Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([CH:8]1[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][CH2:16][N:17]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[C:18]([CH:20]2[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]2)=[O:19])[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[C:39](Cl)(=[O:41])[CH3:40].C(=O)([O-])O.[Na+]>C1COCC1>[C:39]([N:23]1[CH2:24][CH2:25][CH:20]([C:18]([N:17]([CH2:16][CH2:15][CH2:14][N:11]2[CH2:12][CH2:13][CH:8]([CH2:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)[CH2:9][CH2:10]2)[C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=2)=[O:19])[CH2:21][CH2:22]1)(=[O:41])[CH3:40]
Reactant: O=C(C1CCNCC1)N(CCCN1CCC(Cc2ccccc2)CC1)c1ccccc1
Reactant: CC(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(=O)N1CCC(C(=O)N(CCCN2CCC(Cc3ccccc3)CC2)c2ccccc2)CC1
Reaction time: 0.5 h
Yield: 85 %

Procedure:
The compound obtained in Example 2 (252 mg, 0.60 mmol), triethylamine (0.201 ml) were dissolved in THF (5 ml), and under ice cooling, to the solution was added acetyl chloride (0.085 ml). The mixture was stirred at the same temperature for 30 minutes. To the mixture was added a saturated aqueous solution of sodium hydrogencarbonate (15 ml) under ice cooling, and the mixture was extracted with ethyl acetate (15 ml×3). The organic layer was dried over magnesium sulfate and concentrated under reduced pressure. The concentrate was subjected to column chromatography (silica gel log, ethyl acetate/methanol=1/0 to 9/1 to 4/1), and the desired fraction was concentrated under reduced pressure. To the concentrate was added ethyl acetate and the insolubles were filtered off. The filtrate was concentrated under reduced pressure to give the titled compound (237 mg, 0.51 mmol, Yield 85%) as colorless oily substance.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH:11]1[CH2:16][CH2:15][N:14]([CH3:17])[CH2:13][CH2:12]1.[C:18]1([S:24](Cl)(=[O:26])=[O:25])[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>>[F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([S:24]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)(=[O:26])=[O:25])[CH:6]=[C:5]2[CH:11]1[CH2:16][CH2:15][N:14]([CH3:17])[CH2:13][CH2:12]1
Reactant: CN1CCC(c2c[nH]c3ccc(F)cc23)CC1
Reactant: O=S(=O)(Cl)c1ccccc1
Product: CN1CCC(c2cn(S(=O)(=O)c3ccccc3)c3ccc(F)cc23)CC1

Procedure:
(27.3 mg, 73%) from 5-fluoro-3-(1-methyl-4-piperidinyl)-1H-indole (Example 5c, 25 mg, 0.1 mmol) and phenylsulfonyl chloride (26.4 mg, 0.15 mmol), HRMS-FAB+ for C20H21N2O2SF, calculated MH+ : 373.13861; found: 373.13569.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:10])[CH3:9])=[C:4]([OH:11])[CH:3]=1.CO[CH:14](OC)[N:15]([CH3:17])[CH3:16]>C1C=CC=CC=1>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:10])/[CH:9]=[CH:14]/[N:15]([CH3:17])[CH3:16])=[C:4]([OH:11])[CH:3]=1
Reactant: CC(=O)c1ccc(Br)cc1O
Reactant: COC(OC)N(C)C
Solvent: c1ccccc1
Product: CN(C)/C=C/C(=O)c1ccc(Br)cc1O
Yield: 70.7 %

Procedure:
To 1-(4-bromo-2-hydroxyphenyl)ethanone (35.8 g, 167 mmol) in dry benzene (800 mL) was added N,N-dimethylformamide dimethylacetal (44 mL, 333 mmol) and the solution was heated at reflux for 4 hrs and concentrated to dryness. The resulting residue was dissolved in dichloromethane (300 mL) and filtered over SiO2. The organic layer was concentrated to afford (E)-1-(4-bromo-2-hydroxyphenyl)-3-(dimethylamino)prop-2-en-1-one as a bright yellow solid (31.9 g, 71%). LCMS 270 (M+H); 1H NMR (DMSO-d6) 14.96 (s, 1H), 7.86-7.94 (m, 2H), 6.96-7.02 (dd, 2H), 5.92-5.96 (d, 1H), 3.32 (s, 3H), 3.20 (s, 3H).
Reaction SMILES: [Na].[CH3:2][C:3]1([CH3:12])[C:7](=[N:8]O)[CH2:6][CH2:5][C:4]1=[N:10]O>C(O)CC.[Cl-].[Na+].O>[CH3:2][C:3]1([CH3:12])[CH:7]([NH2:8])[CH2:6][CH2:5][CH:4]1[NH2:10]
Reactant: CC1(C)C(=NO)CCC1=NO
Agent: [Cl-]
Agent: [Na+]
Agent: [Na]
Solvent: CCCO
Solvent: O
Product: CC1(C)C(N)CCC1N
Temperature: 25 °C
Yield: 86.3 %

