Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:3](=[O:35])[NH:4][N:5]=[CH:6][C:7]=1[NH:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[C:12]([O:18][CH2:19][CH2:20][N:21]2[CH2:26][CH2:25][N:24]([CH2:27][C:28]3[CH:33]=[CH:32][C:31]([F:34])=[CH:30][CH:29]=3)[CH2:23][CH2:22]2)[CH:11]=1.[CH2:36](Br)[CH3:37].C(=O)([O-])[O-].[K+].[K+]>CC(=O)CC>[CH2:36]([N:4]1[C:3](=[O:35])[C:2]([Cl:1])=[C:7]([NH:8][CH2:9][C:10]2[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[C:12]([O:18][CH2:19][CH2:20][N:21]3[CH2:26][CH2:25][N:24]([CH2:27][C:28]4[CH:29]=[CH:30][C:31]([F:34])=[CH:32][CH:33]=4)[CH2:23][CH2:22]3)[CH:11]=2)[CH:6]=[N:5]1)[CH3:37]
Reactant: COc1ccc(CNc2cn[nH]c(=O)c2Cl)cc1OCCN1CCN(Cc2ccc(F)cc2)CC1
Reactant: CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: CCn1ncc(NCc2ccc(OC)c(OCCN3CCN(Cc4ccc(F)cc4)CC3)c2)c(Cl)c1=O
Reaction time: 5 h
Yield: 81.3 %

Procedure:
A mixture comprising 500 mg of 4-chloro-5-[3-{2-(4-(4-fluorobenzyl)-piperazin-1-yl)-ethoxy}-4-methoxybenzylamino]-3(2H)-pyridazinone, 130 mg of ethyl bromide, 190 mg of potassium carbonate and 10 ml of 2-butanone, was refluxed under heating with stirring for 5 hours. Inorganic substances were filtered off, and then the solvent was distilled off under reduced pressure. Water was added to the obtained residue, and the mixture was extracted with chloroform. The extract solution was washed with water and a saturated sodium chloride aqueous solution and then dried over anhydrous sodium sulfate. Then, the solvent was distilled off. The obtained residue was purified by silica gel column chromatography (eluent: chloroform/ethanol=19/1) to obtain 429 mg of the above-identified compound as a colorless transparent sticky substance.
Reaction SMILES: [CH:1]([C:4]1[CH:5]=[CH:6][C:7]([N:10]([CH2:21][C:22]2[CH:27]=[CH:26][C:25]([O:28][C:29]([F:32])([F:31])[F:30])=[CH:24][CH:23]=2)[CH2:11][CH2:12][CH2:13][C:14]2[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][CH:15]=2)=[N:8][CH:9]=1)([CH3:3])[CH3:2].C([O:37][C:38](=[O:41])[CH2:39]Br)(C)(C)C.C(O)(C(F)(F)F)=O>>[CH:1]([C:4]1[CH:5]=[CH:6][C:7]([N:10]([CH2:21][C:22]2[CH:23]=[CH:24][C:25]([O:28][C:29]([F:32])([F:30])[F:31])=[CH:26][CH:27]=2)[CH2:11][CH2:12][CH2:13][C:14]2[CH:19]=[CH:18][C:17]([O:20][CH2:39][C:38]([OH:41])=[O:37])=[CH:16][CH:15]=2)=[N:8][CH:9]=1)([CH3:3])[CH3:2]
Reactant: CC(C)c1ccc(N(CCCc2ccc(O)cc2)Cc2ccc(OC(F)(F)F)cc2)nc1
Reactant: CC(C)(C)OC(=O)CBr
Solvent: O=C(O)C(F)(F)F
Product: CC(C)c1ccc(N(CCCc2ccc(OCC(=O)O)cc2)Cc2ccc(OC(F)(F)F)cc2)nc1

Procedure:
Similarly prepared by alkylation of 4-(3-{(5-isopropylpyridin-2-yl)[4-(trifluoromethoxy)benzyl]amino}propyl)phenol with tert-butyl-bromo-acetate followed by standard TFA hydrolysis.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1[CH:18]=[C:17]2[C:12]([CH2:13][CH2:14][CH:15]([CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21])[CH2:16]2)=[CH:11][CH:10]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].[CH3:27]I>CN(C)C=O>[C:1]([O:5][C:6]([N:8]([C:9]1[CH:18]=[C:17]2[C:12]([CH2:13][CH2:14][CH:15]([CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21])[CH2:16]2)=[CH:11][CH:10]=1)[CH3:27])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CI
Reactant: CCOC(=O)CC1CCc2ccc(NC(=O)OC(C)(C)C)cc2C1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)CC1CCc2ccc(N(C)C(=O)OC(C)(C)C)cc2C1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 96 %

