Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[NH:9][C:10]([NH:12][C:13]1[CH:34]=[CH:33][C:16]([O:17][C:18]2[CH:23]=[CH:22][N:21]=[C:20]([C:24]3[CH:25]=[C:26]([C:29]([O:31]C)=[O:30])[NH:27][CH:28]=3)[CH:19]=2)=[CH:15][CH:14]=1)=[O:11].[OH-].[Na+].O.Cl>C1COCC1.CO>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[NH:9][C:10]([NH:12][C:13]1[CH:14]=[CH:15][C:16]([O:17][C:18]2[CH:23]=[CH:22][N:21]=[C:20]([C:24]3[CH:25]=[C:26]([C:29]([OH:31])=[O:30])[NH:27][CH:28]=3)[CH:19]=2)=[CH:33][CH:34]=1)=[O:11]
Reactant: COC(=O)c1cc(-c2cc(Oc3ccc(NC(=O)Nc4cc(C)ccc4F)cc3)ccn2)c[nH]1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: Cc1ccc(F)c(NC(=O)Nc2ccc(Oc3ccnc(-c4c[nH]c(C(=O)O)c4)c3)cc2)c1
Temperature: 70 °C

Procedure:
To a stirred solution of methyl 4-{4-[4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)phenoxy]pyridin-2-yl}-1H-pyrrole-2-carboxylate (220 mg, 0.48 mmol) in THF/MeOH (3 ml/10 ml) was added 1M NaOH (4.0 ml, 4.0 mmol). The mixture was heated at 70° C. for 2 hours, cooled to room temperature and poured into 100 ml of water. 1M HCl was added until pH=4 and the resulting precipitates were filtered, washed with water and dried in vacuo to give 4-{4-[4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)phenoxy]pyridin-2-yl}-1H-pyrrole-2-carboxylic acid.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[NH:10][CH:9]=2)[C:5]([CH3:17])=[CH:4][N:3]=1.[NH2:18][C:19]1[CH:24]=[CH:23][C:22]([N:25]2[CH2:30][CH2:29][CH:28]([N:31]([CH3:33])[CH3:32])[CH2:27][CH2:26]2)=[CH:21][C:20]=1[O:34][CH3:35]>>[CH3:32][N:31]([CH3:33])[CH:28]1[CH2:27][CH2:26][N:25]([C:22]2[CH:23]=[CH:24][C:19]([NH:18][C:2]3[N:7]=[C:6]([C:8]4[C:16]5[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=5)[NH:10][CH:9]=4)[C:5]([CH3:17])=[CH:4][N:3]=3)=[C:20]([O:34][CH3:35])[CH:21]=2)[CH2:30][CH2:29]1
Reactant: Cc1cnc(Cl)nc1-c1c[nH]c2ccccc12
Reactant: COc1cc(N2CCC(N(C)C)CC2)ccc1N
Product: COc1cc(N2CCC(N(C)C)CC2)ccc1Nc1ncc(C)c(-c2c[nH]c3ccccc23)n1

Procedure:
Starting materials: 3-(2-chloro-5-methylpyrimidin-4-yl)-1H-indole (INTERMEDIATE 1) and 1-(4-amino-3-methoxyphenyl)-N,N-dimethylpiperidin-4-amine (INTERMEDIATE 28).
Reaction SMILES: [C:1](#[N:3])[CH3:2].[Li]CCCC.CO[C:11]([C:13]1([CH3:26])[CH2:18][CH2:17][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:15][CH2:14]1)=[O:12].Cl>C1COCC1>[C:22]([O:21][C:19]([N:16]1[CH2:15][CH2:14][C:13]([C:11](=[O:12])[CH2:2][C:1]#[N:3])([CH3:26])[CH2:18][CH2:17]1)=[O:20])([CH3:23])([CH3:24])[CH3:25]
Reactant: CC#N
Reactant: COC(=O)C1(C)CCN(C(=O)OC(C)(C)C)CC1
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(C)(C(=O)CC#N)CC1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 68 %

