Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[N:8]=[C:7]([C:9]2[CH:10]=[C:11]([S:15]([NH2:18])(=[O:17])=[O:16])[CH:12]=[CH:13][CH:14]=2)[CH:6]=[C:5]([NH:19][CH2:20][CH2:21][C:22]2[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[CH:24][CH:23]=2)[N:4]=1.[H-].[Na+].Cl[C:33]([O:35][CH3:36])=[O:34].O>C1COCC1>[CH3:36][O:35][C:33]([NH:18][S:15]([C:11]1[CH:12]=[CH:13][CH:14]=[C:9]([C:7]2[CH:6]=[C:5]([NH:19][CH2:20][CH2:21][C:22]3[CH:23]=[CH:24][C:25]([O:28][CH3:29])=[CH:26][CH:27]=3)[N:4]=[C:3]([O:2][CH3:1])[N:8]=2)[CH:10]=1)(=[O:16])=[O:17])=[O:34]
Reactant: COc1ccc(CCNc2cc(-c3cccc(S(N)(=O)=O)c3)nc(OC)n2)cc1
Reactant: COC(=O)Cl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: COC(=O)NS(=O)(=O)c1cccc(-c2cc(NCCc3ccc(OC)cc3)nc(OC)n2)c1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
A solution of 3-{2-methoxy-6-[2-(4-methoxy-phenyl)-ethylamino]-pyrimidin-4-yl}-benzenesulfonamide [100 mg, Example 3] in THF (10 mL) is treated with sodium hydride (20 mg). The mixture is stirred at 0° C. for 60 minutes, treated with methyl chloroformate (1 mL) and stirring is continued 0° C. for a further 60 minutes. The reaction mixture is poured into water and extracted twice with EtOAc (50 mL). The combined extracts are washed with water, dried over sodium sulfate, filtered, and evaporated. The residue is subjected to chromatography on silica gel eluting with EtOAc in heptanes (1:1, v/v) to give N-methoxycarbonyl-3-{2-methoxy-6-[2-(4-methoxy-phenyl)-ethylamino]-pyrimidin-4-yl}-benzenesulfonamide [41 mg, Example 4(c)] as a solid. MS: 473 (M+H), 1H NMR [(CD3)2SO]: δ 12.2 (1H, s); 8.4 (1H, s); 8.15 (1H, m); 8 (1H, d, J=3 Hz); 7.65-7.8 (1H, m); 7.2 (2H, d, J=7 Hz); 6.9 (2H, d, J=7 Hz); 6.7 (1H, s); 3.9 (3H, s); 3.7 (3H, s); 3.5-3.6 (2H, m); 3.6 (3H, s); 2.8 (2H, t).
Reaction SMILES: C(N(CC)CC)C.[OH:8][CH2:9][CH2:10][C:11]1([C:16]2[CH:21]=[CH:20][C:19]([Cl:22])=[C:18]([Cl:23])[CH:17]=2)[CH2:15][CH2:14][NH:13][CH2:12]1.[CH:24]([O:27][C:28]1[CH:29]=[C:30]([CH2:34][C:35](O)=[O:36])[CH:31]=[CH:32][CH:33]=1)([CH3:26])[CH3:25]>C(Cl)Cl>[OH:8][CH2:9][CH2:10][C:11]1([C:16]2[CH:21]=[CH:20][C:19]([Cl:22])=[C:18]([Cl:23])[CH:17]=2)[CH2:15][CH2:14][N:13]([C:35](=[O:36])[CH2:34][C:30]2[CH:31]=[CH:32][CH:33]=[C:28]([O:27][CH:24]([CH3:25])[CH3:26])[CH:29]=2)[CH2:12]1
Reactant: CC(C)Oc1cccc(CC(=O)O)c1
Reactant: OCCC1(c2ccc(Cl)c(Cl)c2)CCNC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)Oc1cccc(CC(=O)N2CCC(CCO)(c3ccc(Cl)c(Cl)c3)C2)c1
Temperature: 0 °C

