Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH2:11][CH2:10][C@@H:9]1[CH2:14][O:15][C:16]1[C:25]2[C:24]([NH2:26])=[N:23][S:22](=[O:28])(=[O:27])[NH:21][C:20]=2[CH:19]=[CH:18][CH:17]=1)=O)(C)(C)C.[ClH:29]>C(O)C>[ClH:29].[NH2:26][C:24]1[C:25]2[C:16]([O:15][CH2:14][C@H:9]3[CH2:10][CH2:11][CH2:12][CH2:13][NH2+:8]3)=[CH:17][CH:18]=[CH:19][C:20]=2[NH:21][S:22](=[O:27])(=[O:28])[N:23]=1
Reactant: CC(C)(C)OC(=O)N1CCCC[C@@H]1COc1cccc2c1C(N)=NS(=O)(=O)N2
Agent: Cl
Solvent: CCO
Product: NC1=NS(=O)(=O)Nc2cccc(OC[C@H]3CCCC[NH2+]3)c21
Temperature: 60 °C
Reaction time: 4 h
Yield: 85 %

Procedure:
To a solution of (R)-tert-butyl-2-(((4-amino-2,2-dioxido-1H-benzo[c][1,2,6]thiadiazin-5-yl)oxy)methyl)piperidine-1-carboxylate (Example 15b, 10.7 g, 26.1 mmol) in ethanol (175 mL) was added HCl in ethanol (104 mL, 2.5M, 261 mmol). The reaction stirred at 60° C. under nitrogen for 4 hours. The compound was collected by filtration as an off white solid (7.70 g. 85% yield for three steps). 1H NMR (400 MHz, DMSO-d6) δ 1.03-1.90 (br m, 6H), 2.89 (br t, J=2.8 Hz, 1H), 3.27 (br m, 1H), 3.61 (br m, 1H), 4.27-4.40 (br m, 2H), 6.67 (d, J=7.6 Hz, 1H), 6.80 (d, J=8.8 Hz, 1H), 7.46 (t, J=8.0 Hz, 1H), 7.79 (br s, 1H), 8.35 (br s, 1H), 9.26 (br s, 2H), 10.97 (br s, 1H). MS 311 (MH+).
Reaction SMILES: C([NH:5][C:6]1[C:11]([C:12]2[N:16]([C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([F:23])[C:18]=3[F:24])[N:15]=[N:14][N:13]=2)=[CH:10][CH:9]=[CH:8][N:7]=1)(C)(C)C.Cl.[OH-].[Na+]>CO>[F:24][C:18]1[C:19]([F:23])=[CH:20][CH:21]=[CH:22][C:17]=1[N:16]1[C:12]([C:11]2[C:6]([NH2:5])=[N:7][CH:8]=[CH:9][CH:10]=2)=[N:13][N:14]=[N:15]1
Reactant: CC(C)(C)Nc1ncccc1-c1nnnn1-c1cccc(F)c1F
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: Nc1ncccc1-c1nnnn1-c1cccc(F)c1F

Procedure:
Crude N-tert-butyl-3-(1-(2,3-difluorophenyl)-1H-tetrazol-5-yl)pyridin-2-amine was dissolved in MeOH (10 mL), treated with 6N HCl (20 mL), and heated to reflux for 2 hours. The mixture was subsequently cooled to RT and neutralized with 6N NaOH. The resulting precipitate was collected, washed with water, and dried in vacuo to give 3-(1-(2,3-difluorophenyl)-1H-tetrazol-5-yl)pyridin-2-amine as white solid. Using the same procedure, 3-(1-(2,3-dichlorophenyl)-1H-tetrazol-5-yl)pyridin-2-amine and 3-(1-(3-chloro-2-fluorophenyl)-1H-tetrazol-5-yl)pyridin-2-amine can be produced from N-tert-butyl-3-(1-(2,3-dichlorophenyl)-1H-tetrazol-5-yl)pyridin-2-amine and N-tert-butyl-3-(1-(3-chloro-2-fluorophenyl)-1H-tetrazol-5-yl)pyridin-2-amine, respectively.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7](F)=[CH:6][C:5]=1[N+:11]([O-:13])=[O:12])([O-:3])=[O:2].[CH3:14][O:15][C:16]([C:18]1[N:19]=[CH:20][NH:21][CH:22]=1)=[O:17].[H-].[Na+].Cl>C1COCC1.C1(C)C=CC=CC=1>[CH3:14][O:15][C:16]([C:18]1[N:19]=[CH:20][N:21]([C:7]2[CH:8]=[CH:9][C:4]([N+:1]([O-:3])=[O:2])=[C:5]([N+:11]([O-:13])=[O:12])[CH:6]=2)[CH:22]=1)=[O:17]
Reactant: COC(=O)c1c[nH]cn1
Reactant: O=[N+]([O-])c1ccc(F)cc1[N+](=O)[O-]
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: COC(=O)c1cn(-c2ccc([N+](=O)[O-])c([N+](=O)[O-])c2)cn1
Temperature: 0 °C
Reaction time: 3 h