Procedure:
In 10 ml of N,N-dimethylformamide, 0.67 g of ethyl 7-[N-(t-butoxycarbonyl)amino]-1,2,3,4-tetrahydro-naphthalene-2-acetate was dissolved and 0.096 g of 60% sodium hydride was added under cooling and stirred for 5 minutes at room temperature. To the mixture, 0.57 g of methyl iodide was dropwise added and allowed to stand overnight at room temperature. The reaction mixture was concentrated under reduced pressure and the concentrated residue was extracted with ethyl acetate. The ethyl acetate solution was dried with anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, then the obtained crude product was purified by silica gel column chromatography using a mixture, ethyl acetate:n-hexane=1:10, as a developer to give 0.67 g of ethyl 7-[N-(t-butoxycarbonyl)-N-methylamino]-1,2,3,4-tetrahydronaphthalene-2-acetate.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][CH2:5][C:6]([C:8]1[CH:13]=[CH:12][C:11]([Cl:14])=[CH:10][CH:9]=1)=[O:7].[NH:15]1[CH2:20][CH2:19][CH:18]([C:21]2[CH:22]=[C:23]([NH:27][C:28](=[O:31])[CH2:29][CH3:30])[CH:24]=[CH:25][CH:26]=2)[CH2:17][CH2:16]1>>[Cl:14][C:11]1[CH:12]=[CH:13][C:8]([C:6](=[O:7])[CH2:5][CH2:4][CH2:3][CH2:2][N:15]2[CH2:20][CH2:19][CH:18]([C:21]3[CH:22]=[C:23]([NH:27][C:28](=[O:31])[CH2:29][CH3:30])[CH:24]=[CH:25][CH:26]=3)[CH2:17][CH2:16]2)=[CH:9][CH:10]=1
Reactant: O=C(CCCCCl)c1ccc(Cl)cc1
Reactant: CCC(=O)Nc1cccc(C2CCNCC2)c1
Product: CCC(=O)Nc1cccc(C2CCN(CCCCC(=O)c3ccc(Cl)cc3)CC2)c1

Procedure:
Prepared by Procedure K and Scheme B1 using 5-chloro-1-(4-chlorophenyl)-1-pentanone and N-[3-(4-piperidinyl)phenyl]propanamide: ESMS m/e: 427.1 (M+H)+.
Reaction SMILES: I[C:2]1[C:3]([O:8][CH2:9][CH:10]([CH3:12])[CH3:11])=[N:4][O:5][C:6]=1[CH3:7].C([Mg]Br)(C)C.[O:18]1COC[O:20][CH2:19]1.C(=O)=O>C1COCC1.O>[CH2:9]([O:8][C:3]1[C:2]([C:19]([OH:20])=[O:18])=[C:6]([CH3:7])[O:5][N:4]=1)[CH:10]([CH3:12])[CH3:11]
Reactant: C1OCOCO1
Reactant: Cc1onc(OCC(C)C)c1I
Agent: CC(C)[Mg]Br
Agent: O=C=O
Solvent: C1CCOC1
Solvent: O
Product: Cc1onc(OCC(C)C)c1C(=O)O
Temperature: 0 °C
Reaction time: 1 h
Yield: 32.1 %