Procedure:
Triethylamine (22.5 ml) and 3-(2-hydroxyethyl)-3-(3,4-dichlorophenyl)pyrrolidine (22 grams) are added to a solution of 16 grams of 3-isopropoxyphenylacetic acid in 500 ml of methylene chloride. The mixture is cooled to 0° C. and 42.6 grams of benzotriazolyl-N-oxytrisdimethylaminophosphonium hexafluorophosphate are then added and the reaction mixture is allowed to warm up to room temperature. After thirty minutes, the mixture is concentrated under vacuum and the residue is taken up in diethyl ether and washed successively with water, a dilute sodium hydroxide solution, a saturated sodium chloride solution, a dilute hydrochloric acid solution, a saturated sodium chloride solution, and a solution of sodium bicarbonate. The organic fraction is dried over magnesium sulfate, filtered, and concentrated in vacuo to yield the title intermediate.
Reaction SMILES: [CH:1]([OH:4])([CH3:3])[CH3:2].[H-].[Na+].[I:7][C:8]1[N:9]=[N:10][C:11](I)=[CH:12][CH:13]=1.O>C1COCC1>[I:7][C:8]1[N:9]=[N:10][C:11]([O:4][CH:1]([CH3:3])[CH3:2])=[CH:12][CH:13]=1
Reactant: Ic1ccc(I)nn1
Reactant: CC(C)O
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)Oc1ccc(I)nn1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
0.50 mL (6.6 mmol) isopropanol are added to 289 mg (7.23 mmol) sodium hydride (60%) in 100 mL THF and the mixture is stirred for 30 min at rt. After that time, 2.0 g (6.0 mmol) 3,6-diiodo-pyridazine are added and the mixture is stirred for 14 h at rt and for 14 h at 50° C. After that time, the mixture is poured into water and extracted with EtOAc. The organic layer is washed with water (2×) and dried over sodium sulphate. The solvent is removed in vacuo and the residue is purified by column chromatography (silicia gel; heptane:EtOAc gradient 0 to 50%).
Reaction SMILES: [CH3:1][N:2]1[C:9](Cl)=[CH:8][C:6](=[O:7])[N:5]([CH:11]2[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]2)[C:3]1=[O:4].C([O-])(=O)C.[Na+].Cl.[NH2:23][OH:24]>COCCO>[CH3:1][N:2]1[C:9]([NH:23][OH:24])=[CH:8][C:6](=[O:7])[N:5]([CH:11]2[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]2)[C:3]1=[O:4]
Reactant: NO
Reactant: Cn1c(Cl)cc(=O)n(C2CCCCC2)c1=O
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: COCCO
Product: Cn1c(NO)cc(=O)n(C2CCCCC2)c1=O
Reaction time: 1 h
Yield: 58 %

Procedure:
A mixture of 7 g of 1-methyl-3-cyclohexyl-6-chlorouracil, 18 g of sodium acetate (trihydrate), 7 g of hydroxylamine hydrochloride and 100 ml of methyl-cellosolve is boiled for 1 hour and, when cold, the insolubles are removed by filtration. The filtrate is concentrated and recrystallized from water-ethanol. By the above procedure is obtained 4 g of 1-methyl-3-cyclohexyl-6-hydroxyaminouracil, melting point: 153°-155° C.
Reaction SMILES: [C:1]([CH:4]1[C:16]2[NH:15][C:14]3[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=3)[C:8]=2[CH2:7][CH2:6][NH:5]1)(=[O:3])[CH3:2].[H-].[Na+].[CH2:19](Br)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>CN(C)C=O>[C:1]([CH:4]1[C:16]2[N:15]([CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[C:14]3[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=3)[C:8]=2[CH2:7][CH2:6][NH:5]1)(=[O:3])[CH3:2]
Reactant: CC(=O)C1NCCc2c1[nH]c1ccccc21
Reactant: BrCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(=O)C1NCCc2c1n(Cc1ccccc1)c1ccccc21
Reaction time: 1 h