Procedure:
Acetonitrile (3.07 mL, 58.4 mmol) is added to THF (75 mL). At −78° C. 1.6 M BuLi in hexanes is slowly added. After 15 minutes, 4-methylpiperidine-1,4-dicarboxylic acid 1-tert-butyl ester 4-methyl ester (6.83 g, 26.5 mmol) dissolved in THF (75 mL) is added dropwise. After 1 hour 2.2 equivalents of 5N HCl is added at −78° C. The reaction is warmed to room temperature and concentrated to about 50 mL volume. EtOAc (50 mL) and saturated aqueous sodium chloride (25 mL) are added to the mixture. The organic layer is separated, dried over Na2SO4, concentrated, and chromatographed on silica gel, eluting with 0-20% EtOAc in dichloromethane, to give the title compound (4.80 g, 68% yield).
Reaction SMILES: CN(C)C(=N)N(C)C.[CH2:9]([O:16][C:17]1[CH:24]=[CH:23][C:20]([CH:21]=O)=[CH:19][CH:18]=1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.[Cl-].[CH2:26]([O:28][CH:29]([P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[C:30]([O:32][CH2:33][CH3:34])=[O:31])[CH3:27]>C(Cl)(Cl)Cl>[CH2:33]([O:32][C:30](=[O:31])[C:29]([O:28][CH2:26][CH3:27])=[CH:21][C:20]1[CH:23]=[CH:24][C:17]([O:16][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[CH:18][CH:19]=1)[CH3:34]
Reactant: CCOC(=O)C(OCC)[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: O=Cc1ccc(OCc2ccccc2)cc1
Agent: CN(C)C(=N)N(C)C
Agent: [Cl-]
Solvent: ClC(Cl)Cl
Product: CCOC(=O)C(=Cc1ccc(OCc2ccccc2)cc1)OCC
Temperature: 25 °C
Yield: 85.7 %

Procedure:
Tetramethylguanidine (42.3 g; 0.37 mole) was slowly added to a solution of 4-benzyloxybenzaldehyde (75.6 g; 0.36 mole) and (1,2-diethoxy-2-oxoethyl) (triphenyl)phosphonium chloride (130.7 g; 0.304 mole) dissolved in chloroform (800 ml) at 0° C. After stirring at room temperature over night, the solvent was evaporated in vacuo. The residue was dissolved in diethyl ether, insoluble material was filtered off and the filtrate was washed with sodium bicarbonate and dried (magnesium sulfate). The procedure was repeated once and thereafter the crude product was stirred overnight with a sodium bisulfite saturated water solution. The solid material was filtered off, the product was extracted with diethyl ether, dried (magnesium sulfate) and the solvent was evaporated in vacuo to give 85 g (yield 73%) of the desired product.
Reaction SMILES: CN(C=O)C.S(Cl)(Cl)=O.[NH:10]1[C:14]([C:15]([OH:17])=O)=[N:13][N:12]=[N:11]1.[N:18]1[CH:23]=[CH:22][CH:21]=[C:20]([C:24]2[S:25][CH:26]=[C:27]([NH2:29])[N:28]=2)[CH:19]=1.Cl>C(#N)C.N1C=CC=CC=1.O.C1C=CC=CC=1>[N:18]1[CH:23]=[CH:22][CH:21]=[C:20]([C:24]2[S:25][CH:26]=[C:27]([NH:29][C:15]([C:14]3[NH:13][N:12]=[N:11][N:10]=3)=[O:17])[N:28]=2)[CH:19]=1
Reactant: Nc1csc(-c2cccnc2)n1
Reactant: O=C(O)c1nnn[nH]1
Agent: Cl
Solvent: CC#N
Solvent: O
Solvent: O=S(Cl)Cl
Product: O=C(Nc1csc(-c2cccnc2)n1)c1nnn[nH]1
Temperature: 25 °C
Yield: 37.8 %