Procedure:
To a stirred solution of 4-iodo-3-isobutoxy-5-methyl-isoxazole (669 mg, 2.38) in THF (10 mL) at −30° C. and under argon was added isopropylmagnesium bromide (1.49 mL of a 2.0 M solution in THF) dropwise. The reaction mixture was warmed to 0° C. and stirred for 1 h, then 1,3,5-trioxane (429 mg, 4.76 mmol) in THF (1 mL) was added and the reaction mixture warmed to 50° C. After 1.5 h to the reaction mixture was added further 1,3,5-trioxane (860 mg, 9.52 mmol) and the reaction mixture heated at 70° C. After 2 h the mixture was cooled to 0° C. and solid CO2 (˜10 g) added. After 1 h the reaction mixture was diluted with water (15 mL) then extracted with diethylether. The aqueous phase was acidified with HCl (1 N, 10 mL), then the resultant precipitate filtered off and washed with water (5 mL), then dried under vacuum (60° C.) to afford the title compound (152 mg, 32%) as a white solid. MS: m/e=198.4 [M−H]−.
Reaction SMILES: [NH2:1][C:2]1[C:7]([O:8][CH2:9][C:10]2[C:15]([Cl:16])=[CH:14][CH:13]=[CH:12][C:11]=2[Cl:17])=[CH:6][CH:5]=[CH:4][N:3]=1.Cl.[C:19]1([CH2:25][C:26](=[NH:30])OCC)[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>C(O)C>[ClH:16].[Cl:17][C:11]1[CH:12]=[CH:13][CH:14]=[C:15]([Cl:16])[C:10]=1[CH2:9][O:8][C:7]1[C:2]([NH:1][C:26](=[NH:30])[CH2:25][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[N:3][CH:4]=[CH:5][CH:6]=1
Reactant: CCOC(=N)Cc1ccccc1
Reactant: Nc1ncccc1OCc1c(Cl)cccc1Cl
Agent: Cl
Solvent: CCO
Product: N=C(Cc1ccccc1)Nc1ncccc1OCc1c(Cl)cccc1Cl
Yield: 36 %

Procedure:
A mixture of 2-amino-3-(2,6-dichlorobenzyloxy)pyridine (5.38 g, 20 mmol) and ethyl phenylacetimidate hydrochloride (4.39 g, 22 mmol) in ethanol (80 ml) was heated under reflux for 2 hours. Evaporation of the solvent gave an oil which was purified by flash chromatography (chloroform/methanol) to obtain the product as a hygroscopic foam (1.52 g), m.p. 69°-74° C.
Reaction SMILES: BrCCBr.Cl[C:6]1([F:24])[C:11](Cl)([F:12])[O:10][C:9]([F:18])([C:14]([F:17])([F:16])[F:15])[C:8]([F:23])([C:19]([F:22])([F:21])[F:20])[O:7]1>[Zn].CN(C=O)C>[F:18][C:9]1([C:14]([F:15])([F:16])[F:17])[C:8]([F:23])([C:19]([F:22])([F:21])[F:20])[O:7][C:6]([F:24])=[C:11]([F:12])[O:10]1
Reactant: FC(F)(F)C1(F)OC(F)(Cl)C(F)(Cl)OC1(F)C(F)(F)F
Agent: [Zn]
Solvent: BrCCBr
Solvent: CN(C)C=O
Product: FC1=C(F)OC(F)(C(F)(F)F)C(F)(C(F)(F)F)O1
Temperature: 105 °C
Yield: 43.1 %