Procedure:
2 acetyl-9 benzyl-1,2,3,4-tetrahydro-β-carboline was prepared as follows: Under a nitrogen atmosphere, 8.0 mmol of 2 acetyl-1,2,3,4-tetrahydro-β-carboline (1.71 was dissolved in 4Q mL dry dimethylformamide (DMF). The solution was stirred over ice, and NaH (2 g) was added under N2. The suspension was stirred for 1 hour, and then benzylbromide (9.2 mmol, 1.56 was slowly to the cooled suspension. After a further 2 hours of stirring at ambient temperature, the mixture was filtered and the filtrate added to 320 mL 0.1 N HCl. Crude 2-acetyl- 9-benzyl-1,2,3,4-tetrahydro-β-carboline separated as an oil. The oil was collected by centrifugation, washed with water, and dried over anhydrous MgSO:. The product was purified by standard chromatographic procedures using a 60:40 mixture of ether:hexane.
Reaction SMILES: [CH:1]([C:3]1[CH:7]=[CH:6][NH:5][N:4]=1)=[O:2].[CH2:8]=[O:9].C(N(CC)CC)C>CC(C)=O>[OH:9][CH2:8][N:5]1[CH:6]=[CH:7][C:3]([CH:1]=[O:2])=[N:4]1
Reactant: C=O
Reactant: O=Cc1cc[nH]n1
Solvent: CC(C)=O
Solvent: CCN(CC)CC
Product: O=Cc1ccn(CO)n1
Temperature: 100 °C
Reaction time: 5 h
Yield: 96 %

Procedure:
The mixture of 0.96 g of 3-formyl-1H-pyrazole, 0.60 g of paraformaldehyde and 0.3 ml of triethylamine was stirred at 100° C. for 5 hours. After the reaction mixture was cooled to room temperature, acetone was added to the reaction mixture. The mixture was filtered. The filterate was concentrated under reduced pressure to obtain 1.21 g of 1-(hydroxymethyl)-3-formyl-1H-pyrazole. The crude product was used for next process without purification.
Reaction SMILES: [NH2:1][C:2]1[C:7]([F:8])=[C:6]([C:9]2[CH:14]=[C:13]([F:15])[C:12]([Si](C)(C)C)=[CH:11][C:10]=2[F:20])[N:5]=[C:4]([C:21]([O:23][CH3:24])=[O:22])[C:3]=1[Cl:25].[I:26]Cl.[O-]S([O-])=O.[Na+].[Na+]>C(Cl)Cl>[NH2:1][C:2]1[C:7]([F:8])=[C:6]([C:9]2[CH:14]=[C:13]([F:15])[C:12]([I:26])=[CH:11][C:10]=2[F:20])[N:5]=[C:4]([C:21]([O:23][CH3:24])=[O:22])[C:3]=1[Cl:25]
Reactant: COC(=O)c1nc(-c2cc(F)c([Si](C)(C)C)cc2F)c(F)c(N)c1Cl
Reactant: ClI
Agent: O=S([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Product: COC(=O)c1nc(-c2cc(F)c(I)cc2F)c(F)c(N)c1Cl
Temperature: 20 °C
Reaction time: 8 h
Yield: 74.4 %

Procedure:
To a solution of methyl 4-amino-3-chloro-6-(2,5-difluoro-4-(trimethylsilyl)phenyl)-5-fluoropicolinate (0.280 g, 0.720 mmol) in CH2Cl2 (2.88 mL) at 20° C. was added iodine monochloride (0.144 mL, 2.880 mmol). The reaction mixture was stirred at 20° C. overnight. The mixture was then poured into a 10% aqueous solution of Na2SO3, extracted with EtOAc (3×), dried over Na2SO4, filtered and concentrated. The residue was purified by flash column chromatography (SiO2, hexanes/EtOAc gradient) to afford the title compound as a white solid (0.237 g, 0.536 mmol, 74.4%).
Reaction SMILES: C1([Li])C=CC=CC=1.C(=O)=O.[CH:11](=[N:18][CH2:19][P:20](=[O:35])([O:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)[O:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.Cl[C:37]([O:39][CH2:40][C:41]1[CH:46]=[CH:45][C:44]([N+:47]([O-:49])=[O:48])=[CH:43][CH:42]=1)=[O:38]>O1CCCC1>[CH:11](=[N:18][CH:19]([P:20]([O:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)([O:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=[O:35])[C:37]([O:39][CH2:40][C:41]1[CH:42]=[CH:43][C:44]([N+:47]([O-:49])=[O:48])=[CH:45][CH:46]=1)=[O:38])[C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: O=P(CN=Cc1ccccc1)(Oc1ccccc1)Oc1ccccc1
Reactant: O=C(Cl)OCc1ccc([N+](=O)[O-])cc1
Agent: O=C=O
Agent: [Li]c1ccccc1
Solvent: C1CCOC1
Product: O=C(OCc1ccc([N+](=O)[O-])cc1)C(N=Cc1ccccc1)P(=O)(Oc1ccccc1)Oc1ccccc1
Reaction time: 0.25 h

