Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1Cl)=[CH:13][CH:12]=[CH:11][C:10]=2C)(=[O:5])[CH2:2][CH2:3][CH3:4].[CH3:18][O:19][C:20]1[CH:26]=[CH:25][CH:24]=[CH:23][C:21]=1[NH2:22]>O1CCOCC1>[C:1]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1[NH:22][C:21]1[CH:23]=[CH:24][CH:25]=[CH:26][C:20]=1[O:19][CH3:18])=[CH:13][CH:12]=[CH:11][CH:10]=2)(=[O:5])[CH2:2][CH2:3][CH3:4]
Reactant: CCCC(=O)c1cnc2c(C)cccc2c1Cl
Reactant: COc1ccccc1N
Solvent: C1COCCO1
Product: CCCC(=O)c1cnc2ccccc2c1Nc1ccccc1OC
Yield: 86.8 %

Procedure:
3-Butyryl-4-chloro-8-methylquinoline (2.33 g, 10 mmol), 2-methoxyaniline (1.69 ml, 15 mmol) and dioxan (10 ml) were heated at reflux for 30 minutes, then allowed to cool. The hydrochloride salt was filtered off, converted to free base and recrystallised from ethanol to give 3-butyryl-4-(2-methoxy- phenylamino)quinoline (2.78 g), m.p. 167°-168°.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[N:9]1[C:14]2[N:15]=[C:16](S(C)=O)[N:17]=[C:18]([C:19]3[CH:20]=[C:21]([CH:28]=[CH:29][C:30]=3[CH3:31])[C:22]([NH:24][CH2:25][CH2:26][CH3:27])=[O:23])[C:13]=2[CH2:12][NH:11][C:10]1=[O:35].[CH3:36][CH:37]([NH:39][CH2:40][CH2:41][CH2:42][NH2:43])[CH3:38]>C(Cl)Cl>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[N:9]1[C:14]2[N:15]=[C:16]([NH:43][CH2:42][CH2:41][CH2:40][NH:39][CH:37]([CH3:38])[CH3:36])[N:17]=[C:18]([C:19]3[CH:20]=[C:21]([CH:28]=[CH:29][C:30]=3[CH3:31])[C:22]([NH:24][CH2:25][CH2:26][CH3:27])=[O:23])[C:13]=2[CH2:12][NH:11][C:10]1=[O:35]
Reactant: CCCNC(=O)c1ccc(C)c(-c2nc(S(C)=O)nc3c2CNC(=O)N3c2c(F)cccc2F)c1
Reactant: CC(C)NCCCN
Solvent: ClCCl
Product: CCCNC(=O)c1ccc(C)c(-c2nc(NCCCNC(C)C)nc3c2CNC(=O)N3c2c(F)cccc2F)c1
Yield: 39.3 %

Procedure:
To a solution of compound 3-[8-(2,6-difluorophenyl)-2-(methylsulfinyl)-7-oxo-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-4-yl]-4-methyl-N-propylbenzamide (30 mg, 0.06 mmol) in DCM (5 mL) was added N-(1-methylethyl)-1,3-propanediamine (0.042 mL, 0.30 mmol). The resultant solution was stirred at room temperature over night. The result mixture was concentrated. CombiFlash chromatography (mobile phase DCM/DCM[90]+MeOH[7]+NH4OH[3]) provided the title compound as a white solid (13 mg, 39%). LC-MS m/z 554 (M+H)+; 1H-NMR (MeOD) δ 1.00 (m, 9H), 1.65 (m, 4H), 2.31 (s, 3H), 2.50 (m, 2H), 2.78 (m, 2H), 3.16 (m, 2H), 3.43 (m, 1H), 4.11 (s, 2H), 7.17 (t, 2H), 7.46 (d, 1H), 7.52 (m, 1H), 7.69 (s, 1H), 7.86 (d, 1H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([S:8](Cl)(=[O:10])=[O:9])=[CH:4][C:3]=1[N+:12]([O-:14])=[O:13].[CH2:15]([N:17](CC)CC)C.Cl.CN>C1COCC1.O.O.C(OCC)(=O)C>[F:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:17][CH3:15])(=[O:10])=[O:9])=[CH:4][C:3]=1[N+:12]([O-:14])=[O:13]
Reactant: O=[N+]([O-])c1cc(S(=O)(=O)Cl)ccc1F
Reactant: CCN(CC)CC
Agent: CN
Agent: Cl
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: O
Product: CNS(=O)(=O)c1ccc(F)c([N+](=O)[O-])c1
Temperature: -35 °C
Reaction time: 1 h
Yield: 90.4 %