Procedure:
Sodium (177 mg, 7.68 mmol) was added to a solution of crude 2,2-dimethylcyclopentane-1,3-dione dioxime (120 mg) in n-propanol (10 mL) at 80° C. The mixture was heated to reflux for 2 h, cooled to room temperature and poured into brine (30 mL). The mixture was extracted with dichloromethane (3×50 mL). The combined organic extracts were dried (MgSO4), filtered and concentrated to give crude 2,2-dimethylcyclopentane-1,3-diamine (85 mg), which was used in the next step without purification.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4](Cl)[C:5]2[O:10][CH:9]=[CH:8][C:6]=2[N:7]=1.[CH:12]1([NH2:15])[CH2:14][CH2:13]1>O1CCOCC1.CCOC(C)=O>[Cl:1][C:2]1[N:3]=[C:4]([NH:15][CH:12]2[CH2:14][CH2:13]2)[C:5]2[O:10][CH:9]=[CH:8][C:6]=2[N:7]=1
Reactant: NC1CC1
Reactant: Clc1nc(Cl)c2occc2n1
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: Clc1nc(NC2CC2)c2occc2n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 95.7 %

Procedure:
2,4-Dichlorofuro[3,2-d]pyrimidine (30 g, 159 mmol, ArkPharm) was stirred in 1,4-dioxane (330 mL). TEA (26.5 mL, 190 mmol) and cyclopropylamine (12.2 mL, 175 mmol) were added and the mixture stirred at rt overnight. The mixture was diluted with EtOAc (500 mL) and washed with saturated aqueous NaHCO3 (400 mL). The aqueous layer was extracted with EtOAc (2×150 mL). The organic layers were combined, dried with anhydrous MgSO4, filtered, and concentrated in vacuo. The residue was suspended in water (400 mL) and allowed to stir at rt for about 1 h. The suspension was filtered and the solid was dried in a vacuum oven at about 70° C. overnight to give 2-chloro-N-cyclopropylfuro[3,2-d]pyrimidin-4-amine (31.9 g, 96%); LC/MS (Table 2, Method c) Rt=1.58 min.; MS m/z: 210 (M+H)+, 1H NMR (400 MHz, CDCl3) δ 7.77 (d, J=2.1 Hz, 1H), 6.79 (d, J=2.1 Hz, 1H), 5.57-5.50 (m, 1H), 3.12-3.01 (m, 1H), 1.02-0.88 (m, 2H), 0.77-0.65 (m, 2H).
Reaction SMILES: [CH2:1]([O:3][CH:4]([O:8][CH2:9][CH3:10])[CH2:5][NH:6][NH2:7])[CH3:2].CO[C:13](=[CH2:16])[C:14]#[N:15].C(OCC)(=O)C>O>[CH2:1]([O:3][CH:4]([O:8][CH2:9][CH3:10])[CH2:5][N:6]1[C:14]([NH2:15])=[CH:13][CH:16]=[N:7]1)[CH3:2]
Reactant: C=C(C#N)OC
Reactant: CCOC(CNN)OCC
Solvent: CCOC(C)=O
Solvent: O
Product: CCOC(Cn1nccc1N)OCC
Yield: 19.3 %