Procedure:
Phenyllithium (45 ml of a 2.3 M solution in 7:3 benzene-ether) in added to a dry-ice-cooled, stirring solution of diphenyl N-benzylidene-aminomethylphosphonate (35.1 g) in anhydrous tetrahydrofuran (500 ml). After having been stirred for 15 minutes at -78° under a nitrogen atmosphere, the solution is treated dropwise over 1 hour with p-nitrobenzyl chloroformate (10.8 g) in tetrahydrofuran (100 ml). The resulting solution is stirred an additional 2 hours at -78°, then allowed to warm to 5° over a period of 30 minutes. Evaporation of the solvent under reduced pressure leaves a residue which is partitioned between ethyl ether (500 ml) and 0.5 pH 3 phosphate buffer (200 ml). The aqueous phase is separated and extracted with ethyl ether (2 × 100 ml). The combined ethereal solution is washed with saturated brine, dried over magnesium sulfate, filtered, and concentrated in vacuo. Chromatography of the residue on silica gel affords p-nitrobenzyl N-benzylidene-α-amino-diphenylphosphonoacetate as well as starting material.
Reaction SMILES: [NH2:1][C:2]1[S:6][C:5]([NH:7][C:8]2[CH:17]=[CH:16][C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[CH:9]=2)=[N:4][C:3]=1[C:18]([O:20][CH2:21][CH3:22])=[O:19].[F:23][C:24]1[CH:32]=[CH:31][C:27]([C:28](Cl)=[O:29])=[CH:26][CH:25]=1>N1C=CC=CC=1.CCOC(C)=O>[F:23][C:24]1[CH:32]=[CH:31][C:27]([C:28]([NH:1][C:2]2[S:6][C:5]([NH:7][C:8]3[CH:17]=[CH:16][C:15]4[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=4)[CH:9]=3)=[N:4][C:3]=2[C:18]([O:20][CH2:21][CH3:22])=[O:19])=[O:29])=[CH:26][CH:25]=1
Reactant: CCOC(=O)c1nc(Nc2ccc3ccccc3c2)sc1N
Reactant: O=C(Cl)c1ccc(F)cc1
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Product: CCOC(=O)c1nc(Nc2ccc3ccccc3c2)sc1NC(=O)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 59.5 %

Procedure:
To a solution of ethyl 5-amino-2-(naphthalen-2-ylamino)thiazole-4-carboxylate (170 mg, 0.54 mmol) in pyridine (3 mL) was added 4-fluorobenzoyl chloride (0.09 mL, 0.81 mmol) at 0° C. The mixture was allowed to warm to rt, and stirred overnight. The reaction mixture was diluted with EtOAc, and washed with water. The organic layer was dried over Na2SO4 and concentrated in vacuo. The residue was triturated with EtOAc, and the resulting solids were collected by filtration to give 140 mg (59% Yield) of the titled compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([NH2:9])=[CH:5][N:4]=1.C([O-])(=O)C.[Na+].[Br:15]Br.[OH-].[Na+]>C(O)(=O)C>[NH2:9][C:6]1[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[N:4][C:5]=1[Br:15]
Reactant: BrBr
Reactant: COc1ccc(N)cn1
Agent: CC(=O)[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Product: COc1ccc(N)c(Br)n1
Reaction time: 0.33 h
Yield: 39.5 %