Procedure:
A mixture of 16.4 g (0.25 mol) of zinc dust, 200 mL of dry DMF, and 2 mL of 1,2-dibromoethane was stirred under N2 while a small portion of 41 g (0.112 mol) of 20 was added. The mixture was heated until reaction had started (ca. 90° C.), then the remainder of 20 was added dropwise at a rate sufficient to maintain temperature up to 105° C. in the pot while product was taken overhead as formed, bp 60°-65° C. When the addition had been completed, the pot temperature was increased until distillate was being collected at 135° C. The distillate was washed with water, dried over CaSO4, filtered and distilled to afford 14.2 g (43%) of perfluoro-2,3-dimethyl-2,3-dihydro-1,4-dioxin (21), bp 65°-67.5° C.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:6]=[C:7]([C:12]2[CH:13]=[CH:14][C:15]3[N:16]=[C:17]([NH:30][CH2:31][C:32]4[CH:37]=[CH:36][C:35]([S:38]([NH2:41])(=[O:40])=[O:39])=[CH:34][CH:33]=4)[N:18]=[C:19]([NH:22][C:23]4([C:26]([F:29])([F:28])[F:27])[CH2:25][CH2:24]4)[C:20]=3[N:21]=2)[CH:8]=[CH:9][C:10]=1C)(=[O:4])=[O:3].CS(C1C=C(C2C=CC3N=C(NCC4C=CC(S(N)(=O)=O)=CC=4)N=C(NC4(C(F)(F)[F:69])CC4)C=3N=2)C=CC=1OC)(=O)=O.ClC1C=CC(C2C=CC3N=C(NCC4C=CC(S(N)(=O)=O)=CC=4)N=C(NC4(C(F)(F)F)CC4)C=3N=2)=CC=1S(C)(=O)=O.C1(S(C2C=C(C3C=CC4N=C(NCC5C=CC(S(N)(=O)=O)=CC=5)N=C(NC5(C(F)(F)F)CC5)C=4N=3)C=CC=2OC)(=O)=O)CC1.CS(C1C=C(C2C=CC3N=C(NC(C4C=CC(N5C=NC=N5)=CC=4)C)N=C(NC4(C(F)(F)F)CC4)C=3N=2)C=CC=1OC)(=O)=O>>[F:69][C:10]1[CH:9]=[CH:8][C:7]([C:12]2[CH:13]=[CH:14][C:15]3[N:16]=[C:17]([NH:30][CH2:31][C:32]4[CH:37]=[CH:36][C:35]([S:38]([NH2:41])(=[O:40])=[O:39])=[CH:34][CH:33]=4)[N:18]=[C:19]([NH:22][C:23]4([C:26]([F:28])([F:29])[F:27])[CH2:25][CH2:24]4)[C:20]=3[N:21]=2)=[CH:6][C:5]=1[S:2]([CH3:1])(=[O:4])=[O:3]
Reactant: Cc1ccc(-c2ccc3nc(NCc4ccc(S(N)(=O)=O)cc4)nc(NC4(C(F)(F)F)CC4)c3n2)cc1S(C)(=O)=O
Reactant: COc1ccc(-c2ccc3nc(NCc4ccc(S(N)(=O)=O)cc4)nc(NC4(C(F)(F)F)CC4)c3n2)cc1S(C)(=O)=O
Agent: COc1ccc(-c2ccc3nc(NC(C)c4ccc(-n5cncn5)cc4)nc(NC4(C(F)(F)F)CC4)c3n2)cc1S(C)(=O)=O
Agent: COc1ccc(-c2ccc3nc(NCc4ccc(S(N)(=O)=O)cc4)nc(NC4(C(F)(F)F)CC4)c3n2)cc1S(=O)(=O)C1CC1
Agent: CS(=O)(=O)c1cc(-c2ccc3nc(NCc4ccc(S(N)(=O)=O)cc4)nc(NC4(C(F)(F)F)CC4)c3n2)ccc1Cl
Product: CS(=O)(=O)c1cc(-c2ccc3nc(NCc4ccc(S(N)(=O)=O)cc4)nc(NC4(C(F)(F)F)CC4)c3n2)ccc1F

Procedure:
4-{[6-(3-Methanesulfonyl-4-methyl-phenyl)-4-(1-trifluoromethyl-cyclopropylamino)-pyrido[3,2-d]pyrimidin-2-ylamino]-methyl}-benzenesulfonamide; 4-{[6-(3-Methanesulfonyl-4-methoxy-phenyl)-4-(1-trifluoromethyl-cyclopropylamino)-pyrido[3,2-d]pyrimidin-2-ylamino]-methyl}-benzenesulfonamide; 4-{[6-(4-Chloro-3-methanesulfonyl-phenyl)-4-(1-trifluoromethyl-cyclopropylamino)-pyrido[3,2-d]pyrimidin-2-ylamino]-methyl}-benzenesulfonamide; 4-{[6-(3-Cyclopropanesulfonyl-4-methoxy-phenyl)-4-(1-trifluoromethyl-cyclopropylamino)-pyrido[3,2-d]pyrimidin-2-ylamino]-methyl}-benzenesulfonamide; 6-(3-Methanesulfonyl-4-methoxy-phenyl)-N2-[1-(4-[1,2,4]triazol-1-yl-phenyl)-ethyl]-N4-(1-trifluoromethyl-cyclopropyl)-pyrido[3,2-d]pyrimidine-2,4-diamine
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[C:6]([CH2:9]O)[CH:5]=[CH:4][N:3]=1.BrCC1C=CN=C(Cl)C=1Cl.[CH3:21][C:22]1[N:27]=[C:26]([SH:28])[N:25]=[C:24]([OH:29])[CH:23]=1>>[Cl:1][C:2]1[C:7]([Cl:8])=[C:6]([CH2:9][S:28][C:26]2[N:25]=[C:24]([OH:29])[CH:23]=[C:22]([CH3:21])[N:27]=2)[CH:5]=[CH:4][N:3]=1
Reactant: OCc1ccnc(Cl)c1Cl
Reactant: Cc1cc(O)nc(S)n1
Agent: Clc1nccc(CBr)c1Cl
Product: Cc1cc(O)nc(SCc2ccnc(Cl)c2Cl)n1
Yield: 78 %

