Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[O:10][C:9]([CH3:12])([CH3:11])[C:8]([CH2:13]O)=[C:7]([N:15]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]3=[O:21])[C:6]=2[CH:22]=1.P(Br)(Br)[Br:24].O.C(OCC)(=O)C>C1(C)C=CC=CC=1>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[O:10][C:9]([CH3:12])([CH3:11])[C:8]([CH2:13][Br:24])=[C:7]([N:15]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]3=[O:21])[C:6]=2[CH:22]=1
Reactant: BrP(Br)Br
Reactant: CC1(C)Oc2ccc(Br)cc2C(n2ccccc2=O)=C1CO
Solvent: O
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: CC1(C)Oc2ccc(Br)cc2C(n2ccccc2=O)=C1CBr
Yield: 236.2 %

Procedure:
6-bromo-2,2-dimethyl-3-hydroxymethyl-4-(2-oxo-1,2-dihydropyridin-1-yl)-2H-1-benzopyran (9.0 g, 0.0248 mol) was suspended in toluene (150 ml). Phosphorus tribromide (0.94 ml, 2.69 g, 0.0099 mol) was added and the mixture heated at reflux for two hours. The cooled solution was treated with water and ethyl acetate, the organic phase separated and washed three times with aqueous sodium chloride solution, and then dried and evaporated under reduced pressure. The residue was triturated with pentane and dried to afford 9.94 g of 6-bromo-2,2-dimethyl-3-bromomethyl-4-(2-oxo-1,2-dihydropyridin-1-yl)-2H-1-benzopyran, m.p. 175° C.
Reaction SMILES: [Cl:1][C:2]1[CH:37]=[CH:36][C:5]([C:6]([N:8]2[CH2:14][C:13]3[C:15]([O:19]C)=[CH:16][CH:17]=[CH:18][C:12]=3[N:11]([CH2:21][C:22]3[CH:27]=[CH:26][C:25]([C:28]([N:30]4[CH2:34][CH:33]=[CH:32][CH2:31]4)=[O:29])=[CH:24][CH:23]=3)[C:10](=[O:35])[CH2:9]2)=[O:7])=[CH:4][CH:3]=1.[Br-].[Br-].[Br-].B>ClCCl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([N:8]2[CH2:14][C:13]3[C:15]([OH:19])=[CH:16][CH:17]=[CH:18][C:12]=3[N:11]([CH2:21][C:22]3[CH:27]=[CH:26][C:25]([C:28]([N:30]4[CH2:31][CH:32]=[CH:33][CH2:34]4)=[O:29])=[CH:24][CH:23]=3)[C:10](=[O:35])[CH2:9]2)=[O:7])=[CH:36][CH:37]=1
Reactant: COc1cccc2c1CN(C(=O)c1ccc(Cl)cc1)CC(=O)N2Cc1ccc(C(=O)N2CC=CC2)cc1
Agent: B
Agent: [Br-]
Solvent: ClCCl
Product: O=C(c1ccc(CN2C(=O)CN(C(=O)c3ccc(Cl)cc3)Cc3c(O)cccc32)cc1)N1CC=CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
75 mg (0.15 mmol) of 4-(4-chlorobenzoyl)-1-[4-(2,5-dihydro-1H-pyrrol-1-ylcarbonyl)benzyl]-6-methoxy-1,3,4,5-tetrahydrobenzo[e][1,4]-diazepin-2-on was dissolved in 10 ml of dichloromethane. 1.3 ml of borane tribromide was added to the obtained solution, and they were stirred at room temperature overnight. After the treatment with dichloromethane as the extracting solvent by an ordinary method, the obtained crude product was treated in the same manner as in step 3 in Example 1 to obtain the title compound.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][N:3]=1.[CH2:12]([O:19][C:20]1[CH:25]=[CH:24][C:23](B(O)O)=[CH:22][CH:21]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.[F-].[Cs+]>O1CCOCC1>[CH2:12]([O:19][C:20]1[CH:25]=[CH:24][C:23]([C:2]2[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][N:3]=2)=[CH:22][CH:21]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: OB(O)c1ccc(OCc2ccccc2)cc1
Reactant: FC(F)(F)c1ccc(Cl)nc1
Agent: [Cs+]
Agent: [F-]
Solvent: C1COCCO1
Product: FC(F)(F)c1ccc(-c2ccc(OCc3ccccc3)cc2)nc1
Temperature: 105 °C