Procedure:
A mixture of hydrazinoacetaldehyde diethyl acetal (21 g) and methoxyacrylonitrile (11.8 g) in water (150 ml) was refluxed for 2 days. After the reaction mixture was cooled, to the mixture was added a mixture of water and ethyl acetate. The separated organic layer was washed with brine and dried over magnesium sulfate. The solvent was evaporated and the residue was subjected to column chromatography on silica gel using ethyl acetate as an eluent. Fractions containing the object compound were combined and evaporated to give 1-(2,2-diethoxyethyl)-5-aminopyrazole (5.45 g).
Reaction SMILES: [N+:1]([C:4]1[C:5]([O:19][C:20]2[CH:21]=[C:22]([CH:25]=[CH:26][CH:27]=2)[C:23]#[N:24])=[N:6][C:7]([O:10][C:11]2[CH:12]=[C:13]([CH:16]=[CH:17][CH:18]=2)[C:14]#[N:15])=[CH:8][CH:9]=1)([O-])=O.[H][H]>C(O)C.C(OCC)(=O)C.[Pd]>[NH2:1][C:4]1[C:5]([O:19][C:20]2[CH:21]=[C:22]([CH:25]=[CH:26][CH:27]=2)[C:23]#[N:24])=[N:6][C:7]([O:10][C:11]2[CH:12]=[C:13]([CH:16]=[CH:17][CH:18]=2)[C:14]#[N:15])=[CH:8][CH:9]=1
Reactant: N#Cc1cccc(Oc2ccc([N+](=O)[O-])c(Oc3cccc(C#N)c3)n2)c1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CCO
Product: N#Cc1cccc(Oc2ccc(N)c(Oc3cccc(C#N)c3)n2)c1

Procedure:
To 3,3′-[3-nitro-2,6-pyridinediylbis(oxy)]bis(benzonitrile)(18.5 g, 50 mmol) dissolved in ethanol/ethyl acetate (500 mL, 2/3) was added 10% palladium on carbon (1.8 g). After subjecting the mixture to hydrogen at 15 psi for 2 hours, the reaction was suction filtered through celite. The solvent was removed in vacuo to give 3,3′-[3-amino-2,6-pyridinediylbis(oxy)]bis(benzonitrile); NMR (CDCl3) 7.5 (m,7), 7.2 (m,2), 6.6 (d,1), 3.8 (br,2) ppm.
Reaction SMILES: [C:1]1([CH2:7][C:8]([NH:10][C@@H:11]2[C:42](=[O:43])[N:13]3[C:14]([C:26]([O:28][CH:29]([C:36]4[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=4)[C:30]4[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=4)=[O:27])=[C:15](OS(C(F)(F)F)(=O)=O)[CH2:16][S:17][C@H:12]23)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C[Sn](C)(C)[C:46]1[CH:47]=[CH:48][C:49]2[C:50](=[O:61])[C:51]3[C:56]([C:57]=2[CH:58]=1)=[CH:55][CH:54]=[C:53]([CH2:59][OH:60])[CH:52]=3>CN1CCCC1=O.C(OCC)(=O)C.[Cl-].[Zn+2].[Cl-]>[C:1]1([CH2:7][C:8]([NH:10][C@@H:11]2[C:42](=[O:43])[N:13]3[C:14]([C:26]([O:28][CH:29]([C:36]4[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=4)[C:30]4[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=4)=[O:27])=[C:15]([C:46]4[CH:47]=[CH:48][C:49]5[C:50](=[O:61])[C:51]6[C:56]([C:57]=5[CH:58]=4)=[CH:55][CH:54]=[C:53]([CH2:59][OH:60])[CH:52]=6)[CH2:16][S:17][C@H:12]23)=[O:9])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C(Cc1ccccc1)N[C@@H]1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(OS(=O)(=O)C(F)(F)F)CS[C@H]12
Reactant: C[Sn](C)(C)c1ccc2c(c1)-c1ccc(CO)cc1C2=O
Agent: [Cl-]
Agent: [Zn+2]
Solvent: CN1CCCC1=O
Solvent: CCOC(C)=O
Product: O=C(Cc1ccccc1)N[C@@H]1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(c3ccc4c(c3)-c3ccc(CO)cc3C4=O)CS[C@H]12
Reaction time: 0.75 h
Yield: 61.2 %