Procedure:
(2,3-dichloropyridin-4-yl)methanol was converted to 4-(bromomethyl)-2,3-dichloropyridine. The reaction of 4-(bromomethyl)-2,3-dichloropyridine and 6-methyl-2-sulfanylpyrimidin-4-ol provided 2-{[(2,3-dichloropyridin-4-yl)methyl]sulfanyl}-6-methylpyrimidin-4-ol as a white solid (0.98 g, 78% yield); 1H NMR (400 MHz, DMSO-d6): δ 2.21 (s, 3H), 3.82 (s, 3H), 4.47 (s, 2H), 6.04 (bs, 1H), 7.68 (d, J=4.7 Hz, 1H), 8.32 (d, J=4.7 Hz, 1H); M+302.2.
Reaction SMILES: [C:1]([C:3]1[N:4]=[C:5]([NH:13][C@H:14]2[CH2:18][CH2:17][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:15]2)[C:6]2[C:11]([CH:12]=1)=[CH:10][CH:9]=[CH:8][CH:7]=2)#[N:2].CN1C(=O)CCC1.[NH:33]([C:35](OCC)=[O:36])[NH2:34]>CCOC(C)=O>[O:36]=[C:35]1[NH:33][N:34]=[C:1]([C:3]2[N:4]=[C:5]([NH:13][C@H:14]3[CH2:18][CH2:17][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:15]3)[C:6]3[C:11]([CH:12]=2)=[CH:10][CH:9]=[CH:8][CH:7]=3)[NH:2]1
Reactant: CC(C)(C)OC(=O)N1CC[C@H](Nc2nc(C#N)cc3ccccc23)C1
Reactant: CCOC(=O)NN
Solvent: CN1CCCC1=O
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CC[C@H](Nc2nc(-c3n[nH]c(=O)[nH]3)cc3ccccc23)C1
Temperature: 175 °C

Procedure:
To a crude reaction mixture containing (S)-tert-butyl 3-((3-cyanoisoquinolin-1-yl)amino)pyrrolidine-1-carboxylate (717 mg) was added NMP (2 mL) and ethyl hydrazinecarboxylate (883 mg, 8.484 mmol). The reaction mixture was heated at 175° C. overnight and was subsequently cooled, diluted with EtOAc, and washed with aqueous NH4Cl. The organic layer was separated and concentrated to give the title compound, which was used directly in the next step.
Reaction SMILES: C([O:3][C:4](=[O:28])[CH:5]([C:12]1[N:13]([C:21]2[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][CH:22]=2)[N:14]=[C:15]2[C:20]=1[CH2:19][CH2:18][CH2:17][CH2:16]2)[CH:6]1[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]1)C.[OH-].[Na+]>CO>[Cl:27][C:24]1[CH:25]=[CH:26][C:21]([N:13]2[C:12]([CH:5]([CH:6]3[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]3)[C:4]([OH:28])=[O:3])=[C:20]3[C:15]([CH2:16][CH2:17][CH2:18][CH2:19]3)=[N:14]2)=[CH:22][CH:23]=1
Reactant: CCOC(=O)C(c1c2c(nn1-c1ccc(Cl)cc1)CCCC2)C1CCCCC1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)C(c1c2c(nn1-c1ccc(Cl)cc1)CCCC2)C1CCCCC1