Procedure:
A mixture of 2-chloro-5-trifluoromethylpyridine (1.81 g, 10 mmol), 4-benzyloxyphenyl boronic acid (2.74 g, 12 mmol) and CsF (5.32 g, 35 mmol) in dioxane (40 mL) is degassed and filled with nitrogen. PdCl2 (dppf) (200 mg) is added under nitrogen, the reaction mixture is heated at 105° C. overnight. The mixture is cooled to room temperature, diluted with ethyl acetate (100 mL), filtered through a pad of Celite. The filtrate is concentrated and the residue is purified by column chromatography on silica gel giving the title compound (2.55 g, 77.4%).
Reaction SMILES: [Br:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][O:8][C:9]2=O)=[C:4]([N+:13]([O-:15])=[O:14])[CH:3]=1.[NH3:16]>CO>[Br:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][NH:16][C:9]2=[O:8])=[C:4]([N+:13]([O-:15])=[O:14])[CH:3]=1
Reactant: O=c1occc2c([N+](=O)[O-])cc(Br)cc12
Reactant: N
Solvent: CO
Product: O=c1[nH]ccc2c([N+](=O)[O-])cc(Br)cc12
Temperature: 60 °C
Reaction time: 8 h
Yield: 83 %

Procedure:
A sealed tube containing 7-bromo-5-nitro-1H-isochromen-1-one (293a, 9.20 g, 34.1 mmol) and 7 N ammonia solution in methanol (100 mL) was stirred at 60° C. overnight. After chilling in an ice bath, the resulting precipitate was collected by filtration, washed with cold methanol, and air-dried to give 7-bromo-5-nitroisoquinolin-1(2H)-one (293b, 7.6 g, 83% yield). as a yellow solid. 1H NMR (400 MHz, DMSO-d6) δ 11.82 (br. s., 1H), 8.56-8.64 (m, 2H), 7.48 (d, J=7.58 Hz, 1H), 6.89 (d, J=7.58 Hz, 1H). MS: 267/269 [M−1].
Reaction SMILES: [CH2:1](OC(C1OC2C=CC(O)=CC=2N=1)=O)[CH2:2][CH3:3].[Cl:17][C:18]1[CH:19]=[CH:20][C:21]2[O:25][C:24]([C:26]([O-:28])=[O:27])=[N:23][C:22]=2[C:29]=1[OH:30]>>[Cl:17][C:18]1[CH:19]=[CH:20][C:21]2[O:25][C:24]([C:26]([O:28][CH2:1][CH2:2][CH3:3])=[O:27])=[N:23][C:22]=2[C:29]=1[OH:30]
Reactant: CCCOC(=O)c1nc2cc(O)ccc2o1
Reactant: O=C([O-])c1nc2c(O)c(Cl)ccc2o1
Product: CCCOC(=O)c1nc2c(O)c(Cl)ccc2o1

Procedure:
When the carboxylic acid of Example 29 is replaced by 5-chloro-4-hydroxybenzoxazole-2-carboxylate, n-propyl 5-chloro-4-hydroxybenzoxazole-2-carboxylate is obtained.
Reaction SMILES: [Br:1][C:2]1[S:6][C:5]([C:7](=[O:9])[CH3:8])=[CH:4][CH:3]=1.[C:10](=O)([O:14]CC)[O:11][CH2:12][CH3:13].[H-].[Na+]>C1COCC1>[Br:1][C:2]1[S:6][C:5]([C:7](=[O:9])[CH2:8][C:10]([O:11][CH2:12][CH3:13])=[O:14])=[CH:4][CH:3]=1
Reactant: CCOC(=O)OCC
Reactant: CC(=O)c1ccc(Br)s1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOC(=O)CC(=O)c1ccc(Br)s1
Temperature: 56 °C