Procedure:
A mixture, obtained oy adding dry DMF (0.197 ml, 2.63 mmol) and then thionyl chloride (0.192 ml, 2.63 mmol) to dry benzene (1 ml) under ice-cooling, was allowed to warm up to room temperature and to react for 10 minutes upon which the mixture separated into two layers. The lower layer was added dropwise to dipotassium salt of 1H-tetrazole-5-carboxylic acid (333 mg, 1.75 mmol) suspended in dry acetonitrile (5 ml) under ice-cooling. The mixture was allowed to react for 15 minutes. After adding dropwise a mixed solution of 2-(3-pyridyl)4-thiazolamine (330 mg, 1.86 mmol) in dry acetonitrile (3 ml) and dry pyridine (1 ml) under the same conditions, the mixture was allowed to warm up to room temperature and to react for 1 hour. After dissolution was effected with addition of water, the reaction mixture was neutralized under ice-cooling with 2N-HCl to pH 7. The deposited solids were filtered with suction, was recrystallized from methanol-THF-water to give yellow crystals (181 mg, yield 38%) of N-(2-(3-pyridyl)-4-thiazolyl)-1H-tetrazole-5-carboxamide (Ia-23), m.p. 263°-265° C.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([Br:8])=[CH:4][C:3]=1[C:9]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=O.[CH3:17][S:18]([CH2:21][C:22](=O)[CH3:23])(=[O:20])=[O:19].[Na]>CC(O)C>[Br:8][C:5]1[CH:4]=[C:3]2[C:2](=[CH:7][CH:6]=1)[N:1]=[C:22]([CH3:23])[C:21]([S:18]([CH3:17])(=[O:20])=[O:19])=[C:9]2[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: Nc1ccc(Br)cc1C(=O)c1ccccc1
Reactant: CC(=O)CS(C)(=O)=O
Agent: [Na]
Solvent: CC(C)O
Product: Cc1nc2ccc(Br)cc2c(-c2ccccc2)c1S(C)(=O)=O
Yield: 34 %

Procedure:
(2-Amino-5-bromo-phenyl)-phenyl-methanone (10 g, 36 mmol), methanesulfonylacetone (7.4 g, 54 mmol) and sodium tetrachloroaureate(III) dihydrate (720 mg, 1.8 mmol) were heated at reflux in 2-propanol (100 mL) for 4.5 days. The resulting suspension was evaporated to dryness and the residue extracted with dichloromethane (2×), 1 N NaOH (2×), which removes excess of methanesulfonylacetone, and sat. NaCl (1×). The crude product was purified twice by chromatography in dichloromethane and then crystallized from dichloromethane/heptane by evaporation of dichloromethane. One obtained 4.6 g (33%) of beige crystals. MS: m/z=375/377 (M).
Reaction SMILES: [CH:1]([N:4]1[C:9](=[O:10])[C:8]([C:11]([O:13]CC)=[O:12])=[CH:7][C:6]2[CH:16]=[CH:17][S:18][C:5]1=2)([CH3:3])[CH3:2].[OH-].[Na+]>CO>[CH:1]([N:4]1[C:9](=[O:10])[C:8]([C:11]([OH:13])=[O:12])=[CH:7][C:6]2[CH:16]=[CH:17][S:18][C:5]1=2)([CH3:3])[CH3:2]
Reactant: CCOC(=O)c1cc2ccsc2n(C(C)C)c1=O
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CC(C)n1c(=O)c(C(=O)O)cc2ccsc21
Temperature: 25 °C
Yield: 81.3 %

Procedure:
A mixture of ethyl 6,7-dihydro-7-isopropyl-6-oxothieno[2,3-b]pyridine-5-carboxylate (1.12 g, 4.2 mmol), sodium hydroxide (6.3 mL, 2 N solution in water, 12.6 mmol) and methanol (20 mL) was heated at reflux for 18 h, cooled to room temperature and concentrated to remove methanol. The concentrate was diluted with water, cooled to 0° C. and acidified with concentrated hydrochloric acid. The resulting precipitates were collected by vacuum filtration and dried to provide the title compound as an off-white solid (0.81 g, 82% yield). 1H NMR (400 MHz, CDCl3): □ 8.86 (s, 1H), 7.25 (d, 1H), 7.16 (d, 1H), 4.87 (br, 1H), 1.73 (d, 6H).
Reaction SMILES: [C:1]([O:9][CH2:10][CH3:11])(=[O:8])[CH2:2][C:3]([O:5][CH2:6][CH3:7])=[O:4].[H-].[Na+].[Br:14][C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([Cl:21])[C:16]=1[CH2:22]Br.[NH4+].[Cl-]>CN(C=O)C.ClCCl.O.C(OCC)C>[Br:14][C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([Cl:21])[C:16]=1[CH2:22][CH:2]([C:3]([O:5][CH2:6][CH3:7])=[O:4])[C:1]([O:9][CH2:10][CH3:11])=[O:8]
Reactant: CCOC(=O)CC(=O)OCC
Reactant: Clc1cccc(Br)c1CBr
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: ClCCl
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)C(Cc1c(Cl)cccc1Br)C(=O)OCC
Temperature: 0 °C
Reaction time: 8 h