Procedure:
To a solution of 4-fluoro-3-nitrobenzenesulfonyl chloride (43 g, 179.5 mmol) in THF (500 mL), was added triethylamine (150 mL, 1.08 mol). The mixture was cooled to −35° C. and methylamine hydrochloride (14.5 g, 215.4 mmol) in water was added dropwise. After 1 h, the mixture was warmed to room temperature and diluted with 1:1 water/ethyl acetate. The organic layer was separated and washed with saturated aqueous sodium bicarbonate, then brine, dried over MgSO4, filtered and concentrated in vacuo. The crude residue was purified via column chromatography (20% ethyl acetate/petroleum ether) to give 4-fluoro-N-methyl-3-nitrobenzenesulfonamide (38 g, 90% yield) as a yellow solid.
Reaction SMILES: [Br:1][CH2:2][CH2:3][CH2:4][OH:5].[Br:6][CH:7]([CH3:11])[C:8](Br)=[O:9].C([O-])([O-])=O.[Na+].[Na+]>C1(C)C=CC=CC=1>[Br:1][CH2:2][CH2:3][CH2:4][O:5][C:8](=[O:9])[CH:7]([Br:6])[CH3:11]
Reactant: OCCCBr
Reactant: CC(Br)C(=O)Br
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: CC(Br)C(=O)OCCCBr
Temperature: 25 °C
Reaction time: 6 h
Yield: 96.1 %

Procedure:
3-Bromopropanol (10.75 g, 0.075 mol) is added over 20 minutes to a solution of 2-bromopropionylbromide (17.9 g, 0.079 mol) in toluene (75 ml) while keeping the temperature between 15-20° C. The mixture is stirred for 6 h at room temperature and is then poured under vigorous stirring into 1M solution of Na2CO3 (80 ml). The organic layer is separated, washed with water (3×50 ml), dried over MgSO4 and evaporated to afford 19.75 g of the title compound as a colorless oil.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[NH:11][C:12]([C:23]3[CH:28]=[CH:27][C:26]([N+:29]([O-])=O)=[CH:25][CH:24]=3)=[C:13]([C:15]([NH:17][C:18]3[S:19][CH:20]=[CH:21][N:22]=3)=[O:16])[N:14]=2)=[CH:6][CH:5]=1)([O-])=O.[Sn](Cl)Cl>CO.Cl>[NH2:1][C:4]1[CH:5]=[CH:6][C:7]([C:10]2[NH:11][C:12]([C:23]3[CH:28]=[CH:27][C:26]([NH2:29])=[CH:25][CH:24]=3)=[C:13]([C:15]([NH:17][C:18]3[S:19][CH:20]=[CH:21][N:22]=3)=[O:16])[N:14]=2)=[CH:8][CH:9]=1
Reactant: O=C(Nc1nccs1)c1nc(-c2ccc([N+](=O)[O-])cc2)[nH]c1-c1ccc([N+](=O)[O-])cc1
Agent: Cl
Agent: Cl[Sn]Cl
Solvent: CO
Product: Nc1ccc(-c2nc(C(=O)Nc3nccs3)c(-c3ccc(N)cc3)[nH]2)cc1

Procedure:
2,5-bis(4-Nitrophenyl)-N-(2-thiazolyl)imidazole-4-carboxamide obtained in Example 53 is suspended in methanol and ice-cooled. To the suspension is added a solution of tin(II) chloride 6 hydrate in 6 M hydrochloric acid solution and the mixture is reacted and treated in the same manner as in Example 48 to give 2,5-bis(4-aminophenyl)-N-(2-thiazolyl)imidazole-4-carboxamide.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6](Cl)[N:5]=[C:4]([NH:9][C@H:10]([C:12]2[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=2)[CH3:11])[CH:3]=1.[NH2:19][C:20]1[CH:25]=[N:24][CH:23]=[CH:22][N:21]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>O1CCOCC1>[Cl:1][C:2]1[CH:7]=[C:6]([NH:19][C:20]2[CH:25]=[N:24][CH:23]=[CH:22][N:21]=2)[N:5]=[C:4]([NH:9][C@H:10]([C:12]2[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=2)[CH3:11])[CH:3]=1
Reactant: Nc1cnccn1
Reactant: C[C@H](Nc1cc(Cl)cc(Cl)n1)c1ccc(F)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Product: C[C@H](Nc1cc(Cl)cc(Nc2cnccn2)n1)c1ccc(F)cc1
Temperature: 100 °C
Reaction time: 19 h
Yield: 73.9 %