Procedure:
Benzhydryl 7β-phenylacetamido-3-trifluormethanesulfonyloxy-ceph-3-em-4-carboxylate (1.26 g) was dissolved in N-methylpyrrolidone (NMP) and treated with 3-trimethylstannyl-7-hydroxymethyl-9-fluorenone (0.742 g). Zinc chloride (4.0 ml, 1.0M solution in ether) was added followed by Pd2(dba)3 ·CHCl3 (60 mg) and the reaction mixture was stirred under nitrogen for 45 min. The reaction mixture was diluted with ethyl acetate and washed with water five times, then with saturated sodium chloride solution and then dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure and the residue was crystallized from hot ethyl acetate/hexane to give 0.844 g of the desired product in the first crop and a further 0.170 g in the second crop of crystals.
Reaction SMILES: [C:1]([N:4]1[C:8]([CH3:9])=[C:7]([CH2:10][C:11]2[CH:16]=[CH:15][C:14]([CH3:17])=[C:13]([F:18])[CH:12]=2)[C:6](=[O:19])[NH:5]1)(=[O:3])[CH3:2].C(=O)([O-])[O-].[K+].[K+].[C:26]([O:32][C@@H:33]1[C@@H:38]([O:39][C:40](=[O:45])[C:41]([CH3:44])([CH3:43])[CH3:42])[C@H:37]([O:46][C:47](=[O:52])[C:48]([CH3:51])([CH3:50])[CH3:49])[C@@H:36]([CH2:53][O:54][C:55](=[O:60])[C:56]([CH3:59])([CH3:58])[CH3:57])[O:35][C@@H:34]1Br)(=[O:31])[C:27]([CH3:30])([CH3:29])[CH3:28]>C(#N)C.O1CCCC1>[C:1]([N:4]1[C:8]([CH3:9])=[C:7]([CH2:10][C:11]2[CH:16]=[CH:15][C:14]([CH3:17])=[C:13]([F:18])[CH:12]=2)[C:6]([O:19][C@@H:34]2[O:35][C@H:36]([CH2:53][O:54][C:55](=[O:60])[C:56]([CH3:59])([CH3:58])[CH3:57])[C@@H:37]([O:46][C:47](=[O:52])[C:48]([CH3:49])([CH3:50])[CH3:51])[C@H:38]([O:39][C:40](=[O:45])[C:41]([CH3:42])([CH3:43])[CH3:44])[C@H:33]2[O:32][C:26](=[O:31])[C:27]([CH3:30])([CH3:28])[CH3:29])=[N:5]1)(=[O:3])[CH3:2]
Reactant: CC(C)(C)C(=O)OC[C@H]1O[C@H](Br)[C@H](OC(=O)C(C)(C)C)[C@@H](OC(=O)C(C)(C)C)[C@@H]1OC(=O)C(C)(C)C
Reactant: CC(=O)n1[nH]c(=O)c(Cc2ccc(C)c(F)c2)c1C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: C1CCOC1
Product: CC(=O)n1nc(O[C@@H]2O[C@H](COC(=O)C(C)(C)C)[C@@H](OC(=O)C(C)(C)C)[C@H](OC(=O)C(C)(C)C)[C@H]2OC(=O)C(C)(C)C)c(Cc2ccc(C)c(F)c2)c1C
Temperature: 25 °C
Yield: 95.2 %

Procedure:
To a suspension of 1-acetyl-4-[(3-fluoro-4-methyl-phenyl)methyl]-1,2-dihydro-5-methyl-3H-pyrazol-3-one (0.32 g) in acetonitrile (3 mL) and tetrahydrofuran (1 mL) was added potassium carbonate (0.253 g) under stirring at room temperature. After stirring the mixture at 50° C. for 1 hour, 2,3,4,6-tetra-O-pivaloyl-α-D-glucopyranosyl bromide (0.849 g) was added to the mixture. The mixture was stirred at 50° C. for 2 hours. After the reaction completed, the insoluble materials were removed by filtration, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (eluent: ethyl acetate/n-hexane=1/10 to 1/5) to give 1-acetyl-4-[(3-fluoro-4-methyl-phenyl)methyl]-5-methyl-3-(2,3,4,6-tetra-O-pivaloyl-β-D-glucopyranosyloxy)-1H-pyrazole (0.884 g).
Reaction SMILES: [Cl:1][C:2]1[CH:16]=[C:15]([O:17][CH2:18][CH:19]=[C:20]([Cl:22])[Cl:21])[CH:14]=[C:13]([Cl:23])[C:3]=1[O:4][CH2:5][CH2:6][CH2:7][O:8]S(C)(=O)=O.C(=O)([O-])[O-].[K+].[K+].O[C:31]1[CH:36]=[CH:35][C:34]([C:37](=[O:41])[CH2:38][O:39][CH3:40])=[CH:33][CH:32]=1.O>CN(C)C=O>[Cl:1][C:2]1[CH:16]=[C:15]([O:17][CH2:18][CH:19]=[C:20]([Cl:22])[Cl:21])[CH:14]=[C:13]([Cl:23])[C:3]=1[O:4][CH2:5][CH2:6][CH2:7][O:8][C:31]1[CH:36]=[CH:35][C:34]([C:37](=[O:41])[CH2:38][O:39][CH3:40])=[CH:33][CH:32]=1
Reactant: COCC(=O)c1ccc(O)cc1
Reactant: CS(=O)(=O)OCCCOc1c(Cl)cc(OCC=C(Cl)Cl)cc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COCC(=O)c1ccc(OCCCOc2c(Cl)cc(OCC=C(Cl)Cl)cc2Cl)cc1