Procedure:
Diethyl malonate (8.33 mL, 54.59 mmol) was added dropwise to sodium hydride (60% oil dispersion) (2.28 g, 56.97 mmol) in DMF (55 mL) at 0° C. The mixture was stirred for 5 min at ambient temp, wherafter 1-bromo-2-(bromomethyl)-3-chlorobenzene (13.5 g, 47.5 mmol) dissolved in DMF (15 mL) was added dropwise at 0° C. The mixture was stirred at 0° C. for 20 min and ambient temp overnight. NH4Cl (aq) was added to quench the reaction. Diethyl ether was added followed by water. The phases were separated and the aqueous phase was extracted with diethyl ether. The combined organic phases were washed with brine and dried (MgSO4). The aqueous phase was extracted with dichloromethane. The organic phase was washed with brine. The solvents were evaporated to give 18.2 g (quantitative). 4 g of the crude material was dissolved in dichloromethane and purified by column chromatography eluting with gradients of ethyl acetate in heptanes. Fractions containing product were pooled and the solvents were evaporated to give the title compound. Yield: 3.32 g, 19%. 1H NMR (400 MHz, CDCl3) δ ppm 1.23 (t, 7H) 3.62 (d, 2H) 3.84 (m, 1H) 4.20 (q, 4H) 7.06 (t, 1H) 7.35 (dd, 1H) 7.50 (dd, 1H). MS (ES+) m/z 365 [M+H]+.
Reaction SMILES: [CH3:1][S:2]([NH:5][C:6]1[CH:15]=[CH:14][CH:13]=[CH:12][C:7]=1[C:8]([O:10]C)=O)(=[O:4])=[O:3].[CH3:16][Si:17]([CH3:24])([CH3:23])[CH2:18][CH2:19][O:20][CH2:21]Cl.[H-].[Na+]>CN(C)C=O>[O:4]=[S:2]1(=[O:3])[CH2:1][C:8](=[O:10])[C:7]2[CH:12]=[CH:13][CH:14]=[CH:15][C:6]=2[N:5]1[CH2:21][O:20][CH2:19][CH2:18][Si:17]([CH3:24])([CH3:23])[CH3:16]
Reactant: COC(=O)c1ccccc1NS(C)(=O)=O
Reactant: C[Si](C)(C)CCOCCl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: C[Si](C)(C)CCOCN1c2ccccc2C(=O)CS1(=O)=O
Temperature: 0 °C
Reaction time: 0.42 h
Yield: 72 %