Procedure:
To 734 mg of (S)-4,6-dichloro-N-[1-(4-fluorophenyl)ethyl]pyridine-2-amine, 343 mg of 2-aminopyrazine, 1.39 g of tripotassium phosphate, 190 mg of 4,5-bis(diphenylphosphino)-9,9′-dimethylxanthene and 170 mg of tris(dibenzylideneacetone)(chloroform)dipalladium was added 17 ml of 1,4-dioxane, the mixture was subjected to degassing and was substituted with argon, and was stirred at 100° C. for 19 hours. The reaction solution was diluted with ethyl acetate. The solution was washed in turn with water and brine and then dried over magnesium sulfate. The solvent was distilled off under reduced pressure, and then the obtained residue was purified by silica gel column chromatography to obtain 654 mg of the objective compound as brown powder.
Reaction SMILES: [CH2:1]([O:3][P:4]([CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([CH2:16][C:17]#[N:18])[CH:11]=1)(=[O:8])[O:5][CH2:6][CH3:7])[CH3:2]>N.[Ni]>[CH2:6]([O:5][P:4]([CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([CH2:16][CH2:17][NH2:18])[CH:11]=1)(=[O:8])[O:3][CH2:1][CH3:2])[CH3:7]
Reactant: CCOP(=O)(Cc1cccc(CC#N)c1)OCC
Agent: [Ni]
Agent: N
Product: CCOP(=O)(Cc1cccc(CCN)c1)OCC

Procedure:
A solution of diethyl[[3-(cyanomethyl)phenyl]methyl]phosphonate in methanolic ammonia is reduced under a hydrogen atmosphere (50 psi) with Raney nickel as catalyst. The solvent is evaporated to give an oil (4.1 g).
Reaction SMILES: [CH:1]([N:4]1[CH2:9][CH2:8][N:7]([C:10]([C:12]2[CH:19]=[CH:18][C:15]([CH:16]=[O:17])=[CH:14][CH:13]=2)=O)[CH2:6][CH2:5]1)([CH3:3])[CH3:2].Cl.Cl.[CH:22]([N:25]1[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]1)([CH3:24])[CH3:23]>>[CH:22]([N:25]1[CH2:30][CH2:29][N:28]([C:16]([C:15]2[CH:18]=[CH:19][C:12]([CH2:10][N:7]3[CH2:8][CH2:9][N:4]([CH:1]([CH3:3])[CH3:2])[CH2:5][CH2:6]3)=[CH:13][CH:14]=2)=[O:17])[CH2:27][CH2:26]1)([CH3:24])[CH3:23]
Reactant: CC(C)N1CCNCC1
Reactant: CC(C)N1CCN(C(=O)c2ccc(C=O)cc2)CC1
Agent: Cl
Product: CC(C)N1CCN(Cc2ccc(C(=O)N3CCN(C(C)C)CC3)cc2)CC1

Procedure:
Prepared from the product of Example 15 and the product of Example 10.
Reaction SMILES: CON(C)[C:4]([C@H:6]1[CH2:11][CH2:10][C@@H:9]([C:12]2([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=3)[O:16][CH2:15][CH2:14][O:13]2)[CH2:8][CH2:7]1)=[O:5].[Br-].O.Cl>O1CCCC1>[Cl:23][C:20]1[CH:19]=[CH:18][C:17]([C:12]2([C@@H:9]3[CH2:8][CH2:7][C@H:6]([C:4](=[O:5])[CH2:8][CH2:7][CH:6]=[CH2:4])[CH2:11][CH2:10]3)[O:13][CH2:14][CH2:15][O:16]2)=[CH:22][CH:21]=1
Reactant: CON(C)C(=O)[C@H]1CC[C@@H](C2(c3ccc(Cl)cc3)OCCO2)CC1
Agent: Cl
Agent: [Br-]
Solvent: C1CCOC1
Solvent: O
Product: C=CCCC(=O)[C@H]1CC[C@@H](C2(c3ccc(Cl)cc3)OCCO2)CC1
Temperature: 0 °C
Reaction time: 1 h
Yield: 168.3 %