Procedure:
1.8 g of methanesulfonic acid 3-[2,6-dichloro-4-(3,3-dichloro-allyloxy)-phenoxy]-propyl ester, 1.8 g of potassium carbonate and 1.97 g of 1-(4-hydroxy-phenyl)-2-methoxyethanone are stirred in 30 ml of dimethylformamide at 50° C. for 17 hours. The reaction mixture is poured into water and extracted with ethyl acetate. After concentration of the organic phases and purification over silica gel, 1-(4-{3-[2,6-dichloro-4-(3,3-dichloro-allyloxy)-phenoxy]-propoxy}-phenyl)-2-methoxy-ethanone is obtained.
Reaction SMILES: NC1N=C(N)C(C2C=CC([N+:15]([O-:17])=[O:16])=CC=2C2C=CC=C(Cl)C=2Cl)=CN=1.[NH2:26][C:27]1[N:32]=[C:31]([NH2:33])[C:30]([C:34]2[CH:39]=[C:38]([N+]([O-])=O)[CH:37]=[C:36]([Cl:43])[C:35]=2[Cl:44])=[C:29]([CH3:45])[N:28]=1>>[NH2:26][C:27]1[N:32]=[C:31]([NH2:33])[C:30]([C:34]2[CH:39]=[CH:38][C:37]([N+:15]([O-:17])=[O:16])=[C:36]([Cl:43])[C:35]=2[Cl:44])=[C:29]([CH3:45])[N:28]=1
Reactant: Cc1nc(N)nc(N)c1-c1cc([N+](=O)[O-])cc(Cl)c1Cl
Reactant: Nc1ncc(-c2ccc([N+](=O)[O-])cc2-c2cccc(Cl)c2Cl)c(N)n1
Product: Cc1nc(N)nc(N)c1-c1ccc([N+](=O)[O-])c(Cl)c1Cl

Procedure:
This compound was made from the compound of Example 15 in an analogous manner to the compound of Example 39, mp. 265° C. Also obtained from this reaction was 2,4-diamino-5(2,3-dichloro-5-nitrophenyl)-6-methyl pyrimidine.
Reaction SMILES: Br[CH:2]1[CH2:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([Cl:11])[CH:8]=2)[C:3]1=[O:12].[CH3:13][S-:14].[Na+]>C(O)C>[Cl:11][C:7]1[CH:8]=[C:9]2[C:4](=[CH:5][CH:6]=1)[C:3](=[O:12])[CH:2]([S:14][CH3:13])[CH2:10]2
Reactant: O=C1c2ccc(Cl)cc2CC1Br
Reactant: C[S-]
Agent: [Na+]
Solvent: CCO
Product: CSC1Cc2cc(Cl)ccc2C1=O
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 74 %