Procedure:
In analogy to the procedure described in example 4.5, [2-(4-chloro-phenyl)-4,5,6,7-tetrahydro-2H-indazol-3-yl]-cyclohexyl-acetic acid ethyl ester (example 4.3) was treated with aqueous NaOH solution in MeOH to give the title compound as yellow foam which was sufficiently pure to be used in the next step. MS: m/e=373.2 [M+H+].
Reaction SMILES: [Br-].[CH3:2]OC[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.CC(C)([O-])C.[K+].[CH:30]([CH:32]1[CH2:37][CH2:36][CH:35]([C:38]([O:40][CH3:41])=[O:39])[CH2:34][CH2:33]1)=O.O>O1CCCC1>[CH:30]([CH:32]1[CH2:37][CH2:36][CH:35]([C:38]([O:40][CH3:41])=[O:39])[CH2:34][CH2:33]1)=[CH2:2]
Reactant: COC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: COC(=O)C1CCC(C=O)CC1
Agent: CC(C)(C)[O-]
Agent: [Br-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Product: C=CC1CCC(C(=O)OC)CC1
Reaction time: 0.5 h

Procedure:
297.4 g of methoxymethyltriphenylphosphonium bromide was dispersed in 900 mL of tetrahydrofuran (THF) and 95.6 g potassium t-butoxide was added at −8° C. in 3 minutes. After stirring for 30 minutes, all of methyl 4-formylcyclohexanecarboxylate was dissolved in 270 mL of THF and the resulting solution was added dropwise at −6 to 4° C. over 50 minutes. After stirring at 0 to 4° C. for 30 minutes, 15 mL of water was added. The solvent of the reaction mixture was distilled off under reduced pressure and 500 mL of hexane was added, followed by stirring at room temperature for 30 minutes. The precipitate was filtered and the precipitate was suspended and washed again with 500 mL of hexane. After combining with the hexane filtrate, the mixture was washed in turn with a mixed solution of methanol and water (1:1), water, and saturated saline. After drying over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure to obtain 81.2 g of an oily substance. The oily substance was distilled under reduced pressure to obtain 57.3 g of methyl 4-vinylclohexanecarboxylate. A boiling point was 122 to 127° C./48 hPa. The gas chromatography analysis revealed that, the resulting substance is a mixture of a cis isomer and a trans isomer in a mixing ratio of 26:74.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([N:8]2[C:12]([CH3:13])=[C:11]([C:14]([OH:16])=[O:15])[CH:10]=[N:9]2)[C:3]=1[F:17].CN([CH:21]=[C:22]([C:30](=O)C)[C:23](OC(C)(C)C)=O)C>C(#N)C>[Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([N:8]2[C:12]([CH3:13])=[C:11]([C:14]([O:16][C:22]([CH3:30])([CH3:23])[CH3:21])=[O:15])[CH:10]=[N:9]2)[C:3]=1[F:17]
Reactant: CC(=O)C(=CN(C)C)C(=O)OC(C)(C)C
Reactant: Cc1c(C(=O)O)cnn1-c1nccc(Cl)c1F
Solvent: CC#N
Product: Cc1c(C(=O)OC(C)(C)C)cnn1-c1nccc(Cl)c1F
Temperature: 85 °C
Reaction time: 1 h

Procedure:
1-(4-Chloro-3-fluoropyridin-2-yl)-5-methyl-1H-pyrazole-4-carboxylic acid: To a solution of tert-butyl 2-((dimethylamino)methylene)-3-oxobutanoate (0.045 g, 0.211 mmol) in acetonitrile (2 mL) was added TEA (0.030 mL, 0.215 mmol) followed by Intermediate 41B (0.038 g, 0.19 mmol). The dark brown solution was stirred for 1 h at 85° C. The reaction was concentrated, and water (1 mL) and CH2Cl2 (1 mL) were added. The organic layer was concentrated and purified by silica gel chromatography to provide tert-butyl 1-(4-chloro-3-fluoro-pyridin-2-yl)-5-methyl-1H-pyrazole-4-carboxylate as brown oil. MS(ESI) m/z: 312.1 (M+H). 1H NMR (400 MHz, CDCl3) δ 8.39-8.25 (m, 1H), 8.04 (s, 1H), 7.51 (t, J=5.0 Hz, 1H), 2.57 (s, 3H), 1.48 (s, 9H). The oil was stirred with 4 N HCl in dioxane (2 mL) for 12 h at rt. The solution was evaporated to dryness followed by coevaporation with toluene (2×) to give the desired product (12 mg, 22%). MS(ESI) m/z: 256.1 (M+H)+.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:10])[CH3:9])=[C:4]([O:11][CH3:12])[CH:3]=1.Br[CH2:14][CH2:15][CH2:16][Cl:17].C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[Cl:17][CH2:16][CH2:15][CH2:14][O:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:10])[CH3:9])=[C:4]([O:11][CH3:12])[CH:3]=1
Reactant: COc1cc(O)ccc1C(C)=O
Reactant: ClCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: COc1cc(OCCCCl)ccc1C(C)=O

