: 65.1 %

Procedure:
Prepared similar to that described in Example 131 using 2-(3-fluoro-2-methylquinoxalin-5-yl)-6,7-dihydro-1H-pyrrolo[3,2-c]pyridin-4(5H)-one (Example 126; 46.7 mg, 0.106 mmol), 3,3-difluorocyclobutanamine hydrochloride (PharmaStone, Lexington, Mass.; 45.5 mg, 0.317 mmol), and DIPEA (0.110 mL, 0.634 mmol) in DMSO (0.8 mL), heating at 80° C. for 1.5 h. Chromatographic purification (silica gel, 0-100% EtOAc/hexanes, then 0-10% MeOH/DCM) furnished 2434(3,3-difluorocyclobutyl)amino)-2-methylquinoxalin-5-yl)-6,7-dihydro-1H-pyrrolo[3,2-c]pyridin-4(5H)-one (26.5 mg, 0.069 mmol, 66% yield) as a yellow solid: 1H NMR (400 MHz, DMSO-d6) δ ppm 11.97 (1H, br. s.), 7.88 (1H, dd, J=7.6, 1.2 Hz), 7.60 (1H, dd, J=8.0, 1.0 Hz), 7.51 (1H, d, J=5.5 Hz), 7.37 (1H, t, J=7.8 Hz), 7.06 (1H, d, J=2.2 Hz), 6.94 (1H, br. s.), 4.39-4.51 (1H, m), 3.45 (2H, td, J=6.7, 2.5 Hz), 3.04-3.15 (2H, m), 2.88 (2H, t, J=6.7 Hz), 2.86-2.92 (2H, m), 2.57 (3H, s). 19F NMR (377 MHz, DMSO-d6) δ ppm −82.16 to −81.43 (1F, m), −95.87 to −95.05 (1F, m). m/z (ESI, +ve) 384.2 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:15]2[C:23]3[C:18](=[C:19]([CH2:24][S:25][CH3:26])[CH:20]=[CH:21][CH:22]=3)[N:17]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH:16]=2)[CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:4][CH:3]=1.[CH2:34](OC(=O)C(C)C(C1C2C(=C(CSC)C=CC=2)N(C(OC(C)(C)C)=O)C=1)C1C=CC(C(F)(F)F)=CC=1)C>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:15]2[C:23]3[C:18](=[C:19]([CH2:24][S:25][CH3:26])[CH:20]=[CH:21][CH:22]=3)[N:17]([C:27]([O:29][C:30]([CH3:32])([CH3:31])[CH3:33])=[O:28])[CH:16]=2)[CH:9]([CH3:34])[C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:4][CH:3]=1
Reactant: CCOC(=O)C(C)C(c1ccc(C(F)(F)F)cc1)c1cn(C(=O)OC(C)(C)C)c2c(CSC)cccc12
Reactant: CCOC(=O)CC(c1ccc(Cl)cc1)c1cn(C(=O)OC(C)(C)C)c2c(CSC)cccc12
Product: CCOC(=O)C(C)C(c1ccc(Cl)cc1)c1cn(C(=O)OC(C)(C)C)c2c(CSC)cccc12

Procedure:
The title compound was prepared starting from 1.62 g (91% purity, 3.01 mmol) of the compound from Example 30A in analogy to the synthesis of the compound from Example 27A. 0.89 g (59% of theory) of the title compound was obtained as mixture of diastereomers.
Reaction SMILES: Cl[C:2]1[N:3]=[N:4][C:5]([C:8]2[CH:17]=[CH:16][C:11]([C:12]([O:14][CH3:15])=[O:13])=[CH:10][CH:9]=2)=[CH:6][N:7]=1.[NH3:18].C(O)(C)C>O>[NH2:18][C:2]1[N:3]=[N:4][C:5]([C:8]2[CH:17]=[CH:16][C:11]([C:12]([O:14][CH3:15])=[O:13])=[CH:10][CH:9]=2)=[CH:6][N:7]=1
Reactant: N
Reactant: COC(=O)c1ccc(-c2cnc(Cl)nn2)cc1
Solvent: O
Solvent: CC(C)O
Product: COC(=O)c1ccc(-c2cnc(N)nn2)cc1