Procedure:
In a dry round bottom flask under a blanket of nitrogen 60% sodium hydride in mineral oil (1.05 g, 26 mmol) was washed with hexanes and then suspended in N,N-dimethylformamide (50 mL). Mixture was cooled to 0° C. A solution of methyl 2-(methylsulfonamido)benzoate (5.0 g, 22 mmol) in 10 mL N,N-dimethylformamide was added to the mixture drop-wise. Reaction was held at 0° C. with stirring for 25 minutes. 2-(Trimethylsilyl)ethoxymethyl chloride was added to the mixture drop-wise. Reaction stirred for 2 hours slowly warming to ambient temperature. Reaction was quenched with 1N hydrochloric acid. Material was extracted twice with ethyl acetate. Material was washed successively with water and brine. Organic phase was dried (magnesium sulfate), filtered and concentrated to dryness. Residue was dissolved in N,N-dimethylformamide (5 mL) and added drop-wise to a mixture of 60% sodium hydride in mineral oil (1.02 g, 26 mmol) that had been washed with hexanes, suspended in N,N-dimethylformamide (50 mL) and cooled to 0° C. Ice bath was removed and the mixture was allowed to warm to room temperature. Reaction was held at room temperature overnight with stirring. Reaction was quenched with 1N hydrochloric acid. Material was extracted twice with ethyl acetate. Organic phase was washed successively with water and brine. Organic phase was dried (magnesium sulfate), filtered and concentrated to dryness. Silica gel chromatography (ethyl acetate-hexanes) afforded the title compound as a white solid in 72% yield. MS m/e (M−H)−=326.0.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][C:10]2[NH:11][CH:12]=[C:13]([CH2:15][C:16]([CH3:20])([CH3:19])[CH2:17][CH3:18])[N:14]=2)=[CH:4][CH:3]=1.[C:21](Cl)([C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.C(N(CC)CC)C>C(Cl)Cl>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][C:10]2[N:11]([C:21]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)([C:34]3[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=3)[C:28]3[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=3)[CH:12]=[C:13]([CH2:15][C:16]([CH3:19])([CH3:20])[CH2:17][CH3:18])[N:14]=2)=[CH:4][CH:3]=1
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: CCC(C)(C)Cc1c[nH]c(CCc2ccc(Br)cc2)n1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCC(C)(C)Cc1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)c(CCc2ccc(Br)cc2)n1
Reaction time: 2 h

Procedure:
To a solution of 2-[2-(4-bromophenyl)ethyl]-4-(2,2-dimethylbutyl)-1H-imidazole (33.4 g, 100 mmol) in methlyene chloride (500 mL) was added trityl chloride (41.8 g, 150 mmol) and triethylamine (42 mL, 300 mmol). The reaction was stirred for 2 h, then washed with water, dried over sodium sulfate and concentrated to give a residue. The residue was purified by silica gel column chromatography eluting with ethyl acetate/hexanes (2:8). The chromatography was repeated eluting with methylene chloride/2-propanol 99.8:0.02) and then methlyene chloride/methanol (95:5) to provide 2-[2-(4-bromophenyl)ethyl]-4-(2,2-dimethylbutyl)-1-trityl-1H-imidazole.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:22])[C:7]=1[CH2:8][C:9]1[C:18]2[C:13](=[CH:14][C:15]([O:19][CH3:20])=[CH:16][CH:17]=2)[C:12](=[O:21])[NH:11][N:10]=1.[H-].[Na+].[CH2:25](I)[CH3:26]>CN(C=O)C.O>[Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:22])[C:7]=1[CH2:8][C:9]1[C:18]2[C:13](=[CH:14][C:15]([O:19][CH3:20])=[CH:16][CH:17]=2)[C:12](=[O:21])[N:11]([CH2:25][CH3:26])[N:10]=1
Reactant: COc1ccc2c(Cc3c(Cl)cncc3Cl)n[nH]c(=O)c2c1
Reactant: CCI
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCn1nc(Cc2c(Cl)cncc2Cl)c2ccc(OC)cc2c1=O
Yield: 77.9 %

Procedure:
A suspension of 4-(3,5-dichloro-pyridin-4-ylmethyl)-7-methoxy-2H-phthalazin-1-one (0.52 g, 1.55 mmoles), prepared as described in example 38, in DMF (10 ml) was added with NaH (0.057 g, 1.55 mmoles) and, after 1 hour, with ethyl iodide (0.125 ml, 1.55 mmoles). After 1 night the mixture was diluted with water (10 volumes) and extracted twice with ethyl acetate. The organic phase was anhydrified and concentrated to give a solid which was purified by flash chromatography (eluent: ethyl acetate/petrolatum 3:7). There was thus obtained 0.44 g of the title compound (yield: 78%). m.p.: 150.2-151.2° C.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[N:10]=[C:9]([C:11]([CH3:14])([CH3:13])[CH3:12])[N:8]([CH2:15][CH:16]3[CH2:21][CH2:20][O:19][CH2:18][CH2:17]3)[C:5]2=[N:6][CH:7]=1.[CH3:22][CH:23]([SH:25])[CH3:24]>>[C:11]([C:9]1[N:8]([CH2:15][CH:16]2[CH2:21][CH2:20][O:19][CH2:18][CH2:17]2)[C:5]2=[N:6][CH:7]=[C:2]([S:25][CH:23]([CH3:24])[CH3:22])[CH:3]=[C:4]2[N:10]=1)([CH3:14])([CH3:13])[CH3:12]
Reactant: CC(C)S
Reactant: CC(C)(C)c1nc2cc(Br)cnc2n1CC1CCOCC1
Product: CC(C)Sc1cnc2c(c1)nc(C(C)(C)C)n2CC1CCOCC1