Procedure:
A stirred mixture of 2-methoxy-5-aminopyridine (10 g, 0.081 mol, 1.0 equiv) and sodium acetate (6.6 g, 0.081 mol, 1.0 equiv) in 60 mL of acetic acid was treated dropwise with bromine (12.9 g, 0.081 mol, 1.0 equiv). After 20 minutes, the reaction mixture was poured into 1000 mL of 10% aqueous sodium hydroxide solution and extracted with three 250 mL portions of ethyl acetate. The combined organic layers were dried over magnesium sulfate, filtered, and evaporated to dryness. Chromatography on SiO2 (20% hexanes in dichloromethane) gave 5-amino-6-bromo-2-methoxypyridine (6.5 g, 40% yield) as a purple solid.
Reaction SMILES: FC1C=CC(S[C:9]([S:11][C:12]2[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=2)=[S:10])=CC=1.[H-].[Na+].[F:21][C:22]1[CH:27]=[CH:26][C:25]([C:28](=[O:32])[CH2:29][C:30]#[N:31])=[CH:24][CH:23]=1.CN(C=O)C>C1C=CC=CC=1>[C:30]([CH:29]([C:28]([C:25]1[CH:24]=[CH:23][C:22]([F:21])=[CH:27][CH:26]=1)=[O:32])[C:9]([S:11][C:12]1[CH:13]=[CH:14][C:15]([F:18])=[CH:16][CH:17]=1)=[S:10])#[N:31]
Reactant: Fc1ccc(SC(=S)Sc2ccc(F)cc2)cc1
Reactant: N#CCC(=O)c1ccc(F)cc1
Agent: [H-]
Agent: [Na+]
Solvent: c1ccccc1
Solvent: CN(C)C=O
Product: N#CC(C(=O)c1ccc(F)cc1)C(=S)Sc1ccc(F)cc1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 30.6 %

Procedure:
Trithiocarbonate (0.644 g, 2.15 mmol) from step (i) was added to a stirred suspension of sodium hydride (0.165 g, 0.412 mmol) in benzene (2.0 mL). Then, 3-(4-fluorophenyl)-3-oxopropanenitrile (0.320 g, 1.96 mmol) was added as a solution in benzene (2.0 mL). The reaction mixture was stirred for 5 min then DMF (2.0 mL) was added slowly. After addition was complete the reaction mixture was heated to reflux for 30 min and then allowed to cool to ambient temperature before being partitioned between H2O and Et2O. The aqueous layer was separated and washed with two additional portions of Et2O, then acidified with aqueous 2 N HCl. The acidic aqueous layer was then extracted with two portions of EtOAc, which were combined, washed with brine, dried over Na2SO4, and concentrated. The residue was purified by flash chromatography, eluting with a gradient of 25-100% EtOAc/hexanes to afford the product as a yellow solid (0.20 g, 0.60 mmol, 31% yield). MS (M−H)− 332.
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][CH2:3][C:2]1=[O:6].CCCCCC.Cl[C:14]([O:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=[O:15]>C1COCC1>[C:14]([N:1]1[CH2:5][CH2:4][CH2:3][C:2]1=[O:6])([O:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=[O:15]
Reactant: O=C(Cl)OCc1ccccc1
Reactant: O=C1CCCN1
Solvent: C1CCOC1
Solvent: CCCCCC
Product: O=C1CCCN1C(=O)OCc1ccccc1
Yield: 86.9 %