Procedure:
To a stirred, 0° C. solution of 1,2-dinitro-4-fluorobenzene (325 mg, 1.74 mmole) and methyl-4-imidazolecarboxylate (200 mg, 1.59 mmole) in THF (5 mL) was added NaH (70 mg, 1.74 mmole) in one portion. The resulting mixture was stirred at 0° C. for 3 hours, then diluted with toluene and acidified with 6N HCl. The phases were separated and the aqueous phase washed with toluene, cooled to 0° C., and basified with conc. NH4OH. Ethyl acetate was added and the resulting mixture stirred until all solids dissolved. Phases separated, organic phase washed with brine, dried over Na2SO4, filtered, concentrated in vacuo. The mixture of regioisomers were separated and purified via flash chromatography (silica gel, 5%-->20% ethanol/ethyl acetate gradient) to fford the desired adduct 19 (225 mg, 48%) as an off-white solid. 1H NMR (500 MHz, dmso d6): 8.41 (1H, d); 8.13 (1H, d); 7.5(1H, broad s); 7.28 (1H, s); 7.02 (1H, d); 3.80 (3H, s)
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[N:5]2[C:10]=1[CH:9]=[N:8][C:7](SC)=[N:6]2.CC1N=C(C2C=CC=CC=2)N2C=1C=NC(S(C)(=O)=O)=N2.[CH3:39][O:40][C:41]1[CH:46]=[CH:45][C:44]([NH2:47])=[CH:43][CH:42]=1.C1(C)C=CC(S(O)(=O)=O)=CC=1>O1CCCC1>[CH3:1][C:2]1[N:3]=[C:4]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[N:5]2[C:10]=1[CH:9]=[N:8][C:7]([NH:47][C:44]1[CH:45]=[CH:46][C:41]([O:40][CH3:39])=[CH:42][CH:43]=1)=[N:6]2
Reactant: COc1ccc(N)cc1
Reactant: CSc1ncc2c(C)nc(-c3ccccc3)n2n1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: Cc1nc(-c2ccccc2)n2nc(S(C)(=O)=O)ncc12
Solvent: C1CCOC1
Product: COc1ccc(Nc2ncc3c(C)nc(-c4ccccc4)n3n2)cc1
Yield: 23.2 %

Procedure:
A mixture of 5-methyl-2-(methylthio)-7-phenylimidazo[5,1-f][1,2,4]triazine (Intermediate 72) (75 mg, 0.26 mmol), p-anisidine (32 mg, 0.26 mmol) and p-toluenesulfonic acid (5 mg, 0.03 mmol) in tetrahydrofuran (5 mL) was stirred at reflux overnight. The mixture was then reduced under vacuum, and purified by chromatography on silica gel eluting with 40% ethyl acetate in petrol to give a solid which was purified further by trituration with diethyl ether to afford 5-methyl-N-[4-(methyloxy)phenyl]-7-phenylimidazo[5,1-f][1,2,4]triazin-2-amine (20 mg) as a yellow solid. MS m/z 332 (M+1).
Reaction SMILES: [C:1]([CH2:3][NH:4][C:5]([C:7]1[S:8][C:9]([CH:12]([S:17][C:18]2[CH:23]=[C:22]([CH3:24])[C:21]([C:25]3[CH:30]=[CH:29][C:28]([C:31]([CH3:34])([CH3:33])[CH3:32])=[CH:27][CH:26]=3)=[C:20]([CH3:35])[CH:19]=2)[C:13]([CH3:16])([CH3:15])[CH3:14])=[CH:10][CH:11]=1)=[O:6])#[N:2].Cl.C(N(CC)CC)C.[N-:44]=[N+:45]=[N-:46].[Na+].N#N>C1(C)C=CC=CC=1>[N:2]1[NH:44][N:45]=[N:46][C:1]=1[CH2:3][NH:4][C:5]([C:7]1[S:8][C:9]([CH:12]([S:17][C:18]2[CH:23]=[C:22]([CH3:24])[C:21]([C:25]3[CH:30]=[CH:29][C:28]([C:31]([CH3:34])([CH3:33])[CH3:32])=[CH:27][CH:26]=3)=[C:20]([CH3:35])[CH:19]=2)[C:13]([CH3:14])([CH3:15])[CH3:16])=[CH:10][CH:11]=1)=[O:6]
Reactant: [N-]=[N+]=[N-]
Reactant: Cc1cc(SC(c2ccc(C(=O)NCC#N)s2)C(C)(C)C)cc(C)c1-c1ccc(C(C)(C)C)cc1
Agent: Cl
Agent: N#N
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: Cc1cc(SC(c2ccc(C(=O)NCc3nn[nH]n3)s2)C(C)(C)C)cc(C)c1-c1ccc(C(C)(C)C)cc1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 44 %