Procedure:
The title compound was prepared according to the procedure described in Step E of Example 32 from 6-bromo-2-tert-butyl-3-(tetrahydro-2H-pyran-4-ylmethyl)-3H-imidazo[4,5-b]pyridine (Step F of Example 47) and 2-propanethiol (TCI Tokyo Kasei Kogyo Co., Ltd.).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:13])[C:4]1[CH:9]=[CH:8][C:7]([CH2:10]Br)=[N:6][C:5]=1[Cl:12].[CH:14]([NH2:16])=[O:15].[CH:17](N)=[O:18].[Na]>CN(C=O)C>[CH3:1][O:2][C:3](=[O:13])[C:4]1[CH:9]=[CH:8][C:7]([CH2:10][N:16]([CH:17]=[O:18])[CH:14]=[O:15])=[N:6][C:5]=1[Cl:12]
Reactant: COC(=O)c1ccc(CBr)nc1Cl
Reactant: NC=O
Agent: [Na]
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(CN(C=O)C=O)nc1Cl
Temperature: 25 °C
Reaction time: 16 h
Yield: 33 %

Procedure:
To a solution of crude 6-bromomethyl-2-chloronicotinic acid methyl ester (<138 g, <0.54 mol) in DMF (400 mL) was added sodium diformamide (56.3 g, 0.59 mol) and the reaction mixture stirred at room temperature for 16 hours. The reaction mixture rapidly darkened and a small exotherm was observed. The reaction mixture was concentrated in vacuo and the residue dissolved in ethyl acetate (200 mL). The resultant solution was washed with water (400 mL) and the aqueous layer extracted with ethyl acetate (2×200 mL). The combined organic extracts were washed with brine (100 mL), dried (MgSO4) and concentrated in vacuo. The resultant residue was dry-loaded onto silica (150 g) and the residue subjected to flash chromatography (SiO2 400 g, 40% ethyl acetate in cyclohexane) to yield the title compound as a yellow solid (46 g, 33% over two steps). 1H NMR (CDCl3, 400 MHz) 8.46 (2H, br s), 7.56 (1H, d, J=7.7 Hz), 6.66 (1H, d, J=7.9 Hz), 4.39 (2H, br s), 3.36 (3H, s).
Reaction SMILES: [F:1][C:2]([F:27])([F:26])[S:3]([O:6][C:7]1[CH:16]=[C:15]2[C:10]([C:11](=O)[C:12](=[CH:17][C:18]3[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=3)[CH2:13][O:14]2)=[CH:9][CH:8]=1)(=[O:5])=[O:4].Cl.[Cl:29][C:30]1[CH:37]=[C:36]([NH:38][NH2:39])[CH:35]=[CH:34][C:31]=1[C:32]#[N:33]>C(O)C>[F:26][C:2]([F:1])([F:27])[S:3]([O:6][C:7]1[CH:8]=[CH:9][C:10]2[C:11]3=[N:39][N:38]([C:36]4[CH:35]=[CH:34][C:31]([C:32]#[N:33])=[C:30]([Cl:29])[CH:37]=4)[CH:17]([C:18]4[CH:19]=[CH:20][C:21]([F:24])=[CH:22][CH:23]=4)[CH:12]3[CH2:13][O:14][C:15]=2[CH:16]=1)(=[O:5])=[O:4]
Reactant: O=C1C(=Cc2ccc(F)cc2)COc2cc(OS(=O)(=O)C(F)(F)F)ccc21
Reactant: N#Cc1ccc(NN)cc1Cl
Agent: Cl
Solvent: CCO
Product: N#Cc1ccc(N2N=C3c4ccc(OS(=O)(=O)C(F)(F)F)cc4OCC3C2c2ccc(F)cc2)cc1Cl
Temperature: 80 °C
Reaction time: 3 h
Yield: 28 %