Procedure:
To a solution of 2-pyrrolidinone (1.7 g, 21 mmol) in dry THF (25 mL), at −78° C., a 2.5 N solution of n-buthyllithium in n-hexane (8.4 mL, 21 mmol) is added. The mixture is stirred for 30′ and then a solution of benzyl chlorformate (3.03 mL, 21 mmol) in dry THF (30 mL) is added dropwise. The reaction mixture is stirred until the reaction is complete, quenched with saturated aqueous NH4Cl and ectracted with diethyl ether (3×). The combined organic phase is washed with brine and dried over anhydrous Na2SO4. Evaporation of the solvent gives 4 g (87%) of a colourless oil that is used without any further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([F:11])[C:3]=1[C:4]([OH:6])=O.[CH3:12][C:13]1[N:18]=[CH:17][C:16]([CH:19]([N:22]2[CH2:28][CH2:27][CH2:26][O:25][CH2:24][CH2:23]2)[CH2:20][NH2:21])=[CH:15][N:14]=1>>[Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([F:11])[C:3]=1[C:4]([NH:21][CH2:20][CH:19]([C:16]1[CH:17]=[N:18][C:13]([CH3:12])=[N:14][CH:15]=1)[N:22]1[CH2:28][CH2:27][CH2:26][O:25][CH2:24][CH2:23]1)=[O:6]
Reactant: Cc1ncc(C(CN)N2CCCOCC2)cn1
Reactant: O=C(O)c1c(F)cccc1Cl
Product: Cc1ncc(C(CNC(=O)c2c(F)cccc2Cl)N2CCCOCC2)cn1

Procedure:
From 2-chloro-6-fluorobenzoic acid and 2-(2-methylpyrimidin-5-yl)-2-(1,4-oxazepan-4-yl)ethanamine.
Reaction SMILES: Cl.Cl.[NH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[N:10]1[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[C:12]2([CH2:17][CH2:16][N:15]([CH3:18])[CH2:14][CH2:13]2)[CH2:11]1.N(CCO)(CCO)CCO.Cl[C:36]([O:38][CH2:39][CH3:40])=[O:37]>C(Cl)(Cl)Cl>[CH2:39]([O:38][C:36]([NH:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[N:10]1[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[C:12]2([CH2:17][CH2:16][N:15]([CH3:18])[CH2:14][CH2:13]2)[CH2:11]1)=[O:37])[CH3:40]
Reactant: CCOC(=O)Cl
Reactant: CN1CCC2(CC1)CN(c1ccccc1N)c1ccccc12
Agent: Cl
Solvent: OCCN(CCO)CCO
Solvent: ClC(Cl)Cl
Product: CCOC(=O)Nc1ccccc1N1CC2(CCN(C)CC2)c2ccccc21
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A slurry of 10.36 g of 1-(2-aminophenyl)-1'-methylspiro[indoline-3,4'-piperidine] dihydrochloride of Example 1b in 60 ml of chloroform is treated portionwise with 12.3 ml of triethanolamine. The resulting mixture is cooled in an ice bath and treated dropwise over 40 minutes with a solution of 2.7 ml of ethyl chloroformate in 20 ml of chloroform. After stirring at room temperature for 1 hour, an additional 3.0 ml of ethyl chloroformate is added and the mixture is permitted to stand 16 hours. The product is washed thrice with water, brine, dried over anhydrous sodium sulfate, concentrated and pumped on under high vacuum to give a crude carbamate. Chromatography on silica gel (100 g) using ether-methylene chloride affords an oil. The material crystallizes on prolonged standing to yield 1-[2-(ethoxycarbonyl)aminophenyl]-1'-methylspiro[indoline-3,4'-piperidine], mp 99.5°-101.0° C.
Reaction SMILES: [NH2:1][C:2]1[NH:6][N:5]=[CH:4][C:3]=1[CH2:7][CH2:8][CH2:9][CH2:10][C:11]#[N:12].C([O:15][C:16]([N:18]=[C:19]=[S:20])=O)C.[OH-].[NH4+]>CCOC(C)=O>[OH:15][C:16]1[N:6]2[N:5]=[CH:4][C:3]([CH2:7][CH2:8][CH2:9][CH2:10][C:11]#[N:12])=[C:2]2[N:1]=[C:19]([SH:20])[N:18]=1
Reactant: CCOC(=O)N=C=S
Reactant: N#CCCCCc1cn[nH]c1N
Agent: [NH4+]
Agent: [OH-]
Solvent: CCOC(C)=O
Product: N#CCCCCc1cnn2c(O)nc(S)nc12
Temperature: 25 °C