Procedure:
While under a nitrogen atmosphere, a solution of cis-4-[2-(4-chlorophenyl)-[1,3]-dioxolan-2-yl]-cyclohexanecarboxylic acid, methoxy-methyl amide (1.36 g, 3.85 mmol), in tetrahydrofuran (10 mL) was cooled to 0° C. and treated with 4-butenylmagnesiun bromide (0.5 M in THF, 19.24 mL, 9.62 mmol) in a dropwise manner. The solution was stirred for 1 hour at 0° C. then allowed to warm to room temperature overnight. The resulting solution was poured into water, acidified to pH 3-4 with 1 N hydrochloric acid, and extracted with ethyl acetate (3×). The combined organic phase was washed with saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo. Purification by flash column chromatography (silica gel, 0-25% ethyl acetate in heptane) gave cis-1-{4-[2-(4-chlorophenyl)-[1,3]-dioxolan-2-yl]-cyclohexyl}pent-4-en-1-one as a colorless oil (1.13 g, 84%); 1H NMR (CDCl3, 300 MHz) δ 7.31 (d, J=7.5 Hz, 2H), 7.27 (d, J=7.5 Hz, 2H), 5.78 (m, 1H), 4.96 (m, 2H), 3.94 (m, 2H), 3.68 (m, 2H), 2.50 (m, 3H), 2.30 (m, 2H), 2.15 (dd, J=13, 3 Hz, 2H), 1.76 (tt, J=11, 3 Hz, 1H), 1.36-1.56 (m, 4H) and 1.25 (td, J=13, 3 Hz, 2H); MS (+CI): m/z for C20H25ClO3: expected 348.2. found 349.2 (M+H)+.
Reaction SMILES: Cl[C:2]1[C:3]([F:22])=[CH:4][C:5]2[C:6]([CH:21]=1)=[N:7][C:8]1[N:9]([NH:19][CH3:20])[CH:10]=[C:11]([C:16]([OH:18])=[O:17])[C:12](=[O:15])[C:13]=1[CH:14]=2.[NH:23]1[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]1>N1C=CC=CC=1>[F:22][C:3]1[C:2]([N:23]2[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]2)=[CH:21][C:6]2=[N:7][C:8]3[N:9]([NH:19][CH3:20])[CH:10]=[C:11]([C:16]([OH:18])=[O:17])[C:12](=[O:15])[C:13]=3[CH:14]=[C:5]2[CH:4]=1
Reactant: CNn1cc(C(=O)O)c(=O)c2cc3cc(F)c(Cl)cc3nc21
Reactant: C1CNCCN1
Solvent: c1ccncc1
Product: CNn1cc(C(=O)O)c(=O)c2cc3cc(F)c(N4CCNCC4)cc3nc21
Yield: 31.6 %