Procedure:
A solution of methyl 4-(3-chloro-1,2,4-triazin-6-yl)benzoate (180 mg, 0.721 mmol) and 2M of ammonia in isopropyl alcohol (5 ml, 10 mmol) was stirred at 25° C. for 3 h. The reaction was diluted with water, and the precipitate was filtered to give the desired product. LCMS: (M+H2O+H)=249.0.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7]2[N:12]([CH2:13][CH2:14][N:15]3[CH2:19][CH2:18][CH2:17][CH2:16]3)[CH2:11][CH2:10][O:9][C:8]=2[CH:20]=1)([O-])=O.I.[S:22]1[CH:26]=[CH:25][CH:24]=[C:23]1[C:27](SC)=[NH:28]>CCO.C([O-])(O)=O.[Na+].[Pd]>[N:15]1([CH2:14][CH2:13][N:12]2[CH2:11][CH2:10][O:9][C:8]3[CH:20]=[C:4]([NH:1][C:27]([C:23]4[S:22][CH:26]=[CH:25][CH:24]=4)=[NH:28])[CH:5]=[CH:6][C:7]2=3)[CH2:19][CH2:18][CH2:17][CH2:16]1
Reactant: CSC(=N)c1cccs1
Reactant: O=[N+]([O-])c1ccc2c(c1)OCCN2CCN1CCCC1
Agent: [Pd]
Agent: I
Agent: O=C([O-])O
Solvent: CCO
Product: N=C(Nc1ccc2c(c1)OCCN2CCN1CCCC1)c1cccs1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 35.4 %

Procedure:
A suspension of 7-nitro-4-(2-(pyrrolidin-1-yl)ethyl)-3,4-dihydro-2H-benzo[b][1,4]oxazine (330 mg, 1.190 mmol) and Pd—C (252 mg, 0.238 mmol, 10% wt) in dry EtOH (10 mL) was purged with hydrogen gas. The reaction was stirred at room temperature for 1.5 hours under a hydrogen atmosphere (balloon pressure). The reaction mixture was filtered through a Celite pad and washed with EtOH (25 mL). The filtrate was treated with methyl thiophene-2-carbimidothioate hydroiodide (0.678 g, 2.377 mmol) and stirred for three days at room temperature. The reaction was diluted with saturated NaHCO3 solution (50 mL), and the product was extracted into CH2Cl2 (3×25 mL). The combined organic layers were dried (Na2SO4) and concentrated. The residue was subjected to flash chromatography on silica gel using 2:98 MeOH:CH2Cl2 followed by 5:95 (2M NH3 in MeOH):CH2Cl2 to give a yellow solid (150 mg, 36%). 1H-NMR (DMSO-d6) δ 7.70 (d, J=3.6 Hz, 1H), 7.57 (dd, J=5.1, 0.9 Hz, 1H), 7.08 (dd, J=5.1, 3.9 Hz, 1H), 6.65 (d, J=8.4 Hz, 1H), 6.34 (dd, J=2.4, 8.4 Hz, 1H), 6.252 (d, J=2.4, 1H), 6.36-6.25 (m, 2H), 4.15 (t, J=4.2 Hz, 2H), 3.38-3.30 (m, 4H), 2.64 (t, J=7.2 Hz, 2H), 2.58-2.48 (m, 4H), 1.70-1.67 (m, 4H); ESI-MS (m/z, %): 357 (MH+, 100), 260 (40), 98 (27); ESI-HRMS calculated for C19H25N4OS (MH+): 357.1743, observed: 357.1734; HPLC purity: 95.8% by area.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1([C:9]2[CH:14]=[CH:13][C:12]([C:15]3[CH:20]=[CH:19][C:18]([C:21]4[O:25][N:24]=[C:23]([CH3:26])[C:22]=4[NH:27][C:28]4[CH:33]=[CH:32][CH:31]=[C:30]([C:34]#[N:35])[N:29]=4)=[CH:17][CH:16]=3)=[CH:11][CH:10]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2].[N:36]([Sn](CCCC)(CCCC)CCCC)=[N+:37]=[N-:38]>C1C(Cl)=CC=C(Cl)C=1>[CH2:1]([O:3][C:4]([C:6]1([C:9]2[CH:10]=[CH:11][C:12]([C:15]3[CH:20]=[CH:19][C:18]([C:21]4[O:25][N:24]=[C:23]([CH3:26])[C:22]=4[NH:27][C:28]4[CH:33]=[CH:32][CH:31]=[C:30]([C:34]5[N:36]=[N:37][NH:38][N:35]=5)[N:29]=4)=[CH:17][CH:16]=3)=[CH:13][CH:14]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4Nc4cccc(C#N)n4)cc3)cc2)CC1
Reactant: CCCC[Sn](CCCC)(CCCC)N=[N+]=[N-]
Solvent: Clc1ccc(Cl)cc1
Product: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4Nc4cccc(-c5nn[nH]n5)n4)cc3)cc2)CC1
Temperature: 110 °C