Procedure:
In a 250 mL round bottom flask, 1-(4-hydroxy-2-methoxy-phenyl)ethanone (5.0 g, 30.0 mmol), 1-bromo-3-chloro-propane (3.27 mL, 33.1 mmol), and potassium carbonate (4.75 g, 33.1 mmol) in acetonitrile (100 mL) was heated to reflux 14 h. The reaction was cooled and the solvent concentrated under vacuum. The slurry was partitioned between methylene chloride and water, separated, dried over MgSO4. Purification with silica gel chromatography eluting with hexanes/ethyl acetate (3:1) produced 6.18 g (85%). Mp 51-53° C. MS m/z 243 (M+H).
Reaction SMILES: C[O:2][C:3]1[CH:8]=[CH:7][N:6]=[C:5]2[C:9](=[O:26])[N:10]([CH2:17][C:18]3[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][CH:19]=3)[C:11]3([CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]3)[C:4]=12.B(Br)(Br)Br>ClCCl>[OH:2][C:3]1[CH:8]=[CH:7][N:6]=[C:5]2[C:9](=[O:26])[N:10]([CH2:17][C:18]3[CH:19]=[CH:20][C:21]([O:24][CH3:25])=[CH:22][CH:23]=3)[C:11]3([CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]3)[C:4]=12
Reactant: COc1ccc(CN2C(=O)c3nccc(OC)c3C23CCCCC3)cc1
Agent: BrB(Br)Br
Solvent: ClCCl
Product: COc1ccc(CN2C(=O)c3nccc(O)c3C23CCCCC3)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Treat a solution of 4′-methoxy-6′-(4-methoxybenzyl)spiro[cyclohexane-1,5′-pyrrolo[3,4-b]pyridin]-7′(6′H)-one (4, 1.0 mmol, 1 eq) in dichloromethane (25 mL) with boron tribromide (2.0 mmol, 2 eq) at 0° C. Stir the mixture for 2 h at room temperature and quench with water at 0° C. Extract the mixture with ethyl acetate and remove the solvent under reduced pressure to get the crude. Purity the crude by silica gel column chromatography to get 4′-hydroxy-6′-(4-methoxybenzyl)spiro[cyclohexane-1,5′-pyrrolo[3,4-b]pyridin]-7′(6′H)-one (5).
Reaction SMILES: [N+:1]([C:4]1[C:5]([NH2:13])=[CH:6][C:7]2[O:11][CH2:10][CH2:9][C:8]=2[CH:12]=1)([O-])=[O:2].[N:14]#[C:15][NH2:16].[CH]Cl.[OH-].[Na+]>O>[N+:1]1([O-:2])[C:4]2[CH:12]=[C:8]3[CH2:9][CH2:10][O:11][C:7]3=[CH:6][C:5]=2[N:13]=[C:15]([NH2:16])[N:14]=1
Reactant: N#CN
Reactant: Nc1cc2c(cc1[N+](=O)[O-])CCO2
Agent: [CH]Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: Nc1nc2cc3c(cc2[n+]([O-])n1)CCO3
Temperature: 50 °C
Reaction time: 3 h
Yield: 189.7 %

Procedure:
A mixture of nitroaniline 203 (4.0 g, 22.2 mmol) and cyanamide (7.2 g, 171 mmol) were mixed together at 80° C., cooled to 50° C., cHCl (8.0 mL) added carefully and the mixture heated at 80° C. for 4 h. The mixture was cooled to 50° C., 7.5 M NaOH solution added until the mixture was strongly basic, and the mixture stirred at 100° C. for 3 h. The mixture was cooled, diluted with water (20 mL), filtered, washed with water (20 mL) and ether (5 mL), and dried to give 1-oxide 204 (8.6 g, 96%) as a yellow powder: mp (DCM) 293-296° C.; 1H NMR [(CD3)2SO] δ 7.71 (s, 1H, H-9), 6.23 (s, 1H, H-5), 4.59 (t, J=8.5 Hz, 2H, H-7), 3.12 (t, J=8.5 Hz, 2H, H-8), NH2 not observed; HRMS (FAB+) calcd for C9H9N4O2 (MH+) m/z 205.0726, found 205.0725.
Reaction SMILES: [C:1]([O:6]C)(=O)[C:2]([CH3:4])=[CH2:3].[CH:8]([NH2:11])([CH3:10])[CH3:9]>Cl.C(N)(C)C>[CH:8]([NH:11][C:1](=[O:6])[C:2]([CH3:4])=[CH2:3])([CH3:10])[CH3:9]
Reactant: C=C(C)C(=O)OC
Reactant: CC(C)N
Agent: Cl
Product: C=C(C)C(=O)NC(C)C
Yield: 69.5 %