Procedure:
A solution of 5-[1-(4′-tert-Butyl-2,6-dimethyl-biphenyl-4-ylsulfanyl)-2,2-dimethyl-propyl]-thiophene-2-carboxylic acid cyanomethyl-amide (Isomer 1) (220 mg, 0.436 mmol) in toluene (8.7 mL) is treated with triethylamine hydrochloride (300 mg, 2.18 mmol) and sodium azide (142 mg, 2.18 mmol), then heated at reflux overnight (thermal conditions) or alternatively, placed in a CEM microwave reactor for 20 min (300 W, 180° C., N2 cooling) (microwave conditions). After cooling to room temperature, the reaction mixture is partitioned between ethyl acetate and water. The aqueous layer is back-extracted with ethyl acetate, and the combined organic layers are dried and concentrated to give the title compound (105 mg). MS (ES): 548.3 [M+H]+.
Reaction SMILES: [P:1]([O:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)([O:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[O:2]C1C=CC=CC=1.[CH2:23]=O.[CH3:25][C:26]1[CH:27]=[CH:28][C:29]([S:32]([NH2:35])(=[O:34])=[O:33])=[CH:30][CH:31]=1>ClC1C=CC=CC=1>[C:26]1([CH3:25])[CH:27]=[CH:28][C:29]([S:32]([NH:35][CH2:23][P:1](=[O:2])([O:9][C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=2)[O:16][C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)(=[O:34])=[O:33])=[CH:30][CH:31]=1
Reactant: C=O
Reactant: c1ccc(OP(Oc2ccccc2)Oc2ccccc2)cc1
Reactant: Cc1ccc(S(N)(=O)=O)cc1
Solvent: Clc1ccccc1
Product: Cc1ccc(S(=O)(=O)NCP(=O)(Oc2ccccc2)Oc2ccccc2)cc1
Reaction time: 1 h

Procedure:
When a mixture of 77.6 g of triphenyl phosphite, 8.2 g of paraformaldehyde, and 42.8 g of p-toluenesulfonamide in 150 g of chlorobenzene is warmed, heat of reaction is observed at about 95° C., and cooling is needed for a few minutes to keep the temperature below 105°. Warming is continued at 95°-105° for 1 hr and then the solvent and most of the by-product phenol is removed at reduced pressure.
Reaction SMILES: [CH3:1][C:2]1([CH3:10])[CH2:7][CH2:6][C:5](=O)[CH2:4][C:3]1=[O:9].[F:11][C:12]1[CH:19]=[CH:18][C:15]([CH:16]=O)=[CH:14][C:13]=1[C:20]([F:23])([F:22])[F:21].[NH2:24][C:25]1[CH:29]=[CH:28][NH:27][N:26]=1>>[F:11][C:12]1[CH:19]=[CH:18][C:15]([CH:16]2[C:4]3[C:3](=[O:9])[C:2]([CH3:10])([CH3:1])[CH2:7][CH2:6][C:5]=3[NH:24][C:25]3=[CH:29][CH:28]=[N:27][N:26]23)=[CH:14][C:13]=1[C:20]([F:23])([F:22])[F:21]
Reactant: O=Cc1ccc(F)c(C(F)(F)F)c1
Reactant: CC1(C)CCC(=O)CC1=O
Reactant: Nc1cc[nH]n1
Product: CC1(C)CCC2=C(C1=O)C(c1ccc(F)c(C(F)(F)F)c1)n1nccc1N2