Procedure:
1-{4′-[4-(6-Cyano-pyridin-2-ylamino)-3-methyl-isoxazol-5-yl]-biphenyl-4-yl}-cyclopropanecarboxylic acid ethyl ester (0.046 g, 0.1 mmol) and azidotributyltin(IV) (0.0996 g, 0.3 mmol) were dissolved in dichlorobenzene (1 mL) and heated to 110° C. for 14 hours. After cooling the reaction mixture was directly purified by silica gel chromatography to afford the title compound.
Reaction SMILES: Cl.CN(C)CCCN=C=NCC.[CH:13]1([N:18]2[C:26]3[C:21](=[CH:22][CH:23]=[C:24]([C:27]([OH:29])=O)[CH:25]=3)[C:20]([CH2:30][CH3:31])=[N:19]2)[CH2:17][CH2:16][CH2:15][CH2:14]1.Cl.[CH3:33][O:34][C:35](=[O:38])[CH2:36][NH2:37].O.ON1C2C=CC=CC=2N=N1.C(N(CC)CC)C>C(Cl)Cl.C(OCC)(=O)C>[CH3:33][O:34][C:35](=[O:38])[CH2:36][NH:37][C:27]([C:24]1[CH:25]=[C:26]2[C:21]([C:20]([CH2:30][CH3:31])=[N:19][N:18]2[CH:13]2[CH2:14][CH2:15][CH2:16][CH2:17]2)=[CH:22][CH:23]=1)=[O:29]
Reactant: CCc1nn(C2CCCC2)c2cc(C(=O)O)ccc12
Reactant: COC(=O)CN
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: CCc1nn(C2CCCC2)c2cc(C(=O)NCC(=O)OC)ccc12
Reaction time: 18 h

Procedure:
134 mg (0.697 mmol, 1.0 equiv) 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride were added in one portion to a room temperature solution of 180 mg (0.697 mmol, 1.0 equiv) 1-cyclopentyl-3-ethyl-1H-indazole-6-carboxylic acid, 87.5 mg (0.697 mmol, 1.0 equiv) glycine methyl ester hydrochloride, 107 mg (0.697 mmol, 1.0 equiv) 1-hydroxybenzotriazole hydrate, and 194 μL (1.39 mmol, 2.0 equiv) triethylamine in 5 mL CH2Cl2. After 18 h, the reaction mixture was diluted with 150 mL ethyl acetate, washed 1×25 mL each 1N HCl, H2O, brine, and dried over Na2SO4. The crude product was purified on a silica gel column (40% ethyl acetate/hexanes, flash) to give 187 mg (66%) of a white waxy solid: mp 89-93° C.; Anal. calcd for C18H23N3O3; C, 65.63; H, 7.04; N, 12.76. Found: C, 65.74; H, 7.02; N, 12.74.
Reaction SMILES: [O:1]=[C:2]1[CH2:10][CH2:9][CH2:8][C:7]2[NH:6][CH:5]=[C:4]([C:11]([OH:13])=O)[C:3]1=2.[CH3:14][O:15][C:16]1[CH:21]=[CH:20][C:19]([NH2:22])=[CH:18][CH:17]=1.Cl.CN(C)CCCN=C=NCC>O1CCOCC1>[CH3:14][O:15][C:16]1[CH:21]=[CH:20][C:19]([NH:22][C:11]([C:4]2[C:3]3[C:2](=[O:1])[CH2:10][CH2:9][CH2:8][C:7]=3[NH:6][CH:5]=2)=[O:13])=[CH:18][CH:17]=1
Reactant: COc1ccc(N)cc1
Reactant: O=C(O)c1c[nH]c2c1C(=O)CCC2
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: C1COCCO1
Product: COc1ccc(NC(=O)c2c[nH]c3c2C(=O)CCC3)cc1
Temperature: 25 °C
Reaction time: 17 h