Procedure:
To a solution of 1-(5-bromothiophen-2-yl)ethanone (4.10 g, 19.99 mmol) and Diethyl carbonate (30 mL, 248 mmol) in THF (40 ml) at room temperature was added sodium hydride (1.679 g, 42.0 mmol). The resulting off-white slurry solution was gradually warmed to 56° C., and became dark brown clear solution. The reaction mixture was heated at 56° C. for 1.5 hour. The reaction mixture was poured into ice-HOAc—H2O, and extracted with ethyl acetate. The organic phase was washed (brine), dried (MgSO4) and concentrated to give a brown liquid. The crude product was purified via flash chromatography (silica gel cartridge with eluent of 0-5% ethyl acetate/hexane) to afford ethyl 3-(5-bromothiophen-2-yl)-3-oxopropanoate as an amble liquid, 4.713 g (85%). HPLC: Rt 2.856 min.
Reaction SMILES: [F:1][C:2]1[C:7]([N+:8]([O-])=O)=[CH:6][C:5]([C:11]2[C:12](=[O:22])[N:13]([CH3:21])[C:14]([C:17]([F:20])([F:19])[F:18])=[CH:15][N:16]=2)=[CH:4][CH:3]=1.[H][H]>C(OCC)(=O)C.[Pd]>[NH2:8][C:7]1[C:2]([F:1])=[CH:3][CH:4]=[C:5]([C:11]2[C:12](=[O:22])[N:13]([CH3:21])[C:14]([C:17]([F:19])([F:20])[F:18])=[CH:15][N:16]=2)[CH:6]=1
Reactant: [H][H]
Reactant: Cn1c(C(F)(F)F)cnc(-c2ccc(F)c([N+](=O)[O-])c2)c1=O
Agent: [Pd]
Solvent: CCOC(C)=O
Product: Cn1c(C(F)(F)F)cnc(-c2ccc(F)c(N)c2)c1=O
Temperature: 25 °C
Reaction time: 3 h
Yield: 47.9 %

Procedure:
First, 79 mg of 10% palladium/carbon was added to a solution of 0.30 g of 3-(4-fluoro-5-nitrophenyl)-1-methyl-6-trifluoromethyl-2-oxo-1,2-dihydropyrazine (present compound 1-13) in 12 ml of ethyl acetate under an atmosphere of nitrogen, which was then replaced with hydrogen under a pressure of 1 atm., and the mixture was stirred at room temperature for 3 hours. After completion of the reaction, the reaction mixture was filtered through celite and concentrated. The residue was subjected to silica gel column chromatography, which afforded 0.13 g (yield, 47%) of 3-(5-amino-4-fluorophenyl)-1-methyl-6-trifluoromethyl-2-oxo-1,2-dihydropyrazine (present compound 1-19).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([N:8]2[CH2:13][CH2:12][N:11]([CH3:14])[CH2:10][CH2:9]2)[CH:5]=[CH:4][N:3]=1.[C:15]1(B(O)O)[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.C([O-])([O-])=O.[K+].[K+]>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.C1(C)C=CC=CC=1.CCO>[CH3:14][N:11]1[CH2:12][CH2:13][N:8]([C:6]2[CH:5]=[CH:4][N:3]=[C:2]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[N:7]=2)[CH2:9][CH2:10]1
Reactant: CN1CCN(c2ccnc(Cl)n2)CC1
Reactant: OB(O)c1ccccc1
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: [K+]
Solvent: CCO
Solvent: Cc1ccccc1
Product: CN1CCN(c2ccnc(-c3ccccc3)n2)CC1
Temperature: 140 °C

Procedure:
To a microwave tube was added 2-chloro-4-(4-methyl-piperazin-1-yl)-pyrimidine (30 mg, 0.14 mmol), Pd(PPh3)4 (10 mg), phenylboronic acid (24 mg, 0.2 mmol), toluene/EtOH (4:1, 1 mL) and 2 M aqueous K2CO3 (0.2 mL). The resulting mixture was heated at 140° C. for 30 minutes using the microwave instrument. The resulting mixture was extracted with EtOAc. The organic layer was dried and concentrated, and the residue was purified by preparative TLC (hexanes/EtOAc) to yield the title compound as a solid.
Reaction SMILES: [F:1][C@@H:2]1[CH2:6][N:5]([C:7](=[O:17])[CH2:8][O:9][Si:10]([C:13]([CH3:16])([CH3:15])[CH3:14])([CH3:12])[CH3:11])[C@H:4]([C:18]([NH2:20])=O)[CH2:3]1.C(N(CC)CC)C.FC(F)(F)C(OC(=O)C(F)(F)F)=O>O1CCCC1>[F:1][C@@H:2]1[CH2:6][N:5]([C:7](=[O:17])[CH2:8][O:9][Si:10]([C:13]([CH3:14])([CH3:15])[CH3:16])([CH3:12])[CH3:11])[C@H:4]([C:18]#[N:20])[CH2:3]1
Reactant: CC(C)(C)[Si](C)(C)OCC(=O)N1C[C@@H](F)C[C@H]1C(N)=O
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(C)(C)[Si](C)(C)OCC(=O)N1C[C@@H](F)C[C@H]1C#N
Temperature: 25 °C
Reaction time: 1 h
Yield: 98.9 %