Procedure:
4,4-Dimethyl-1,3-cyclohexanedione, 4-fluoro-3-trifluoromethylbenzaldehyde and 3-aminopyrazole were processed as described in General Procedure A to provide the title compound.
Reaction SMILES: [Br-].[CH3:2][O:3][C:4]1[CH:5]=[C:6]([CH:10]([CH3:32])[CH2:11][CH2:12][P+](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[CH:7]=[CH:8][CH:9]=1.[N:33]1[CH:38]=[CH:37][C:36]([CH:39]=O)=[CH:35][CH:34]=1.[H-].[Na+]>CS(C)=O.O1CCCC1>[CH3:2][O:3][C:4]1[CH:5]=[C:6]([CH:10]([CH3:32])[CH2:11][CH:12]=[CH:39][C:36]2[CH:37]=[CH:38][N:33]=[CH:34][CH:35]=2)[CH:7]=[CH:8][CH:9]=1
Reactant: COc1cccc(C(C)CC[P+](c2ccccc2)(c2ccccc2)c2ccccc2)c1
Reactant: O=Cc1ccncc1
Agent: [Br-]
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CS(C)=O
Product: COc1cccc(C(C)CC=Cc2ccncc2)c1
Reaction time: 1 h

Procedure:
A mixture of 3-(3-methoxyphenyl)butyl triphenylphosphonium bromide (17.5 g., 35.4 mmoles) in dimethylsulfoxide (50 ml.) is added to 4-pyridinecarboxaldehyde (3.79 g., 35.4 mmoles) in tetrahydrofuran (40 ml.). The resulting mixture is then added dropwise to a slurry of 50% sodium hydride (1.87 g., 39 mmoles) in tetrahydrofuran (20 ml.) under a nitrogen atmosphere at 0°-5° C. Following completion of addition, the mixture is stirred for one hour at 0°-5° C. and then concentrated under reduced pressure. The concentrate is diluted with water (200 ml.) and then acidified with 6 N HCl. The aqueous acid solution is extracted with benzene (4×50 ml.). It is then made basic and extracted with ethyl acetate (3×50 ml.). Evaporation of the combined extracts after drying (MgSO4) affords 4-(3-methoxyphenyl)-1-(4-pyridyl)-1-pentene as an oil.
Reaction SMILES: [OH:1][CH:2]1[CH2:6][N:5]([C:7](=[O:17])[C:8]2[CH:13]=[CH:12][C:11]3[O:14][CH2:15][O:16][C:10]=3[CH:9]=2)[CH:4]([C:18]([OH:20])=O)[CH2:3]1.C(N(CC)CC)C.ClC(OCC)=O.[NH:34]1[CH2:39][CH2:38][O:37][CH2:36][CH2:35]1>C(#N)C>[OH:1][CH:2]1[CH2:6][N:5]([C:7](=[O:17])[C:8]2[CH:13]=[CH:12][C:11]3[O:14][CH2:15][O:16][C:10]=3[CH:9]=2)[CH:4]([C:18]([N:34]2[CH2:39][CH2:38][O:37][CH2:36][CH2:35]2)=[O:20])[CH2:3]1
Reactant: O=C(O)C1CC(O)CN1C(=O)c1ccc2c(c1)OCO2
Reactant: C1COCCN1
Agent: CCOC(=O)Cl
Solvent: CC#N
Solvent: CCN(CC)CC
Product: O=C(C1CC(O)CN1C(=O)c1ccc2c(c1)OCO2)N1CCOCC1
Reaction time: 0.5 h