Procedure:
0.98 g (4 mmol) of 2-bromo-5-chloroindan-1-one and 0.42 g (6 mmol) of sodium thiomethoxide are suspended in 5 ml of ethanol, treated in an ultrasonic bath for 30 minutes and then stirred at room temperature for 90 minutes. The reaction mixture is concentrated under reduced pressure and chromatographed on silica gel using toluene/ethyl acetate 10/1. The eluates are concentrated under reduced pressure, giving 0.63 g of 5-chloro-2-methylsulfanylindan-1-one of melting point 90° C.
Reaction SMILES: [C:1]([C:4]1[N:5]=[C:6]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[S:7][CH:8]=1)([OH:3])=O.C(N1C=CN=C1)(N1C=CN=C1)=O.C(=O)=O.[NH2:30][C@@H:31]1[CH2:40][CH2:39][C:38]2[C:33](=[C:34]([N:41]3[CH2:46][CH2:45][N:44]([CH3:47])[CH2:43][CH2:42]3)[CH:35]=[CH:36][CH:37]=2)[CH2:32]1>CN(C)C=O>[CH3:47][N:44]1[CH2:45][CH2:46][N:41]([C:34]2[CH:35]=[CH:36][CH:37]=[C:38]3[C:33]=2[CH2:32][C@H:31]([NH:30][C:1]([C:4]2[N:5]=[C:6]([C:9]4[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=4)[S:7][CH:8]=2)=[O:3])[CH2:40][CH2:39]3)[CH2:42][CH2:43]1
Reactant: O=C(O)c1csc(-c2ccccc2)n1
Reactant: CN1CCN(c2cccc3c2C[C@H](N)CC3)CC1
Agent: O=C(n1ccnc1)n1ccnc1
Agent: O=C=O
Solvent: CN(C)C=O
Product: CN1CCN(c2cccc3c2C[C@H](NC(=O)c2csc(-c4ccccc4)n2)CC3)CC1
Temperature: 75 °C
Reaction time: 17 h
Yield: 55.8 %

Procedure:
To a solution of 4-carboxy-2-phenylthiazole (88 mg, 0.43 mmol) in anhydrous N,N-dimethylformamide (25 mL) was added 1,1′-carbonyldiimidazole (73 mg, 0.45 mmol) and the reaction was heated at 75° C. When the carbon dioxide evolution had ceased (after 30 min), the reaction was cooled to room temperature and a solution of (R)-2-amino-8-(4-methylpiperazin-1-yl)-1,2,3,4-tetrahydronaphthalene (100 mg, 0.41 mmol) in anhydrous N,N-dimethylformamide (5 mL) was added. The reaction was allowed to stir at ambient temperature for 17 h and the solvent was evaporated in vacuo. Purification on a silica gel column using chloroform/ethanol saturated with NH3 (100:3) as the eluent gave 99 mg (56% yield) of the title compound as white crystals: mp 175-176° C.; [α]21D '85° (c 1.0, chloroform); EIMS (70 eV) m/z (relative intensity) 432 (6, M+).
Reaction SMILES: C[O-].[Na+].[C:4]([CH2:6][C:7]([O:9][CH3:10])=[O:8])#[N:5].[F:11][C:12]1[CH:17]=[C:16]([F:18])[C:15]([F:19])=[CH:14][C:13]=1[CH:20]=[CH:21][C:22]([O:24][CH2:25]C)=[O:23]>CO>[C:4]([CH:6]([CH:20]([C:13]1[CH:14]=[C:15]([F:19])[C:16]([F:18])=[CH:17][C:12]=1[F:11])[CH2:21][C:22]([O:24][CH3:25])=[O:23])[C:7]([O:9][CH3:10])=[O:8])#[N:5]
Reactant: CCOC(=O)C=Cc1cc(F)c(F)cc1F
Reactant: COC(=O)CC#N
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: COC(=O)CC(c1cc(F)c(F)cc1F)C(C#N)C(=O)OC
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 15 mL (64 mmol, 25% in methanol) of sodium methoxide in 200 mL of methanol was added 5.5 mL (62 mmol) of methyl cyanoacetate and the mixture was stirred at ambient temperature for 30 min. To this solution was added 14 g (62 mmol) of the product of Step A in 50 mL of methanol and the resulting yellow mixture was heated to reflux for 6 h. The mixture was then quenched carefully at ambient temperature with 1N aqueous hydrochloric acid (100 mL) and concentrated to remove methanol. The resulting mixture was extracted with three 300-mL portions of ethyl acetate, and the organic phases combined and washed sequentially with 1N hydrochloric acid, saturated aqueous sodium bicarbonate solution, and saturated aqueous brine (100 mL each). The organic phase was then dried over magnesium sulfate, filtered, and evaporated in vacuo to yield a viscous oil. The crude material was purified by flash chromatography on a Biotage Horizon® system (silica gel, 0 to 25% ethyl acetate/hexanes gradient) to give the title compound as a mixture of stereoisomers. 1H NMR (500 MHz, CDCl3): δ 7.33-6.96 (m, 2H), 4.23-3.93 (series of m, 2H), 3.81-3.67 (series of s, 6H), 3.05-2.84 (m, 2H).
Reaction SMILES: [CH3:1][N:2]1[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][C:5](=[O:12])[N:4]([C:13]2[CH:14]=[CH:15][C:16]3[S:20][N:19]=[C:18]([CH:21]=O)[C:17]=3[CH:23]=2)[C:3]1=[O:24].[CH2:25]([NH:29][CH2:30][CH2:31][SH:32])[CH2:26][CH2:27][CH3:28].C(O)C>O1CCCC1>[CH2:25]([N:29]1[CH2:30][CH2:31][S:32][CH:21]1[C:18]1[C:17]2[CH:23]=[C:13]([N:4]3[C:5](=[O:12])[CH:6]=[C:7]([C:8]([F:9])([F:11])[F:10])[N:2]([CH3:1])[C:3]3=[O:24])[CH:14]=[CH:15][C:16]=2[S:20][N:19]=1)[CH2:26][CH2:27][CH3:28]
Reactant: Cn1c(C(F)(F)F)cc(=O)n(-c2ccc3snc(C=O)c3c2)c1=O
Reactant: CCCCNCCS
Solvent: C1CCOC1
Solvent: CCO
Product: CCCCN1CCSC1c1nsc2ccc(-n3c(=O)cc(C(F)(F)F)n(C)c3=O)cc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 31.7 %