Procedure:
7-Fluoro-1-methylamino-4-oxo-8-(1-piperazinyl)-1,4-dihydro-benzo[b][1,8]naphthyridine-3-carboxylic acid is prepared under the conditions of Reference Example 5 but starting from 2.25 g of 8-chloro-7-fluoro-1-methylamino-4-oxo-1,4-dihydro-benzo[b][1,8]-naphthyridine-3-carboxylic acid and 2.4 g of piperazine in 30 cm3 of pyridine. After recrystallizing 3 times from, in total, 400 cm3 of dimethylformamide, 0.82 g of 7-fluoro-1-methylamino-4-oxo-8-(1-piperazinyl)-1,4-dihydro-benzo[b][1,8]naphthyridine-3-carboxylic acid is obtained in the form of a deep yellow solid melting at 322°-324° C., solvated by 13.6% of dimethylformamide.
Reaction SMILES: [NH2:1][CH2:2][C:3]([OH:5])=[O:4].C(N(CC)CC)C.O1CCOCC1.[CH3:19][C@@H:20]([C@@H:27]1[C@@:31]2([CH3:49])[CH2:32][CH2:33][CH:34]3[C@@:39]4([CH3:48])[CH2:40][CH2:41][CH:42]([O:44][C:45](Cl)=[O:46])[CH2:43][C:38]4=[CH:37][CH2:36][CH:35]3[CH:30]2[CH2:29][CH2:28]1)[CH2:21][CH2:22][CH2:23][CH:24]([CH3:26])[CH3:25]>O>[CH3:26][CH:24]([CH2:23][CH2:22][CH2:21][C@H:20]([C@@H:27]1[C@:31]2([CH3:49])[C@H:30]([C@H:35]3[C@H:34]([CH2:33][CH2:32]2)[C@:39]2([CH3:48])[C:38]([CH2:43][C@@H:42]([O:44][C:45]([NH:1][CH2:2][C:3]([OH:5])=[O:4])=[O:46])[CH2:41][CH2:40]2)=[CH:37][CH2:36]3)[CH2:29][CH2:28]1)[CH3:19])[CH3:25]
Reactant: CC(C)CCC[C@@H](C)[C@H]1CCC2C3CC=C4CC(OC(=O)Cl)CC[C@]4(C)C3CC[C@@]21C
Reactant: NCC(=O)O
Solvent: O
Solvent: CCN(CC)CC
Solvent: C1COCCO1
Product: CC(C)CCC[C@@H](C)[C@H]1CC[C@H]2[C@@H]3CC=C4C[C@@H](OC(=O)NCC(=O)O)CC[C@]4(C)[C@H]3CC[C@]12C
Reaction time: 3 h
Yield: 68.1 %

Procedure:
To a suspension of glycine (1.50 g) in water (100 ml) was added triethylamine (4.04 g). After dioxan (200 ml) and cholesteryl chloroformate (8.98 g) were added to the resulting clear solution at 0° C., the mixture was stirred for 3 hours. The reaction mixture was concentrated under reduced pressure and, 1 N hydrochloric acid (23 ml) and chloroform (100 ml) were added to the residue. The organic phase was separated and washed with water and then dried over magnesium sulfate. The solvent was distilled off to give crude crystals. After washing with ethanol, the crystals were filtered to give N-(cholest-5-ene-3β-oxycarbonyl)glycine (6.64 g) as white crystals.
Reaction SMILES: COC1C=CC(C[N:8]2[C:13]3[NH:14][N:15]=[C:16]([NH:17][C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)[C:12]=3[C:11](=[O:24])[N:10]([CH3:25])[C:9]2=[O:26])=CC=1.C(O)(C(F)(F)F)=O.FC(F)(F)S(O)(=O)=O>C(Cl)Cl>[CH3:25][N:10]1[C:11](=[O:24])[C:12]2[C:16]([NH:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[N:15][NH:14][C:13]=2[NH:8][C:9]1=[O:26]
Reactant: COc1ccc(Cn2c(=O)n(C)c(=O)c3c(Nc4ccccc4)n[nH]c32)cc1
Agent: O=S(=O)(O)C(F)(F)F
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cn1c(=O)[nH]c2[nH]nc(Nc3ccccc3)c2c1=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 95.5 %

Procedure:
To a solution of 7-(4-Methoxybenzyl)-5-methyl-3-(phenylamino)-1H-pyrazolo[3,4-d]pyrimidine-4,6(5H,7H)-dione (6.6 g, 17.5 mmol) in CH2Cl2 (200 mL) added TFA (30 mL) slowly at room temperature, followed by adding trifluoromethanesulfonic acid (10 mL) dropwise. After the reaction mixture is stirred at r.t. for 2 hours, solvent is removed under reduced pressure, and then 200 mL of 1N NaOH is added with cooling. The mixture is extracted with ethyl acetate five times, dried over Na2SO4, and then filtered. The filtrate is evaporated to dryness to give 4.3 g of crude product as white solids (Yield: 96%). MS (ESI) m/z 258.1 [M+H]+.
Reaction SMILES: P([O-])([O-])([O-])=O.[C:6](=[O:9])([O-])[O-].[Ca+2].[Cl:11][CH2:12][CH:13]([OH:17])[CH2:14][CH2:15][OH:16]>>[Cl:11][CH2:12][CH:13]([OH:17])[CH2:14][CH2:15][OH:16].[CH2:6]([OH:9])[CH:13]([OH:17])[CH2:14][CH2:15][OH:16]
Reactant: O=C([O-])[O-]
Agent: O=P([O-])([O-])[O-]
Agent: OCCC(O)CCl
Agent: [Ca+2]
Product: OCCC(O)CO
Reaction time: 24 h