Procedure:
4.5 g (0.016 mol) of 4-hydroxy-1-(3,4-methylenedioxybenzoyl)pyrrolidine-2-carboxylic acid obtained in Example 6 are suspended in 110 ml of acetonitrile at 0° C. 1.1 equivalents of triethylamine are added and the reaction mixture is stirred for 30 minutes, then 1.1 equivalents of ethyl chloroformate are added while maintaining the temperature between 0° and 5° C. After stirring for 30 minutes, 1.1 equivalents of morpholine are added to the filtrate. One equivalent is stirred at room temperature for 2 hours. The precipitate is separated, the filtrate is evaporated under vacuum. The residue is recrystallized.
Reaction SMILES: [NH2:1][C:2]1[C:3]([F:22])=[C:4]([C:18]([F:21])=[CH:19][CH:20]=1)[C:5]([C:7]1[C:15]2[C:10](=[N:11][CH:12]=[C:13]([C:16]#[N:17])[CH:14]=2)[NH:9][CH:8]=1)=[O:6].[F:23][C:24]1[CH:29]=[CH:28][C:27]([F:30])=[CH:26][C:25]=1[S:31](Cl)(=[O:33])=[O:32].Cl>O1CCCC1.N1C=CC=CC=1>[C:16]([C:13]1[CH:14]=[C:15]2[C:7]([C:5]([C:4]3[C:3]([F:22])=[C:2]([NH:1][S:31]([C:25]4[CH:26]=[C:27]([F:30])[CH:28]=[CH:29][C:24]=4[F:23])(=[O:33])=[O:32])[CH:20]=[CH:19][C:18]=3[F:21])=[O:6])=[CH:8][NH:9][C:10]2=[N:11][CH:12]=1)#[N:17]
Reactant: O=S(=O)(Cl)c1cc(F)ccc1F
Reactant: N#Cc1cnc2[nH]cc(C(=O)c3c(F)ccc(N)c3F)c2c1
Agent: Cl
Solvent: C1CCOC1
Solvent: c1ccncc1
Product: N#Cc1cnc2[nH]cc(C(=O)c3c(F)ccc(NS(=O)(=O)c4cc(F)ccc4F)c3F)c2c1
Temperature: 25 °C
Reaction time: 48 h
Yield: 66.1 %

Procedure:
To 3-(3-amino-2,6-difluoro-benzoyl)-1H-pyrrolo[2,3-b]pyridine-5-carbonitrile (28, 100 mg, 0.335 mmol) in 2.7 mL of tetrahydrofuran, 0.24 mL of pyridine was added. 2,5-Difluoro-benzenesulfonyl chloride (29, 107 mg, 0.503 mmol) was added and the solution was stirred at room temperature for 48 hours. The reaction mixture was poured into 1 M aqueous hydrochloric acid and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under vacuum. The crude material was purified by silica gel column chromatography eluting with ethyl acetate and hexane. Appropriate fractions were combined and the solvent removed under reduced pressure to provide the desired compound (P-0004, 105 mg). MS(ESI)[M+H+]+=475.0.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([CH2:8][O:9][CH3:10])[CH:5]=[C:4]([F:11])[C:3]=1[C:12]1[N:17]=[C:16]([C:18]([O:20]C)=[O:19])[CH:15]=[CH:14][C:13]=1[F:22].C1COCC1.[OH-].[Na+]>CO>[F:1][C:2]1[CH:7]=[C:6]([CH2:8][O:9][CH3:10])[CH:5]=[C:4]([F:11])[C:3]=1[C:12]1[N:17]=[C:16]([C:18]([OH:20])=[O:19])[CH:15]=[CH:14][C:13]=1[F:22]
Reactant: COCc1cc(F)c(-c2nc(C(=O)OC)ccc2F)c(F)c1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: COCc1cc(F)c(-c2nc(C(=O)O)ccc2F)c(F)c1
Yield: 98.2 %

Procedure:
The methyl 6-[2,6-difluoro-4-(methoxymethyl)phenyl]-5-fluoropyridine-2-carboxylate was treated with THF (2 mL), MeOH (2 mL) and 1.0 M aq. NaOH (2 mL, 2 mmol) at room temperature for 1 h. The volatile solvents were removed under reduced pressure. The residue was neutralized to pH around 5-6 with 1N HCl. The solids that precipitated were collected by filtration, rinsed with water, and dried to give the sub-title compound as a white solid (374 mg, 98.2%). LCMS calc. for C14H11F3NO3 (M+H)+ m/z=298.1. found: 298.0.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5](B(O)O)=[CH:4][CH:3]=1.[N:11]1([CH2:16][C:17]2[CH:18]=[CH:19][C:20](Br)=[N:21][CH:22]=2)[CH:15]=[CH:14][N:13]=[CH:12]1>>[N:11]1([CH2:16][C:17]2[CH:18]=[CH:19][C:20]([C:5]3[CH:6]=[CH:7][C:2]([NH2:1])=[CH:3][CH:4]=3)=[N:21][CH:22]=2)[CH:15]=[CH:14][N:13]=[CH:12]1
Reactant: Brc1ccc(Cn2ccnc2)cn1
Reactant: Nc1ccc(B(O)O)cc1
Product: Nc1ccc(-c2ccc(Cn3ccnc3)cn2)cc1