Procedure:
A mixture of 3-(4-fluorobenzylidene)-4-oxochroman-7-yl trifluoromethanesulfonate; Preparation 35 (200 mg, 0.50 mmol), 2-chloro-4-hydrazinylbenzonitrile hydrochloride (Preparation 1) (152 mg, 0.75 mmol), and ethanol (5 mL) was stirred under argon at 80° C. for three hours. The mixture was cooled to room temperature and concentrated. Water was added, the residue extracted three times with methylene chloride, washed with brine, dried over magnesium sulfate, filtered and condensed. The crude product was purified by normal phase flash column chromatography on a 20 g silica gel column (100% methylene chloride). Pure fractions were pooled and condensed to give the title compound (yellow solid, 75 mg, 0.14 mmol, 28% yield). The title compound was largely present as (±)-(3SR,3aSR)-2-(3-chloro-4-cyanophenyl)-3-(4-fluorophenyl)-2,3,3a,4-tetrahydrochromeno[4,3-c]pyrazol-7-yl trifluoromethanesulfonate. 1H NMR (400 MHz, DMSO-d6) δ ppm 3.25 (dd, J=12.89, 10.47 Hz, 1H), 4.22-4.35 (m, 1H), 4.42 (dd, J=10.34, 6.04 Hz, 1H), 6.00 (d, J=11.28 Hz, 1H), 6.77-7.51 (m, 8H), 7.68 (d, J=8.59 Hz, 1H), 8.10 (d, J=9.40 Hz, 1H). ES-MS m/z 553 (M+H).
Reaction SMILES: C(N(CC)CC)C.[N+:8]([C:11]1[N:12]=[C:13]2[N:18]([CH:19]=1)[CH2:17][CH2:16][C@H:15]([CH2:20][O:21][C:22]1[CH:27]=[CH:26][C:25]([N:28]3[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]3)=[CH:24][CH:23]=1)[O:14]2)([O-:10])=[O:9].[CH3:34][S:35](Cl)(=[O:37])=[O:36].Cl>C(Cl)Cl>[CH3:34][S:35]([N:31]1[CH2:32][CH2:33][N:28]([C:25]2[CH:26]=[CH:27][C:22]([O:21][CH2:20][C@@H:15]3[O:14][C:13]4=[N:12][C:11]([N+:8]([O-:10])=[O:9])=[CH:19][N:18]4[CH2:17][CH2:16]3)=[CH:23][CH:24]=2)[CH2:29][CH2:30]1)(=[O:37])=[O:36]
Reactant: CS(=O)(=O)Cl
Reactant: O=[N+]([O-])c1cn2c(n1)O[C@@H](COc1ccc(N3CCNCC3)cc1)CC2
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CS(=O)(=O)N1CCN(c2ccc(OC[C@H]3CCn4cc([N+](=O)[O-])nc4O3)cc2)CC1
Reaction time: 14 h