Procedure:
A nutrient medium (100 ml, pH 7.2) consisting of polypeptone (1.0%), yeast extract (1.0%) and glycerin (1.0%) were poured into an Erlenmeyer flask (500 ml) with a baffle and the flask was sterilized at 121° C. for 15 minuets. Previously, Pseudomonas sp. DS-K-436-1 were made stationary incubation in the agar medium (pH 7.2) containing polypeptone (1.0%), yeast extract (1.0%) and glycerin (1.0%) at 30° C. for 24 hours to prepare seed strains and a loopful of the strains was seeded to the above medium. The culture medium was cultivated with agitation (125 rpm) at 30° C. for 24 hours. After the cultivation, the culture broth was taken out, the cells were collected by centrifugation and washed three times by phosphate buffer (20 m M, pH 7.2) containing magnesium sulfate (2 mM) to prepare resting cells. The cells were suspended in the phosphate buffer containing 1.0% of calcium carbonate in an Erlenmeyer flask (500 ml) equipped with a baffle. To the suspension was added 1 ml of racemic 4-chloro-1,3-butanediol and the mixture was reacted at 30° C. under stirring. At that time the remaining amount of racemic 4-chloro-1,3-butanediol was measured with gas chromatography (column support: PEG20M, 60-80 mesh) to be 35% in the remaining ratio. After the reaction, the reaction mixture was concentrated to about 1 ml and extracted with ethanol. The extract was dried over magnesium sulfate and the solvent was removed in vacuo to give 368 mg of 4-chloro-1,3-butanediol and 590 mg of 1,2,4-butanetriol. The identification and determination of these compounds was made by subjecting to the above gas chromatography and GC-MS.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[NH:7]1[C:15]2[C:10](=[CH:11][CH:12]=[C:13]3[CH2:19][CH2:18][CH2:17][CH2:16][C:14]3=2)[C:9](=O)[C:8]1=O.O.[OH-].[Na+]>O1CCCC1>[NH:7]1[C:15]2[C:10](=[CH:11][CH:12]=[C:13]3[CH2:19][CH2:18][CH2:17][CH2:16][C:14]3=2)[CH:9]=[CH:8]1
Reactant: O=C1Nc2c(ccc3c2CCCC3)C1=O
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: c1cc2ccc3c(c2[nH]1)CCCC3
Temperature: 0 °C
Reaction time: 1 h
Yield: 61.5 %

Procedure:
To a suspension of lithium aluminium hydride (2.85 g, 75.0 mmol) in dry tetrahydrofuran (150 mL) was added 6,7,8,9-tetrahydro-1H-benz[g]indole-2,3-dione (3.018 g, 15.0 mmol) portionwise over 30 min. The green suspension was heated under reflux for 18 h and then cooled to 0° C. The suspension was treated with water (2.8 mL), 5 N aqueous sodium hydroxide (2.1 mL), and water (9.2 mL), and was stirred for an additional 1 h. The suspension was then filtered, the residue was washed with tetrahydrofuran. and the filtrate then concentrated in vacuo. The residue obtained was purified by column chromatography [SiO2; ethyl acetate-heptane (1:19)] and triturated with hexane to give the title indole (1.58 g, 62%) as a white solid: mp. 93–94° C. (lit. [Khim. Geterotsikl. Soedin., 1978, 14, 634) 89–90° C.); Found: C, 84.25; H, 7.65; N, 8.16%. C12H13N requires C, 84.17; H, 7.65; N, 8.18%.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[N:6][C:7]2[C:12]([C:13]=1[NH:14][CH2:15][C:16]1([OH:22])[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1)=[CH:11][CH:10]=[CH:9][CH:8]=2)([O-])=O>[Pt].C(OCC)(=O)C>[NH2:1][C:4]1[CH:5]=[N:6][C:7]2[C:12]([C:13]=1[NH:14][CH2:15][C:16]1([OH:22])[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1)=[CH:11][CH:10]=[CH:9][CH:8]=2
Reactant: O=[N+]([O-])c1cnc2ccccc2c1NCC1(O)CCCCC1
Agent: [Pt]
Solvent: CCOC(C)=O
Product: Nc1cnc2ccccc2c1NCC1(O)CCCCC1