Procedure:
Synthesized using 4-aminophenylboronic acid (173 mg, 1.26 mmol) and 1a (150 mg, 0.63 mmol) according to Method C. White solid. Yield: 35 mg, 0.14 mmol, 22%. 1H NMR (500 MHz, CDCl3): δH (ppm): 5.14 (s, 2H), 6.76 (d, J=8.5 Hz, 2H), 6.92 (s, 1H), 6.93 (brs, 1H), 7.12 (s, 1H), 7.43 (dd, J=8.5, 2.5 Hz, 1H), 7.60 (brs, 1H), 7.62 (d, J=8.5 Hz, 1H), 7.82 (d, J=8.5 Hz, 2H), 8.52 (d, J=1.5 Hz, 1H); MS (ESI): m/z=250.74 [M+H]+.
Reaction SMILES: S(C1C=CC(C)=CC=1)([O-])(=O)=O.[O:12]1[CH2:17][CH2:16][CH:15]([O:18][C:19](=[O:25])[C@@H:20]([NH2:24])[CH:21]([CH3:23])[CH3:22])[CH2:14][CH2:13]1.[P:26](Cl)(Cl)(=[O:38])[O:27][C:28]1[C:37]2[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=2)[CH:31]=[CH:30][CH:29]=1.C(N(CC)CC)C.[Cl:48]CCl>>[Cl:48][C:29]1[CH:30]=[CH:31][C:32]2[C:37](=[CH:36][CH:35]=[CH:34][CH:33]=2)[C:28]=1[O:27][P:26](=[N:24][C@@H:20]([CH:21]([CH3:23])[CH3:22])[C:19]([O:18][CH:15]1[CH2:14][CH2:13][O:12][CH2:17][CH2:16]1)=[O:25])=[O:38]
Reactant: O=P(Cl)(Cl)Oc1cccc2ccccc12
Reactant: ClCCl
Reactant: CC(C)[C@H](N)C(=O)OC1CCOCC1
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Solvent: CCN(CC)CC
Product: CC(C)[C@H](N=[P+]([O-])Oc1c(Cl)ccc2ccccc12)C(=O)OC1CCOCC1
Yield: 67 %

Procedure:
Using the general procedure for synthesizing naphthylalene (amino acid ester) phosphorochloridates and tosylate salt of (S)-tetrahydro-2H-pyran-4-yl-2-amino-3-methylbutanoate (3.76 g, 10.0 mmol), naphthalene-1-yl phosphorodichloridate (2.62 g, 10.0 mmol), triethylamine (2.81 mL, 2.0 mmol) and dichloromethane (54 mL) were combined to give 2.89 g of desired (2S)-tetrahydro-2H-pyran-4-yl 2-(chloro(naphthalen-1-yloxy)phosphorylamino)-3-methylbutanoate as a pale yellow viscous oil in 67% yield.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]([CH:9]=[CH:10][C:11]=1[OH:12])[C:7]#[N:8])(=[O:3])[CH3:2].[CH3:13][C:14]([CH3:16])=O.N1CCCC1.C1(C)C=CC=CC=1>O>[CH3:13][C:14]1([CH3:16])[CH2:2][C:1](=[O:3])[C:4]2[C:11](=[CH:10][CH:9]=[C:6]([C:7]#[N:8])[CH:5]=2)[O:12]1
Reactant: CC(=O)c1cc(C#N)ccc1O
Reactant: CC(C)=O
Solvent: O
Solvent: C1CCNC1
Solvent: Cc1ccccc1
Product: CC1(C)CC(=O)c2cc(C#N)ccc2O1
Reaction time: 1 h

Procedure:
A mixture of 81 g of 3-acetyl-4-hydroxybenzonitrile, 48 ml of acetone, 11.8 ml of pyrrolidine and 300 ml of toluene is allowed to stand at 20° for 1 hour, then boiled for 2 hours in a water separator and cooled. After customary working up, 2,2-dimethyl-6-cyano-4-chromanone is obtained, m.p. 119-120°.
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][CH:5]=[CH:4][C:3]=1[C:12]([C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([OH:20])[CH:15]=1)=O.[F:21][C:22]1[CH:27]=[CH:26][C:25]([CH2:28][CH:29]=O)=[CH:24][CH:23]=1>>[F:21][C:22]1[CH:27]=[CH:26][C:25]([C:28]2[CH:29]=[N:1][C:2]3[C:3]([C:12]=2[C:14]2[CH:15]=[C:16]([OH:20])[CH:17]=[CH:18][CH:19]=2)=[CH:4][CH:5]=[CH:6][C:7]=3[C:8]([F:11])([F:10])[F:9])=[CH:24][CH:23]=1
Reactant: O=CCc1ccc(F)cc1
Reactant: Nc1c(C(=O)c2cccc(O)c2)cccc1C(F)(F)F
Product: Oc1cccc(-c2c(-c3ccc(F)cc3)cnc3c(C(F)(F)F)cccc23)c1