Procedure:
500 g (5 mols) of methyl methacrylate, 325 g (5.5 mols) of isopropylamine, and 12.4 g (0.13 mol) of isopropylamine hydrochloride were reacted in the presence of 0.03 mol of ferric acetylacetonate for 21/2 hours in a steel autoclave at 220° C. The pressure increased to a maximum of 18 atmospheres. The methyl methacrylate reacted to the extent of 80% and gave 442 g of N-isopropylmethacrylic acid amide (corresponding to a 68% yield referred to the methyl methacrylate used).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([N:16]2[C:20](=[O:21])[CH2:19][C@@H:18]([NH:22]C(=O)OCC3C=CC=CC=3)[CH2:17]2)[CH:5]=[CH:6][C:7]=1[S:8]([N:11]1[CH2:15][CH2:14][CH2:13][CH2:12]1)(=[O:10])=[O:9].[H][H]>CO.[Pd]>[NH2:22][C@H:18]1[CH2:17][N:16]([C:4]2[CH:5]=[CH:6][C:7]([S:8]([N:11]3[CH2:15][CH2:14][CH2:13][CH2:12]3)(=[O:10])=[O:9])=[C:2]([CH3:1])[CH:3]=2)[C:20](=[O:21])[CH2:19]1
Reactant: [H][H]
Reactant: Cc1cc(N2C[C@H](NC(=O)OCc3ccccc3)CC2=O)ccc1S(=O)(=O)N1CCCC1
Agent: [Pd]
Solvent: CO
Product: Cc1cc(N2C[C@H](N)CC2=O)ccc1S(=O)(=O)N1CCCC1

Procedure:
45 mg (98 μmol) benzyl(R)-{1-[3-methyl-4-(pyrrolidine-1-sulphonyl)-phenyl]-5-oxo-pyrrolidin-3-yl}-carbamate are dissolved in 10 ml of methanol, combined with 25 mg palladium on charcoal and hydrogenated for 8 hours in a Parr apparatus at 3 bar hydrogen pressure at ambient temperature.
Reaction SMILES: [CH3:1][O:2][C:3]1[S:7][C:6]([N:8]=[C:9]=[O:10])=[N:5][N:4]=1.[Cl:11][CH2:12][CH2:13][NH:14][CH:15]([CH2:18][O:19][CH3:20])[CH:16]=[O:17]>C1C=CC=CC=1>[Cl:11][CH2:12][CH2:13][N:14]([CH:15]([CH2:18][O:19][CH3:20])[CH:16]=[O:17])[C:9]([NH:8][C:6]1[S:7][C:3]([O:2][CH3:1])=[N:4][N:5]=1)=[O:10]
Reactant: COc1nnc(N=C=O)s1
Reactant: COCC(C=O)NCCCl
Solvent: c1ccccc1
Product: COCC(C=O)N(CCCl)C(=O)Nc1nnc(OC)s1

Procedure:
5-Methoxy-1,3,4-thiadiazol-2-yl isocyanate dimer (0.05 mole), the dimethyl acetal of 2-β-chloroethylamino-3-methoxypropionaldehyde (0.1 mole) and benzene (60 ml) are charged into a glass reaction vessel equipped with a mechanical stirrer, thermometer and reflux condenser. The reaction mixture is heated at reflux for a period of about 30 minutes. After this time the mixture is stripped of benzene under reduced pressure to yield a solid product as the residue. This residue is then recrystallized to yield the desired product the dimethyl acetal of 2-[1-β-chloroethyl-3-(5-methoxy-1,3,4-thiadiazol-2-yl)ureido]-3-methoxypropionaldehyde.