Procedure:
A mixture of 1-[(3-nitroquinolin-4-ylamino)methyl]cyclohexanol (10.0 g, 33.2 mmol), 5% platinum on carbon (1.0 g), and ethyl acetate (140 mL) was placed under hydrogen pressure (40 psi, 2.8×105 Pa) for 2.5 hours. The reaction mixture was filtered through a layer of CELITE filter aid and the filter cake was rinsed with ethyl acetate (100 mL). The filtrate was concentrated under reduced pressure to provide 1-[(3-aminoquinolin-4-ylamino)methyl]cyclohexanol as an orange gooey solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:7]=[CH:8][C:9]=1[N:10]1[CH:14]=[C:13]([CH3:15])[N:12]=[CH:11]1)[NH2:6].Cl[C:17]1[N:22]=[C:21]([NH:23][CH:24]2[CH2:26][CH2:25]2)[CH:20]=[C:19]([CH2:27][O:28][CH2:29][C:30]([F:33])([F:32])[F:31])[N:18]=1.C(=O)([O-])[O-].[Cs+].[Cs+].C1(P(C2CCCCC2)C2C=CC=CC=2C2C=CC=CC=2)CCCCC1>O1CCOCC1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH:24]1([NH:23][C:21]2[CH:20]=[C:19]([CH2:27][O:28][CH2:29][C:30]([F:32])([F:33])[F:31])[N:18]=[C:17]([NH:6][C:5]3[CH:7]=[CH:8][C:9]([N:10]4[CH:14]=[C:13]([CH3:15])[N:12]=[CH:11]4)=[C:3]([O:2][CH3:1])[CH:4]=3)[N:22]=2)[CH2:26][CH2:25]1
Reactant: COc1cc(N)ccc1-n1cnc(C)c1
Reactant: FC(F)(F)COCc1cc(NC2CC2)nc(Cl)n1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Product: COc1cc(Nc2nc(COCC(F)(F)F)cc(NC3CC3)n2)ccc1-n1cnc(C)c1
Temperature: 120 °C

Procedure:
A mixture of 3-methoxy-4-(4-methyl-1H-imidazol-1-yl)aniline (91 mg, 0.45 mmol), 2-chloro-N-cyclopropyl-6-((2,2,2-trifluoroethoxy)methyl)pyrimidin-4-amine (63 mg, 0.22 mmol), cesium carbonate (146 mg, 0.45 mmol), palladium(II) acetate (8 mg, 0.03 mmol) and 2-(dicyclohexyl-phosphino)biphenyl (12 mg, 0.03 mmol) in dioxane (1.5 mL) was heated at 120° C. in a microwave reactor for 90 minutes. The mixture was filtered through diatomeous earth, the filter pad was eluted with methanol. The eluate was concentrated in vacuum and the residue purified by preparative chromatography to give the title compound as a solid, 45 mg (45%).
Reaction SMILES: [Cl:1][C:2]1[CH:15]=[C:14]([F:16])[C:13]([N:17]2[C:22](=[O:23])[CH:21]=[C:20]([C:24]([F:27])([F:26])[F:25])[N:19]([CH3:28])[C:18]2=[O:29])=[CH:12][C:3]=1[O:4][C:5]1[C:10]([OH:11])=[CH:9][CH:8]=[CH:7][N:6]=1.Br[CH:31]([CH3:36])[C:32]([O:34][CH3:35])=[O:33].C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[Cl:1][C:2]1[CH:15]=[C:14]([F:16])[C:13]([N:17]2[C:22](=[O:23])[CH:21]=[C:20]([C:24]([F:27])([F:26])[F:25])[N:19]([CH3:28])[C:18]2=[O:29])=[CH:12][C:3]=1[O:4][C:5]1[C:10]([O:11][CH:31]([C:32]([O:34][CH3:35])=[O:33])[CH3:36])=[CH:9][CH:8]=[CH:7][N:6]=1
Reactant: Cn1c(C(F)(F)F)cc(=O)n(-c2cc(Oc3ncccc3O)c(Cl)cc2F)c1=O
Reactant: COC(=O)C(C)Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: COC(=O)C(C)Oc1cccnc1Oc1cc(-n2c(=O)cc(C(F)(F)F)n(C)c2=O)c(F)cc1Cl
Temperature: 60 °C
Reaction time: 2 h
Yield: 32.1 %