Procedure:
The title compound was prepared from [2-amino-3-(trifluoromethyl)phenyl]-(3-hydroxy-phenyl)methanone and (4-Fluoro-phenyl)-acetaldehyde following the procedure of Example 457: MS m/z 384; HRMS: calcd for C22H13F4NO+H+, 384.10060; found (ESI, [M+H]+), 384.0997.
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]([F:11])[CH:8]=[C:7]2[C:3]=1[CH:4]=[C:5]([C:12]([OH:14])=O)[NH:6]2.[CH3:15][C:16]1([CH3:23])[CH2:21][CH2:20][CH:19]([NH2:22])[CH2:18][CH2:17]1.Cl.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[CH3:15][C:16]1([CH3:23])[CH2:21][CH2:20][CH:19]([NH:22][C:12]([C:5]2[NH:6][C:7]3[C:3]([CH:4]=2)=[C:2]([F:1])[CH:10]=[C:9]([F:11])[CH:8]=3)=[O:14])[CH2:18][CH2:17]1
Reactant: CC1(C)CCC(N)CC1
Reactant: O=C(O)c1cc2c(F)cc(F)cc2[nH]1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC1(C)CCC(NC(=O)c2cc3c(F)cc(F)cc3[nH]2)CC1
Temperature: 25 °C
Reaction time: 17 h

Procedure:
A mixture of 4,6-difluoro-1H-indole-2-carboxylic acid (5 g, 25.36 mmol×4 batches) and 4,4-dimethylcyclohexylamine.HCl (I-6b: 4.6 g, 28.10 mmol, for each batch) in dry DMF (75 mL) was cooled to 0° C. and HATU (11.62 g, 30.57 mmol, for each batch) was added followed by DIPEA (22 mL, 127.9 mmol, for each batch) drop-wise and the mixture was stirred under inert atmosphere at room temperature for 17h. Ice-cold water (50 mL) was added to the reaction mixture with vigorous stirring. The precipitated solid was collected by filtration and dried thoroughly. The crude compound obtained from combining all the batches was purified by column chromatography over silica gel (100-200 mesh) using a solvent gradient of 30%-40% ethyl acetate in hexanes as eluent to afford 23 g of off-white solid. It was triturated with ether/hexanes (3:7) in five cycles to afford 20.6 g (66.2%) of 4,6-difluoro-N-(4,4-dimethylcyclohexyl)-1H-indole-2-carboxamide (2A) as an white solid.
Reaction SMILES: [Br:1][C:2]1[C:12]([OH:13])=[C:11]([Br:14])[CH:10]=[CH:9][C:3]=1[C:4]([O:6][CH2:7][CH3:8])=[O:5].C(=O)([O-])[O-].[K+].[K+].IC.[CH2:23](N(CC)C=O)[CH3:24]>CN(C=O)C>[Br:1][C:2]1[C:12]([O:13][CH2:23][CH3:24])=[C:11]([Br:14])[CH:10]=[CH:9][C:3]=1[C:4]([O:6][CH2:7][CH3:8])=[O:5]
Reactant: CCN(C=O)CC
Reactant: CCOC(=O)c1ccc(Br)c(O)c1Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: CN(C)C=O
Product: CCOC(=O)c1ccc(Br)c(OCC)c1Br
Temperature: 85 °C