Procedure:
A mixture of 5-[3,6-dihydro-3-methyl-2,6-dioxo-4-(trifluoromethyl)-1(2H)-pyrimidinyl]-1,2-benzisothiazole-3-carboxaldehyde (0.500 g, 1.41 mmol), 2-(butylamino)ethanethiol (0.250 ml, 1.69 mmol), ethanol and tetrahydrofuran is stirred overnight at room temperature and concentrated in vacuo. The residue is chromatographed on silica gel with ethyl acetate-hexanes to afford the title compound as a light yellow solid (0.210 g, 31.7%, mp 78-82° C.) which is identified by NMR spectral analysis.
Reaction SMILES: [F:1][C:2]1[C:3]([CH2:14][N:15]([CH3:23])[C:16](=[O:22])[O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[CH:4][NH:5][C:6]=1[C:7]1[C:8]([F:13])=[N:9][CH:10]=[CH:11][CH:12]=1.[H-].[Na+].C1OCCOCCOCCOCCOC1.[CH:41]1([S:47](Cl)(=[O:49])=[O:48])[CH2:46][CH2:45][CH2:44][CH2:43][CH2:42]1>O1CCCC1.O>[CH:41]1([S:47]([N:5]2[C:6]([C:7]3[C:8]([F:13])=[N:9][CH:10]=[CH:11][CH:12]=3)=[C:2]([F:1])[C:3]([CH2:14][N:15]([CH3:23])[C:16](=[O:22])[O:17][C:18]([CH3:19])([CH3:20])[CH3:21])=[CH:4]2)(=[O:49])=[O:48])[CH2:46][CH2:45][CH2:44][CH2:43][CH2:42]1
Reactant: O=S(=O)(Cl)C1CCCCC1
Reactant: CN(Cc1c[nH]c(-c2cccnc2F)c1F)C(=O)OC(C)(C)C
Agent: C1COCCOCCOCCOCCO1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CN(Cc1cn(S(=O)(=O)C2CCCCC2)c(-c2cccnc2F)c1F)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 89.3 %