Procedure:
200 mg of 2-{2-chloro-4-fluoro-5-[3-methyl-2,6-dioxo-4-(trifluoromethyl)-1,2,3,6-tetrahydropyrimidin-1-yl]phenoxy}-3-hydroxypyridine and 80 mg of methyl 2-bromopropionate were dissolved in acetonitrile, to this was added 66 mg of potassium carbonate, and the mixture was stirred for 2 hours at 60° C. This reaction solution was poured into ice water, and extracted with ethyl acetate. The organic layer was washed with saturated saline, dried over anhydrous magnesium sulfate, and concentrated. The residue was subjected to silica gel column chromatography to obtain 77 mg of 2-{2-chloro-4-fluoro-5-[3-methyl-2,6-dioxo-4-(trifluoromethyl)-1,2,3,6-tetrahydropyrimidin-1-yl]phenoxy}-3-{1-(methoxycarbonyl)ethoxy}pyridine [present compound 2-2].
Reaction SMILES: [OH:1][CH:2]1[CH2:6][CH2:5][N:4]([C:7]([C:9]2[CH:14]=[C:13]([S:15]([CH3:18])(=[O:17])=[O:16])[CH:12]=[CH:11][C:10]=2[O:19][CH:20]([CH3:22])[CH3:21])=[O:8])[CH2:3]1.[F:23][C:24]1[CH:25]=[C:26](O)[CH:27]=[C:28]([C:30]([F:33])([F:32])[F:31])[CH:29]=1>>[F:23][C:24]1[CH:25]=[C:26]([CH:27]=[C:28]([C:30]([F:31])([F:32])[F:33])[CH:29]=1)[O:1][CH:2]1[CH2:6][CH2:5][N:4]([C:7]([C:9]2[CH:14]=[C:13]([S:15]([CH3:18])(=[O:17])=[O:16])[CH:12]=[CH:11][C:10]=2[O:19][CH:20]([CH3:22])[CH3:21])=[O:8])[CH2:3]1
Reactant: CC(C)Oc1ccc(S(C)(=O)=O)cc1C(=O)N1CCC(O)C1
Reactant: Oc1cc(F)cc(C(F)(F)F)c1
Product: CC(C)Oc1ccc(S(C)(=O)=O)cc1C(=O)N1CCC(Oc2cc(F)cc(C(F)(F)F)c2)C1
Yield: 45 %

Procedure:
Prepared in analogy to Example 4 from rac-(3-hydroxy-pyrrolidin-1-yl)-(2-isopropoxy-5-methanesulfonyl-phenyl)-methanone (Example 9(a)) and 3-fluoro-5-(trifluoromethyl)phenol. The crude material was purified by reversed phase HPLC (acetonitrile/water) to yield the title compound as an amorphous white solid (yield 45%). MS (m/e): 490.1 (M+H+, 100%).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([F:12])=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8].[F:13][C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([F:20])[C:15]=1[S:21](Cl)(=[O:23])=[O:22]>>[F:13][C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([F:20])[C:15]=1[S:21]([NH:1][C:2]1[CH:3]=[CH:4][C:5]([F:12])=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8])(=[O:23])=[O:22]
Reactant: O=S(=O)(Cl)c1c(F)cccc1F
Reactant: COC(=O)c1cc(N)ccc1F
Product: COC(=O)c1cc(NS(=O)(=O)c2c(F)cccc2F)ccc1F
Yield: 100 %

Procedure:
Following a procedure analogous to the procedure described in Example 5, Step A using methyl 5-amino-2-fluorobenzoate (10 g, 59.2 mmol) and 2,6-difluorobenzene-1-sulfonyl chloride (13.2 g, 62.2 mmol) the title compound of Step B was obtained (21 g, 100% yield). 1H NMR (400 MHz, CDCl3) δ ppm 7.58-7.60 (m, 1H), 7.38-7.48 (m, 2H), 7.10-7.15 (br, 1H), 6.89-6.97 (m, 2H), 6.97-7.06 (m, 1H), 3.85 (s, 3H).