Procedure:
(2S,4S)-4-fluoro-1-[2-(tert-butyldimethylsilyloxy)acetyl]pyrrolidine-2-carboxamide (6.05 g) was dissolved in dehydrated tetrahydrofuran (130 mL). While the solution was cooled in an ice bath, triethylamine (9.70 mL) was added, followed by dropwise addition of trifluoroacetic anhydride (4.30 mL) and subsequent stirring at room temperature for 1 hour. The reaction mixture was then concentrated under reduced pressure and the resulting residue was dissolved in ethyl acetate (400 mL). The ethyl acetate solution was washed successively with water (50 mL), saturated aqueous sodium bicarbonate solution (50 mL) and saturated brine (50 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting residue was purified on a silica gel column (hexane:ethyl acetate=1:2) to give (2S,4S)-4-fluoro-1-[2-(tert-butyldimethylsilyloxy)acetyl]pyrro lidine-2-carbonitrile as a white solid (5.63 g).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[N:16]([CH2:17][C:18]([OH:20])=O)[C:11]3=[N:12][CH:13]=[CH:14][CH:15]=[C:10]3[N:9]=2)[CH:5]=[CH:6][CH:7]=1.[C:21](N1C=CN=C1)([N:23]1C=CN=C1)=O.CN>O1CCCC1>[ClH:1].[Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[N:16]([CH2:17][C:18]([NH:23][CH3:21])=[O:20])[C:11]3=[N:12][CH:13]=[CH:14][CH:15]=[C:10]3[N:9]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)Cn1c(-c2cccc(Cl)c2)nc2cccnc21
Reactant: O=C(n1ccnc1)n1ccnc1
Agent: CN
Solvent: C1CCOC1
Product: CNC(=O)Cn1c(-c2cccc(Cl)c2)nc2cccnc21
Product: Cl
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A suspension of 2-(3-chlorophenyl)-3H-imidazo[4,5-b]pyridine-3-acetic acid (2.89 g, 0.010 mole), 1,1'-carbonyldiimidazole (1.62 g, 0.010 mole), and anhydrous tetrahydrofuran (125 ml) was stirred at room temperature with a stream of nitrogen bubbling through it for 41/2 hours. A solution of 1 M methylamine in tetrahydrofuran (15 ml, 0.015 mole) was added and the resulting solution was stoppered and stirred overnight at room temperature. The reaction mixture was concentrated in vacuo and the residue triturated twice in water (2×75 ml) and filtered. The filter cake (mp 186°-189° C.) was dissolved in isopropyl alcohol and treated with excess ethereal hydrogen chloride, giving 1.6 g (47%) of a white flocculent solid which melted from 195°-199° C. after a few crystals had melted between 185°-190° C. It was also observed that prolonged heating decreases the melting point.
Reaction SMILES: O1CCCC1.[O:6]=[C:7]([CH2:15][O:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[CH2:8]P(=O)(OC)OC.[H-].[Na+].[CH:25]([C@@H:27]1[C@@H:35]2[C@@H:30]([S:31][C@@H:32]([CH2:36][CH2:37][CH2:38][C:39]([O:41][CH3:42])=[O:40])[CH2:33][CH2:34]2)[CH2:29][C@H:28]1[O:43][CH:44]1[CH2:49][CH2:48][CH2:47][CH2:46][O:45]1)=O>C(OCC)(=O)C.C(O)(=O)C>[O:6]=[C:7]([CH2:15][O:16][C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1)/[CH:8]=[CH:25]/[C@@H:27]1[C@@H:35]2[C@@H:30]([S:31][C@@H:32]([CH2:36][CH2:37][CH2:38][C:39]([O:41][CH3:42])=[O:40])[CH2:33][CH2:34]2)[CH2:29][C@H:28]1[O:43][CH:44]1[CH2:49][CH2:48][CH2:47][CH2:46][O:45]1
Reactant: COC(=O)CCC[C@H]1CC[C@@H]2[C@@H](C=O)[C@H](OC3CCCCO3)C[C@@H]2S1
Reactant: COP(=O)(CC(=O)COc1ccccc1)OC
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: COC(=O)CCC[C@H]1CC[C@@H]2[C@@H](/C=C/C(=O)COc3ccccc3)[C@H](OC3CCCCO3)C[C@@H]2S1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 92.1 %