Procedure:
To a solution of tert-butyl {[4-fluoro-5-(2-fluoropyridin-3-yl)-1H-pyrrol-3-yl]methyl}methylcarbamate (324 mg) in tetrahydrofuran (20 mL) was added sodium hydride (60% in oil, 121 mg) and the mixture was stirred at room temperature for 15 min. 15-Crown-5 (664 mg) was added dropwise, and the mixture was stirred for 5 min. Cyclohexanesulfonyl chloride (367 mg) was added and the mixture was further stirred for 2 hr. The reaction mixture was diluted with water, and extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane-ethyl acetate=7:3→1:1) to give the title compound as a colorless oil (yield 420 mg, 89%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]2[CH2:10][C@H:9]2C(O)=O)=[CH:4][CH:3]=1.C([N:16](CC)CC)C.ClC(OCC)=O.[N-]=[N+]=[N-].[Na+]>CC(C)=O.O.O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]2[CH2:10][C@H:9]2[NH2:16])=[CH:4][CH:3]=1
Reactant: CCN(CC)CC
Reactant: O=C(O)[C@@H]1C[C@H]1c1ccc(F)cc1
Agent: CCOC(=O)Cl
Agent: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: O
Solvent: CC(C)=O
Product: N[C@@H]1C[C@H]1c1ccc(F)cc1

Procedure:
To a solution of the product from step c) (2.6 g) and triethylamine (2.7 ml) in acetone/water (10:1, 33 ml) at 0° C. was added ethyl chloroformate (2.0 ml) over 5 min. The solution was maintained at 0° C. for 30 minutes before addition of sodium azide (1.52 g) in water (6 ml). After a further hour, water (350 ml) was added and the reaction mixture extracted with toluene (3×100 ml). The organic extracts were combined and dried, then heated at reflux for 2 hours behind a blast screen. After cooling the solution, 6M HCl (50 ml) was added and the mixture heated at reflux for 3 hours. Water (150 ml) was added and the aqueous phase basified with 2M NaOH (aq), then extracted into dichloromethane (3×100 ml). The organic phase was dried and concentrated to give the subtitle compound as a colourless oil (1.31 g).
Reaction SMILES: [OH:1]/[N:2]=[C:3](\[NH2:37])/[CH:4]=[CH:5]/[C:6]1[CH:11]=[CH:10][C:9](/[C:12](/[C:22]2[CH:23]=[C:24]3[C:28](=[CH:29][CH:30]=2)[N:27]([CH:31]2[CH2:36][CH2:35][CH2:34][CH2:33][O:32]2)[N:26]=[CH:25]3)=[C:13](\[C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)/[CH2:14][CH3:15])=[CH:8][CH:7]=1.C(C(CCCC)[CH2:41][O:42]C(Cl)=O)C.N1C=CC=CC=1>CN(C=O)C>[C:16]1(/[C:13](/[CH2:14][CH3:15])=[C:12](\[C:9]2[CH:8]=[CH:7][C:6](/[CH:5]=[CH:4]/[C:3]3[NH:37][C:41](=[O:42])[O:1][N:2]=3)=[CH:11][CH:10]=2)/[C:22]2[CH:23]=[C:24]3[C:28](=[CH:29][CH:30]=2)[N:27]([CH:31]2[CH2:36][CH2:35][CH2:34][CH2:33][O:32]2)[N:26]=[CH:25]3)[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: CCCCC(CC)COC(=O)Cl
Reactant: CC/C(=C(/c1ccc(/C=C/C(N)=N/O)cc1)c1ccc2c(cnn2C2CCCCO2)c1)c1ccccc1
Solvent: CN(C)C=O
Solvent: c1ccncc1
Product: CC/C(=C(/c1ccc(/C=C/c2noc(=O)[nH]2)cc1)c1ccc2c(cnn2C2CCCCO2)c1)c1ccccc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 48.2 %

Procedure:
To a solution of (1Z,2E)-N′-hydroxy-3-(4-((E)-2-phenyl-1-(1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-5-yl)but-1-en-1-yl)phenyl)acrylimidamide (51 mg, 0.1 mmol) in anhydrous DMF (0.4 mL) was added 2-ethylhexylchloroformate (20 μL, 0.1 mmol) followed by pyridine (9 μL, 0.11 mmol). The reaction mixture was stirred at 0° C. for 1 h and then partitioned between water and EtOAc. The aqueous layer was extracted with EtOAc (2×), and the combined organics were dried over MgSO4 and concentrated. The residue was dissolved in xylenes (1 mL), heated at 130° C. for 2 h, and then concentrated to afford 25 mg of the title compound. LCMS: 519 (M+H)+.