Procedure:
Triethylamine (0.31 ml) was added to a methylene chloride suspension (6 ml) of (R)-2-nitro-7-(4-piperazin-1-ylphenoxymethyl)-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazine (0.40 g). Subsequently, methanesulfonyl chloride (0.09 ml) was added thereto dropwise under ice cooling, and the mixture was stirred for 14 hours while it gradually returned to room temperature. A 0.5 N hydrochloric acid aqueous solution was added to the reaction mixture, followed by extraction with methylene chloride. The organic layer was washed with water and a saturated sodium chloride aqueous solution, dried over anhydrous sodium sulfate, and the solvent was then distilled off under reduced pressure. The resulting residue was purified by silica gel column chromatography (methylene chloride:methanol=90:10) and recrystallized from methylene chloride-methanol to afford the title compound as a beige powder (0.15 g).
Reaction SMILES: [C:1]1([CH3:11])[CH:6]=[CH:5][C:4]([S:7](Cl)(=[O:9])=[O:8])=[CH:3][CH:2]=1.[C:12]([S:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][O:43][CH2:44][CH2:45][O:46][CH2:47][CH2:48][O:49][CH2:50][CH2:51][O:52][CH2:53][CH2:54][O:55][CH2:56][CH2:57][O:58][CH2:59][CH2:60][OH:61])([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.N1C=CC=CC=1>C(Cl)Cl>[C:12]([S:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][O:43][CH2:44][CH2:45][O:46][CH2:47][CH2:48][O:49][CH2:50][CH2:51][O:52][CH2:53][CH2:54][O:55][CH2:56][CH2:57][O:58][CH2:59][CH2:60][O:61][S:7]([C:4]1[CH:5]=[CH:6][C:1]([CH3:11])=[CH:2][CH:3]=1)(=[O:9])=[O:8])([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: OCCOCCOCCOCCOCCOCCOCCCCCCCCCCCSC(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: c1ccncc1
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)OCCOCCOCCOCCOCCOCCOCCCCCCCCCCCSC(c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
p-Toluenesulfonyl chloride (900 mg, 4.7 mmol) was added to a solution of alcohol 4 (910 mg, 1.28 mmol) dissolved in 12 mL of CH2Cl2 and 2 mL of pyridine at 0° C. The solution was warmed to room temperature and stirred for 16 hours. The reaction mixture was rinsed with brine (2×30 mL) and H2O (2×30 mL), and then the organics were dried over MgSO4. After the solvent was evaporated, the crude residue was purified by flash chromatography (gradient, 1:1 hexanes/EtOAc to EtOAc) to afford 1.01 g (91%) of pure 5. 1H NMR (CDCl3, 400 MHz) d 7.79 (d, J=8.0 Hz, 2 H), 7.40 (d, J=7.8 Hz, 6 H), 7.33 (d, J=8.0 Hz, 2 H), 7.26 (t, J=7.8 Hz, 6 H), 7.19 (t, J=7.8 Hz, 3 H), 4.15 (t, J=4.8 Hz, 2 H), 3.67 (t, J=5.2 Hz, 2 H), 3.64-3.54 (br m, 20 H), 3.43 (t, J=6.8 Hz, 2 H), 2.45 (s, 3 H), 2.12 (t, J=7.2 Hz, 2 H), 1.56 (m, 2 H), 1.42-0.90 (br, 16 H).
Reaction SMILES: [CH:1]1[CH:2]=[CH:3][C:4]2[O:11][C:9](=[O:10])[CH2:8][CH2:7][C:5]=2[CH:6]=1.OS(O)(=O)=O.C([O-])([O-])=O.[K+].[K+].[CH3:23][OH:24]>O>[OH:24][C:23]1[CH:3]=[CH:2][CH:1]=[CH:6][C:5]=1[CH2:7][CH2:8][C:9]([O:11][CH3:4])=[O:10]
Reactant: CO
Reactant: O=C1CCc2ccccc2O1
Agent: O=C([O-])[O-]
Agent: O=S(=O)(O)O
Agent: [K+]
Solvent: O
Product: COC(=O)CCc1ccccc1O
Temperature: 55 °C
Yield: 90 %

Procedure:
To a stirred solution of dihydrocoumarin (10 mL, 78.9 mmol) and a catalytic amount of conc. H2SO4 in dry methanol (300 mL) was added and the reaction mixture was then heated at 55° C. for 8 hours. Methanol was evaporated to dryness to give crude product which was subjected to neutralize with K2CO3. The residue was diluted with water and extracted with dichloromethane. Purification of the crude product by column chromatography (20% CH2Cl2:3% EtOAc:77% Hexane as eluent) gave the desired ester as colorless oil (12.80 g, 90%). 1H NMR (400 MHz, CDCl3): 2.71 (3H, t, J=6.4 Hz), 2.89 (2H, t, J=6.4 Hz), 3.67 (3H, s), 6.83-6.87 (2H, m), 7.06-7.12 (2H, m),