Procedure:
To a solution of compound (2) (4.6 g. 14 mmol) in EtOAc (50 mL) was added Ethoxycarbonyli-sothiocyanate (1.69 mL, 15 mmol) drop wise with stirring at ambient temperature. The reaction mixture was refluxed for 2 h, and cooled to room temperature. Ammonium hydroxide (10 mL) was added and the reaction mixture stirred at room temperature for 20 h. The reaction mixture was extracted twice with 1 M NaOH and the aqueous extractions were combined, acidified with concentrate HCl, and extracted twice with EtOAc. The combined organic extracts were dried with anhydrous Na2SO4 and concentrated to give 5-(4-hydroxy-2-mercapto-pyrazolo[1,5-a][1,3,5]triazin-8-yl)-pentanenitrile (3), as a white solid (2.5 g, 67%).
Reaction SMILES: [CH3:1][SH:2].[H-].[Na+].[Cl:5][C:6]1[C:12](Cl)=[CH:11][C:9]([NH2:10])=[C:8]([N+:14]([O-:16])=[O:15])[CH:7]=1.O>CN(C=O)C>[Cl:5][C:6]1[C:12]([S:2][CH3:1])=[CH:11][C:9]([NH2:10])=[C:8]([N+:14]([O-:16])=[O:15])[CH:7]=1
Reactant: CS
Reactant: Nc1cc(Cl)c(Cl)cc1[N+](=O)[O-]
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CSc1cc(N)c([N+](=O)[O-])cc1Cl
Reaction time: 0.5 h

Procedure:
Methyl mercaptan gas was passed into a stirred suspension of 1.16 g (30 mmol) of 60% oil-dispersed NaH in 45 mL of DMF until evolution of H2 gas ceased. 5 g (24 mmol) of 4,5-dichloro-2-nitroaniline (Aldrich) was then added portionwise. After 30 min of stirring, the reaction mixture was poured into 200 mL of water. Yellow precipitate formed was collected by filtration and dried. This gave 3.8 g (72%) of the title compound as a yellow solid. 1H NMR (DMSO-d6) δ2.5 (s, 3H, CH3), 6.9 (s, 1H, aromatic), 7.6 (br s, 2H, NH2), 8.0 (s, 1H, aromatic)
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:9]([CH3:11])[C:5]([C:6](N)=[O:7])=[C:4]([O:12][CH3:13])[CH:3]=1.N(OS(=O)(=O)O)=[O:15]>C(Cl)Cl.O>[Br:1][C:2]1[CH:10]=[C:9]([CH3:11])[C:5]([C:6]([OH:15])=[O:7])=[C:4]([O:12][CH3:13])[CH:3]=1
Reactant: COc1cc(Br)cc(C)c1C(N)=O
Reactant: O=NOS(=O)(=O)O
Solvent: O
Solvent: ClCCl
Product: COc1cc(Br)cc(C)c1C(=O)O
Reaction time: 2 h
Yield: 96 %

Procedure:
4-Bromo-2-methoxy-6-methylbenzamide (2.0 g, 8.2 mmol), dissolved in CH2Cl2, was added dropwise to nitrosyl sulfuric acid (14.0 mL) in water (6.0 mL) at 0° C. and stirred for 2 hours. The reaction mixture was poured over ice and extracted with CH2Cl2, and the solvent was removed under reduced pressure to afford a light pink solid (1.93 g, 96%). 1H NMR (300 MHz, CDCl3): δ 7.07 (s, 1H), 7.00 (s, 1H), 3.93 (s, 3H), 2.46 (s, 3H).
Reaction SMILES: [NH2:1][CH:2]1[CH2:14][O:13][C:12]2[CH:11]=[CH:10][C:9]3[CH2:8][NH:7][C:6](=[O:15])[C:5]=3[C:4]=2[CH2:3]1.[F:16][C:17]1[CH:18]=[C:19]2[C:23](=[CH:24][CH:25]=1)[NH:22][CH:21]=[C:20]2[CH2:26][CH2:27][CH2:28][CH:29]=O.C(O)(=O)C.[BH3-]C#N.[Na+]>CO>[F:16][C:17]1[CH:18]=[C:19]2[C:23](=[CH:24][CH:25]=1)[NH:22][CH:21]=[C:20]2[CH2:26][CH2:27][CH2:28][CH2:29][NH:1][CH:2]1[CH2:14][O:13][C:12]2[CH:11]=[CH:10][C:9]3[CH2:8][NH:7][C:6](=[O:15])[C:5]=3[C:4]=2[CH2:3]1
Reactant: NC1COc2ccc3c(c2C1)C(=O)NC3
Reactant: O=CCCCc1c[nH]c2ccc(F)cc12
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: O=C1NCc2ccc3c(c21)CC(NCCCCc1c[nH]c2ccc(F)cc12)CO3
Reaction time: 1.5 h
Yield: 78 %