Procedure:
Ethyl 2,4-dibromo-3-hydroxybenzoate (5.0 g) was added to a stirred suspension of potassium carbonate (106.4 g) in dry N,N-diethylformamide (DMF). A solution of iodomethane (25.7 g) in DMF was added over 18 minutes, and the resulting mixture was heated at 85° C. for 1.3 hours. The cooled mixture was poured onto water and extracted with ether. The extract was washed (brine solution), dried (anhydrous magnesium sulphate) and the solvent evaporated in vacuo to give ethyl 2,4-dibromo-3-ethoxybenzoate (52.08 g), NMR 1.4(t,3H), 1.5(t,3H), 4.1(q,2H), 4.4(q,2H), 7.35(d,1H), 7.55(d,1H).
Reaction SMILES: FC(F)(F)C([O-])=O.[C:8]([CH2:11][N:12]1[C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=2[NH+:14]=[CH:13]1)([OH:10])=O.[F:21][C:22]1[CH:23]=[C:24]([CH:26]=[CH:27][C:28]=1[F:29])[NH2:25]>>[N:12]1([CH2:11][C:8]([NH:25][C:24]2[CH:26]=[CH:27][C:28]([F:29])=[C:22]([F:21])[CH:23]=2)=[O:10])[C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=2[N:14]=[CH:13]1
Reactant: O=C(O)Cn1c[nH+]c2ccccc21
Reactant: Nc1ccc(F)c(F)c1
Agent: O=C([O-])C(F)(F)F
Product: O=C(Cn1cnc2ccccc21)Nc1ccc(F)c(F)c1

Procedure:
The title compound was synthesised according to the procedure described in Example 92, from 3-carboxymethyl-3H-benzoimidazol-1-ium trifluoro-acetate and 3,4-difluoroaniline Yield 9.1 mg (26%). Calculated for C15H11F2N3O m/z: 287.2, found 288.3 [M+H]+. 1H NMR (400 MD, MeOD) δ ppm 5.2 (s, 2H), 7.3 (m, 4 H), 7.5 (d, J=7.1 Hz, 1H), 7.7 (m, 2H),8.2(s, 1H).
Reaction SMILES: Br.[Br:2][C:3]1[CH:4]=[C:5]([CH2:10]Br)[C:6]([NH2:9])=[N:7][CH:8]=1.[NH:12]1[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1>CC#N.CCOCC>[Br:2][C:3]1[CH:4]=[C:5]([CH2:10][N:12]2[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]2)[C:6]([NH2:9])=[N:7][CH:8]=1
Reactant: C1CCNCC1
Reactant: Nc1ncc(Br)cc1CBr
Agent: Br
Solvent: CC#N
Solvent: CCOCC
Product: Nc1ncc(Br)cc1CN1CCCCC1
Temperature: 25 °C
Reaction time: 3.5 h
Yield: 53.5 %

Procedure:
An ice-cold suspension of 5-bromo-3-bromomethyl-pyridin-2-ylamine hydrobromide (10.0 g, 28.8 mmol) in MeCN (100 mL) was treated with piperidine (6.4 mL, 64.8 mmol). After stirring at room temperature for 3.5 h, the mixture was diluted with Et2O (500 mL). The solution was filtered and then concentrated to give the title compound (4.16 g, 53%) as a pale, yellow solid: MS (ESI) m/e 270 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:8]([C:20]2[C:29]([OH:30])=[C:28]3[C:23]([CH:24]=[CH:25][CH:26]=[N:27]3)=[C:22]([Cl:31])[CH:21]=2)[NH:9][C:10](=[O:19])[CH2:11][O:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:5]=[CH:6][CH:7]=1.CCN(C(C)C)C(C)C.[C:41](Cl)(=[O:43])[CH3:42]>C(Cl)Cl>[C:41]([NH:1][C:2]1[CH:3]=[C:4]([CH:8]([C:20]2[C:29]([OH:30])=[C:28]3[C:23]([CH:24]=[CH:25][CH:26]=[N:27]3)=[C:22]([Cl:31])[CH:21]=2)[NH:9][C:10](=[O:19])[CH2:11][O:12][C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH:5]=[CH:6][CH:7]=1)(=[O:43])[CH3:42]
Reactant: Nc1cccc(C(NC(=O)COc2ccccc2)c2cc(Cl)c3cccnc3c2O)c1
Reactant: CC(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(=O)Nc1cccc(C(NC(=O)COc2ccccc2)c2cc(Cl)c3cccnc3c2O)c1
Yield: 57.6 %

Procedure:
To the suspension of N-[(3-aminophenyl)(5-chloro-8-hydroxyquinolin-7-yl)methyl]-2-phenoxyacetamide (150 mg, 0.35 mmol) in methylenechloride (4 ml) cooled to 0 C was added DIEA (50 mg, 0.38 mmol) followed by acetylchloride (32.4 mg, 0.42 mmol). Purification by flush chromatography (eluent 30% acetone/DCM) afforded 96 mg (57%) of N-[[3-(acetylamino)phenyl](5-chloro-8-hydroxyquinolin-7-yl)methyl]-2-phenoxyacetamide as a white solid.