Procedure:
To an anhydrous tetrahydrofuran (2.7 mL) solution of dimethyl (2-oxo-3-phenoxypropyl)phosphonate (194 mg) was added sodium hydride (24.8 mg) in an ice bath, and the mixture was stirred at room temperature for 1.5 hours. Thereto was added dropwise an anhydrous tetrahydrofuran (2 mL) solution of the compound 11 (200 mg), and the mixture was reacted at room temperature for 4.5 hours. Acetic acid was added in a small amount, and the reaction liquid was then diluted with ethyl acetate. This solution was washed with water and a saturated saline, dried with anhydrous magnesium sulfate, and then concentrated to obtain a titled compound (250 mg) having the following physical property values.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11](=O)[CH:10]([F:15])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:16]([NH2:23])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.C([BH3-])#N.[Na+]>CO.C(O)(=O)C>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C@@H:11]([NH:23][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C@H:10]([F:15])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C@H:11]([NH:23][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C@H:10]([F:15])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCC(=O)C(F)C1
Reactant: NCc1ccccc1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: CC(C)(C)OC(=O)N1CC[C@@H](NCc2ccccc2)[C@H](F)C1
Product: CC(C)(C)OC(=O)N1CC[C@H](NCc2ccccc2)[C@H](F)C1
Temperature: 25 °C
Reaction time: 3 h
Yield: 23 %
Yield: 26 %

Procedure:
A stirred solution of 3-Fluoro-4-oxo-piperidine-1-carboxylic acid tert-butyl ester (2.00 g, 9.21 mmol) in methanol (20 ml) and acetic acid (1 ml) was treated with benzyl amine (1.106 ml, 10.013 mmol) and stirred at ambient temperature for three hours. The mixture was then treated with sodium cyanoborohydride (0.8678 g, 13.81 mmol) and left to stand overnight. The reaction was quenched with a saturated solution of sodium bicarbonate (20 ml) and extracted with three portions of dichloromethane (50 ml). Combined organic layers were dried with magnesium sulfate and concentrated under vacuum to give crude product. Purification by column chromatography on silica gel (gradient: 0 to 60% ethyl acetate in heptane) gave 734 mg (26%) of trans-4-benzylamino-3-fluoro-piperidine-1-carboxylic acid tert-butyl ester and 653 mg (23%) of cis-4-benzylamino-3-fluoro-piperidine-1-carboxylic acid tert-butyl ester.
Reaction SMILES: O.NN.[N:4]1[C:13]2[CH:12]([CH2:14][CH2:15][CH2:16][NH:17][C:18]3[C:23]([N+:24]([O-])=O)=[CH:22][C:21]([CH2:27][C:28]4[CH:29]=[N:30][CH:31]=[CH:32][CH:33]=4)=[CH:20][N:19]=3)[CH2:11][CH2:10][CH2:9][C:8]=2[CH:7]=[CH:6][CH:5]=1>CO.[Ni]>[NH2:24][C:23]1[C:18]([NH:17][CH2:16][CH2:15][CH2:14][CH:12]2[C:13]3[N:4]=[CH:5][CH:6]=[CH:7][C:8]=3[CH2:9][CH2:10][CH2:11]2)=[N:19][CH:20]=[C:21]([CH2:27][C:28]2[CH:29]=[N:30][CH:31]=[CH:32][CH:33]=2)[CH:22]=1
Reactant: O=[N+]([O-])c1cc(Cc2cccnc2)cnc1NCCCC1CCCc2cccnc21
Agent: [Ni]
Agent: NN
Solvent: O
Solvent: CO
Product: Nc1cc(Cc2cccnc2)cnc1NCCCC1CCCc2cccnc21
Reaction time: 0.42 h