Procedure:
A mixture of 4-Oxo-4,5,6,7-tetrahydro-1H-indole-3-carboxylic acid (179 mg, 1 mmol), p-anisidine (616 mg. 5 mmol), and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride [EDCI] (959 mg, 5 mmol) in 50% aqueous 1,4-dioxane (10 mL) was stirred at ambient temperature for 17 h. After concentrating in vacuo, the residue was taken up in 10% methanol in ethyl acetate, washed with 1.3M hydrochloric acid then with aqueous sodium bicarbonate, dried over magnesium sulfate, filtered, and concentrated in vacuo. Recrystallization from ethyl acetate afforded N-(4-Methoxyphenyl)-4-oxo-4,5,6,7-tetrahydro-1H-indole-3-carboxamide (Compound 1); mp 219°-220° C.
Reaction SMILES: [Cl:1][C:2]1[CH:25]=[CH:24][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12](/[CH:16]=[C:17]4/[C:18](=[O:23])[NH:19][C:20](=[O:22])[S:21]/4)=[CH:13][CH:14]=3)[CH:9]=[N:8]2)=[C:4]([C:26]([F:29])([F:28])[F:27])[CH:3]=1.Br[CH2:31][C:32]1[CH:33]=[C:34]([CH:39]=[CH:40][CH:41]=1)[C:35]([O:37][CH3:38])=[O:36]>>[CH3:38][O:37][C:35](=[O:36])[C:34]1[CH:39]=[CH:40][CH:41]=[C:32]([CH2:31][N:19]2[C:18](=[O:23])/[C:17](=[CH:16]/[C:12]3[CH:11]=[C:10]4[C:15](=[CH:14][CH:13]=3)[N:7]([CH2:6][C:5]3[CH:24]=[CH:25][C:2]([Cl:1])=[CH:3][C:4]=3[C:26]([F:27])([F:29])[F:28])[N:8]=[CH:9]4)/[S:21][C:20]2=[O:22])[CH:33]=1
Reactant: COC(=O)c1cccc(CBr)c1
Reactant: O=C1NC(=O)/C(=C/c2ccc3c(cnn3Cc3ccc(Cl)cc3C(F)(F)F)c2)S1
Product: COC(=O)c1cccc(CN2C(=O)S/C(=C\c3ccc4c(cnn4Cc4ccc(Cl)cc4C(F)(F)F)c3)C2=O)c1

Procedure:
3-{[(5Z)-5-({1-[4-Chloro-2-(trifluoromethyl)benzyl]-1H-indazol-5-yl}methylidene)-2,4-dioxo-1,3-thiazolidin-3-yl]methyl}benzoic acid methyl ester was prepared from [(5Z)-5-({1-[4-chloro-2-(trifluoromethyl)benzyl]-1H-indazol-5-yl}methylidene)-2,4-dioxo-1,3-thiazolidine (from Example 1) and methyl 3-bromomethylbenzoate following General Procedure S.
Reaction SMILES: O[CH2:2][C:3]#[N:4].[CH2:5]([NH2:11])[CH2:6][CH2:7][CH2:8][CH2:9][CH3:10]>CO>[CH2:5]([NH:11][CH2:2][C:3]#[N:4])[CH2:6][CH2:7][CH2:8][CH2:9][CH3:10]
Reactant: N#CCO
Reactant: CCCCCCN
Solvent: CO
Product: CCCCCCNCC#N
Reaction time: 24 h

Procedure:
In a flask of 100 ml, 5.7 gr of hydroxyacetonitrile (0.1 mol) were mixed with 11 gr of hexylamine (0.11 mol) dissolved in 10 ml of MeOH. The temperature quickly raised during mixing. The solution was allowed to stand for 24 hours. The methanol was evaporated and the obtained liquid was distilled at 72° under 0.8 mm Hg.