Procedure:
To a mixture of (1) (60 mg, 0.294 mmol), 4-(5-fluoro-1H-indol-3-yl)butanal (21), 63 mg, 0.294 mmol) in acetic acid (37 μl, 0.62 mmol) and methanol (4 ml) was added NaBH3CN (37 mg, 0.588 mmol) in portions. Resulting mixture was stirred for 1.5 hr. The solvent was removed in vacuo and the residue was dissolved in CH2Cl2 and washed with 1 N NaOH and saturated NaCl. The organic solution was dried over Na2SO4 and concentrated in vacuo. The compound was purified on silica gel eluting with 60% EtOAc/Hexane to give (25) as a solid (90 mg, 78%). MS (ES) m/z 394.2;
Reaction SMILES: [CH3:1][C:2]1([CH3:10])[O:9][C:7](=[O:8])[CH2:6][C:4](=[O:5])[O:3]1.C(N(CC)CC)C.[C:18](Cl)(=[O:28])[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27]>ClCCl>[C:18]([CH:6]1[C:7](=[O:8])[O:9][C:2]([CH3:10])([CH3:1])[O:3][C:4]1=[O:5])(=[O:28])[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27]
Reactant: CC1(C)OC(=O)CC(=O)O1
Reactant: CCCCCCCCCC(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCCCCCCCCC(=O)C1C(=O)OC(C)(C)OC1=O
Temperature: 25 °C
Reaction time: 12 h

Procedure:
Meldrum's acid (7.20 g, 50 mmol) and triethyl amine (5.56 g, 55 mmol) were dissolved in dichloromethane (50 mL), and decanoic acid chloride (10.48 g, 55 mmol) was added to the resulting mixture dropwise while cooling with ice. The reaction mixture was stirred at room temperature for about 12 hours, and then concentrated under reduced pressure. The ethyl acetate layer thus obtained was washed with diluted hydrochloric acid and an aqueous saturated sodium chloride solution, dried over magnesium sulfate, and then concentrated under reduced pressure. The resulting residue was purified using silica gel chromatography (developing solvent: n-hexane/ethyl acetate=3/7) to obtain 5-decanoyl-2,2-dimethyl-1,3-dioxane-4,6-dione.
Reaction SMILES: [C:1]([C:3]1[CH:9]=[CH:8][C:7]([C:10]([F:13])([F:12])[F:11])=[CH:6][C:4]=1[NH2:5])#[N:2].[N:14]([O-])=O.[Na+]>Cl>[NH2:2][C:1]1[C:3]2[C:4](=[CH:6][C:7]([C:10]([F:11])([F:12])[F:13])=[CH:8][CH:9]=2)[NH:5][N:14]=1
Reactant: N#Cc1ccc(C(F)(F)F)cc1N
Reactant: O=N[O-]
Agent: Cl
Agent: [Na+]
Product: Nc1n[nH]c2cc(C(F)(F)F)ccc12

Procedure:
To a mixture of 18.6 g. of 2-cyano-5-trifluoromethylaniline and 120 ml. of concentrated hydrochloric acid is added dropwise 8.0 g. of sodium nitrite in aqueous solution. The resulting diazo solution is added dropwise to 152 g. of stannous chloride in concentrated hydrochloric acid at 0° C. After allowing the mixture to stand for several hours at 0° C., it is filtered. The solid is treated with boiling water and the solution is made alkaline. The precipitate is recrystallized from benzene to give 3-amino-6-trifluoromethylindazole, M.P. 168°-169° C.