Procedure:
Hydrazine hydrate (7 ml) in methanol (25 ml) was added with stirring over 25 minutes to a cooled (5-10° C.) solution of 2-[3-(5,6,7,8-tetrahydroquinol-8-yl)propylamino-3-nitro-5-(pyrid-3-ylmethyl)pyridine (6.1 g) in methanol (300 ml) containing Raney Nickel (ca. 12 g). The solution was stirred for a further hour at 5° C., the catalyst was removed by filtration and the filtrate was concentrated to dryness in vacuo giving the title compound as an orange oil (theoretical yield assumed) which was used unpurified in the next reaction.
Reaction SMILES: Br[CH2:2][C:3]1[N:8]=[C:7]([N+:9]([O-:11])=[O:10])[C:6]([O:12][CH3:13])=[CH:5][CH:4]=1.C[CH:15]([SH:19])[C:16]([O-:18])=[O:17].[C:20](=O)([O-])[O-].[K+].[K+]>CO>[CH3:13][O:12][C:6]1[CH:5]=[CH:4][C:3]([CH2:2][S:19][CH2:15][C:16]([O:18][CH3:20])=[O:17])=[N:8][C:7]=1[N+:9]([O-:11])=[O:10]
Reactant: COc1ccc(CBr)nc1[N+](=O)[O-]
Reactant: O=C([O-])[O-]
Reactant: CC(S)C(=O)[O-]
Agent: [K+]
Solvent: CO
Product: COC(=O)CSCc1ccc(OC)c([N+](=O)[O-])n1
Temperature: 25 °C
Reaction time: 10 h

Procedure:
A mixture of 6-(bromomethyl)-3-methoxy-2-nitropyridine (30 mmol, 0.74 g), methythioglycolate (2.7 mL, 30 mmol), and potassium carbonate (5.5 g, 40 mmol) in methanol (200 mL) was stirred at room temperature for 10 hours. After concentrated the mixture was purified by column chromatography using PE/DCM (1:1, v/v) followed by DCM to the titled compound. 1H-NMR (CDCl3): δ 3.27 (S, 2H, CH2), 3.74 (S, 3H, OCH3), 3.93 (S, 2H, CH2), 3.99 (S, 3H, OCH3), 7.51 (d, 1H, J=8.6 Hz, Py-H), 7.65 (d, 1H, J=8.6 Hz, Py-H); HR-MS (ESI+) m/z 272.0467 [M+H]+ C10H12N2O5S requires 273.0547.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH2:18][S:19]([NH:22][CH3:23])(=[O:21])=[O:20])[CH:5]=[C:6]2[C:10]=1[NH:9][CH:8]=[C:7]2[CH2:11][C@H:12]1[CH2:16][CH2:15][CH2:14][N:13]1[CH3:17].[H][H]>[OH-].[OH-].[Pd+2]>[CH3:23][NH:22][S:19]([CH2:18][C:4]1[CH:5]=[C:6]2[C:10](=[CH:2][CH:3]=1)[NH:9][CH:8]=[C:7]2[CH2:11][C@H:12]1[CH2:16][CH2:15][CH2:14][N:13]1[CH3:17])(=[O:20])=[O:21]
Reactant: [H][H]
Reactant: CNS(=O)(=O)Cc1cc(Br)c2[nH]cc(C[C@H]3CCCN3C)c2c1
Agent: [Pd+2]
Agent: [OH-]
Product: CNS(=O)(=O)Cc1ccc2[nH]cc(C[C@H]3CCCN3C)c2c1
Yield: 58 %

Procedure:
A solution of (R)-7-bromo-5-(methylaminosulfonylmethyl)-3-(N-methylpyrrolidin-2-ylmethyl)-1H-indole (193 g) in industrial methylated spirit (950 mL) containing Pearlman's catalyst (47.6 g total) was exposed to hydrogen gas (50 psi). The catalyst was then filtered through an Arbacel pad, washing with hot industrial methylated spirit (2×100 mL) and the combined filtrate and washings evaporated in vacuo to an organic residue. The filtered solids (catalyst +filter aid) were then reslurried in 2N hydrochloric acid (500 mL) then refiltered (through Arbacel)and the filtrand washed with 2N hydrochloric acid (4×250 mL) and water (2×100 mL). The aqueous filtrate and washes were combined with the organic residue and then once washed with ethyl acetate (1000 mL). The aqueous solution was chilled then made basic by addition of 40% aqueous sodium hydroxide solution precipitating the title compound as a pale-yellow solid. This solid was filtered, washed with water (2×100 mL) and dried in vacuo to give the title compound (89.9 g). TLC (methyl iso-butyl ketone/acetic acid/water 2:1:1 Top phase): Rf=0.23. 1H NMR(d6DMSO) δ10.85 (s, 1H), 7.5 (s, 1H), 7.3 (d, 1H), 7.15 (s, 1H), 7.05 (d, 1H), 6.8 (q, 1H), 4.35 (s, 2H), 3.0 (m, 2H), 2.55-2.4 (d, 3H and m, 2H), 2.35 (s, 3H), 2.1 (m, 1H), 1.7-1.4 (m, 4H).
Reaction SMILES: [CH:1]1([C:4]2[C:5]([O:13][CH2:14][C:15]([F:18])([F:17])[F:16])=[N:6][CH:7]=[C:8]([CH:12]=2)[C:9]([OH:11])=O)[CH2:3][CH2:2]1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C(N(CC)C(C)C)(C)C.Cl.[F:51][C:52]1[CH:57]=[CH:56][C:55]([N:58]([CH3:60])[NH2:59])=[CH:54][CH:53]=1>CN(C=O)C.O1CCCC1>[F:51][C:52]1[CH:57]=[CH:56][C:55]([N:58]([CH3:60])[NH:59][C:9](=[O:11])[C:8]2[CH:12]=[C:4]([CH:1]3[CH2:2][CH2:3]3)[C:5]([O:13][CH2:14][C:15]([F:18])([F:17])[F:16])=[N:6][CH:7]=2)=[CH:54][CH:53]=1
Reactant: O=C(O)c1cnc(OCC(F)(F)F)c(C2CC2)c1
Reactant: CN(N)c1ccc(F)cc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: CN(NC(=O)c1cnc(OCC(F)(F)F)c(C2CC2)c1)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
In a 10 mL two-necked flask, the above synthesized 5-cyclopropyl-6-(2,2,2-trifluoroethoxy)nicotinic acid (50 mg, 191 μmol, Eq: 1.00) was combined with tetrahydrofuran (1.00 ml) and DMF (1 ml) to give a colorless solution. TBTU (92.2 mg, 287 μmol, Eq: 1.5) and N,N-diisopropylethylamine (124 mg, 167 μl, 957 μmol, Eq: 5) were added and the reaction mixture was stirred for 10 min at rt; then 1-(4-fluorophenyl)-1-methylhydrazine hydrochloride (40.6 mg, 230 μmol, Eq: 1.2; CAN 1978-54-7) was added and the reaction allowed to proceed over night at rt. The reaction mixture was then quenched with 1 M HCl (10 mL) and extracted with EtOAc (2×20 mL). The organic layers were washed with 1 M NaOH, then with H2O/NaCl solution. The organic layers were combined, dried over Na2SO4 and concentrated in vacuo. Purification by flash chromatography (silica gel, 10 g, 15% to 50% EtOAc in heptane) delivered finally 70 mg of the title product as white semisolid; MS (EI) 384.3 (M+H)+.
Reaction SMILES: C[C@H](OC1N=C2C(N=C(OC)N2CCCCNC2CCOCC2)=C(N)N=1)CCC.Cl[CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][N:36]1[C:44]([O:45][CH3:46])=[N:43][C:42]2[C:37]1=[N:38][C:39]([O:48][C@@H:49]([CH3:53])[CH2:50][CH2:51][CH3:52])=[N:40][C:41]=2[NH2:47].[O:54]1[CH2:59][CH2:58][CH:57]([CH2:60][NH2:61])[CH2:56][CH2:55]1>>[CH3:53][C@H:49]([O:48][C:39]1[N:38]=[C:37]2[C:42]([N:43]=[C:44]([O:45][CH3:46])[N:36]2[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31][NH:61][CH2:60][CH:57]2[CH2:58][CH2:59][O:54][CH2:55][CH2:56]2)=[C:41]([NH2:47])[N:40]=1)[CH2:50][CH2:51][CH3:52]
Reactant: CCC[C@H](C)Oc1nc(N)c2nc(OC)n(CCCCCCl)c2n1
Reactant: NCC1CCOCC1
Agent: CCC[C@H](C)Oc1nc(N)c2nc(OC)n(CCCCNC3CCOCC3)c2n1
Product: CCC[C@H](C)Oc1nc(N)c2nc(OC)n(CCCCCNCC3CCOCC3)c2n1
Temperature: 70 °C

Procedure:
Prepared similarly to Intermediate 36 from 9-(5-chloropentyl)-2-{[(1S)-1-methylbutyl]oxy}-8-(methyloxy)-9H-purin-6-amine and (tetrahydro-2H-pyran-4-ylmethyl)amine but with heating at 70° C. for an additional 20 hours.
Reaction SMILES: [CH2:1]([C:3](=[CH:7][CH:8]=[CH:9][C:10]1[CH:15]=[CH:14][C:13]2[O:16][CH2:17][O:18][C:12]=2[CH:11]=1)[CH2:4][CH2:5]Br)[CH3:2].[I-:19].[Na+]>CC(C)=O>[CH2:1]([C:3](=[CH:7][CH:8]=[CH:9][C:10]1[CH:15]=[CH:14][C:13]2[O:16][CH2:17][O:18][C:12]=2[CH:11]=1)[CH2:4][CH2:5][I:19])[CH3:2]
Reactant: CCC(=CC=Cc1ccc2c(c1)OCO2)CCBr
Reactant: [I-]
Agent: [Na+]
Solvent: CC(C)=O
Product: CCC(=CC=Cc1ccc2c(c1)OCO2)CCI

Procedure:
D11. 3-Ethyl-6-(3,4-methylenedioxyphenyl)-3,5-hexadienyl iodide [IX; Ar is 3,4-methylenedioxyphenyl, R is C2H5 ] was prepared from 10 g. of 3-ethyl-6-(3,4-methylenedioxyphenyl)-3,5-hexadienyl bromide (Preparation C10) and 6 g. of sodium iodide in 120 ml. of acetone, to give 10.5 g. of product as an oil.
Reaction SMILES: C(OC([N:8]1[CH2:12][C@@H:11]([CH2:13][NH:14][C:15]([C:17]2[N:18]=[CH:19][S:20][CH:21]=2)=[O:16])[CH2:10][C@H:9]1[C:22]([N:24]1[CH2:28][CH2:27][S:26][CH2:25]1)=[O:23])=O)(C)(C)C.Cl.O1CCOCC1>CO.O>[S:26]1[CH2:27][CH2:28][N:24]([C:22]([C@H:9]2[NH:8][CH2:12][C@@H:11]([CH2:13][NH:14][C:15]([C:17]3[N:18]=[CH:19][S:20][CH:21]=3)=[O:16])[CH2:10]2)=[O:23])[CH2:25]1
Reactant: CC(C)(C)OC(=O)N1C[C@@H](CNC(=O)c2cscn2)C[C@H]1C(=O)N1CCSC1
Agent: Cl
Solvent: O
Solvent: C1COCCO1
Solvent: CO
Product: O=C(NC[C@@H]1CN[C@H](C(=O)N2CCSC2)C1)c1cscn1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of Example 55A (4.8 g, 11.3 mmol) in anhydrous methanol (10 mL) a solution of 4 M HCl in dioxane (22.5 mL, 90 mmol) was slowly added via addition funnel at 0° C. over 30 minutes. The mixture was stirred for 4 hours at room temperature and concentrated under reduced pressure to provide a yellow oil. The oil was dissolved in water, frozen, and lyophilized to provide a white power as the titled product. MS (ESI) m/e 327 (M+H)+, 325 (M−H)−; 1H NMR (500 MHz, CD3OD) δ ppm 1.80 (m, 1H), 2.74 (m, 1H), 2.84 (m, 1H), 3.09 (m, 1H), 3.16 (t, 1H), 3.24 (m, 1H), 3.52 (dd, 2H), 3.55 (m, 1H), 3.74 (m, 1H), 3.88 (m, 1H), 4.51 (m, 1H), 4.65 (d, 1H), 4.70 (d, 1H), 8.33 (s, 1H) 9.11 (s, 1H).