Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH:4]1[CH:9]([NH:10][C:11]2[N:16]=[C:15]([N:17]3[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]3)[CH:14]=[CH:13][N:12]=2)[CH2:8][CH2:7][CH2:6][N:5]1[CH:24]1[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]1.N=C=N.[C:33]([O:37][C:38]([N:40]1[CH2:45][CH2:44][CH:43]([C:46](O)=[O:47])[CH2:42][CH2:41]1)=[O:39])([CH3:36])([CH3:35])[CH3:34].OC1C2N=NNC=2C=CC=1.C(=O)([O-])[O-]>ClCCl.CN(C)C=O>[N:17]1([C:15]2[CH:14]=[CH:13][N:12]=[C:11]([NH:10][CH:9]3[CH2:8][CH2:7][CH2:6][N:5]([CH:24]4[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]4)[CH:4]3[CH2:3][CH2:2][NH:1][C:46]([CH:43]3[CH2:44][CH2:45][N:40]([C:38]([O:37][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:39])[CH2:41][CH2:42]3)=[O:47])[N:16]=2)[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1
Reactant: CC(C)(C)OC(=O)N1CCC(C(=O)O)CC1
Reactant: NCCC1C(Nc2nccc(N3CCCCCC3)n2)CCCN1C1CCCCC1
Agent: N=C=N
Agent: O=C([O-])[O-]
Agent: Oc1cccc2[nH]nnc12
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCC(C(=O)NCCC2C(Nc3nccc(N4CCCCCC4)n3)CCCN2C2CCCCC2)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
N-[(2RS,3SR)-2-(2-aminoethyl)-1-cyclohexylpiperidin-3-yl]-4-azepan-1-ylpyrimidin-2-amine (63 mg) was dissolved in dichloromethane (3 mL), PS-carbodiimide (327 mg) was added and then 0.5 M of a solution (0.47 mL) of 1-(tert-butoxycarbonyl)piperidine-4-carboxylic acid in dimethylformamide:dichloromethane=1:1 and 0.5 M of a mixture solution (0.53 mL) of hydroxybenzotriazole in dimethylformamide:dichloromethane=1:1 were added and stirred at room temperature for overnight. MP-carbonate (271 mg) was added into the reaction solution, stirred for 1 hour and then filtered and concentrated. The residue was purified by silica gel column chromatography (ethyl acetate:methanol=90:10) to obtain the title compound (81 mg) having the following physical properties.
Reaction SMILES: [C:1]1([N:7]=[C:8]=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl.[NH2:11][C@H:12]([CH:28]([CH3:30])[CH3:29])[C:13]([N:15]1[CH2:20][CH2:19][CH:18]([C:21]2[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][CH:22]=2)[CH2:17][CH2:16]1)=[O:14].O1CCOCC1>CO>[Cl:27][C:24]1[CH:25]=[CH:26][C:21]([CH:18]2[CH2:17][CH2:16][N:15]([C:13](=[O:14])[C@H:12]([NH:11][C:8]([NH:7][C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)=[O:9])[CH:28]([CH3:30])[CH3:29])[CH2:20][CH2:19]2)=[CH:22][CH:23]=1
Reactant: O=C=Nc1ccccc1
Reactant: CC(C)[C@@H](N)C(=O)N1CCC(c2ccc(Cl)cc2)CC1
Agent: Cl
Solvent: CO
Solvent: C1COCCO1
Product: CC(C)[C@@H](NC(=O)Nc1ccccc1)C(=O)N1CCC(c2ccc(Cl)cc2)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A reaction tube was charged with phenyl isocyanate (12 mg), (R)-2-amino-1-(4-(4-chlorophenyl)piperidin-1-yl)-3-methylbutan-1-one hydrochloride (17 mg) and 1,4-dioxane (0.75 mL). The reaction mixture was shaken overnight at rt. After this time, the resulting solution was diluted with MeOH and purified by preparative LC-MS to provide Example 201. MS found: (M+H)+=429.
Reaction SMILES: [Br:1][C:2]1[C:3]([C:7]([N:9]([CH3:11])[CH3:10])=[O:8])=[N:4][NH:5][CH:6]=1.C(=O)([O-])[O-].[K+].[K+].CS(O[CH:23]1[CH2:28][CH2:27][N:26]([C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[CH2:25][CH2:24]1)(=O)=O>C(#N)C>[Br:1][C:2]1[C:3]([C:7](=[O:8])[N:9]([CH3:11])[CH3:10])=[N:4][N:5]([CH:23]2[CH2:28][CH2:27][N:26]([C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[CH2:25][CH2:24]2)[CH:6]=1
Reactant: CC(C)(C)OC(=O)N1CCC(OS(C)(=O)=O)CC1
Reactant: CN(C)C(=O)c1n[nH]cc1Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CN(C)C(=O)c1nn(C2CCN(C(=O)OC(C)(C)C)CC2)cc1Br
Yield: 41.1 %

Procedure:
4-bromo-N,N-dimethyl-1H-pyrazole-3-carboxamide (450 mg), potassium carbonate (456 mg) and tert-butyl 4-(methylsulfonyloxy)piperidine-1-carboxylate (900 mg) in acetonitrile (13 mL) were stirred at 90° C. overnight. The mixture was concentrated and the residue was dissolved in ethylacetate, washed with water, brine dried over magnesium sulfate and concentrated. The crude product was purified by flash chromatography on silica gel eluting with 50 to 90% ethyl acetate in petroleum ether. The solvent was evaporated to dryness to afford tert-butyl 4-[4-bromo-3-(dimethylcarbamoyl)pyrazol-1-yl]piperidine-1-carboxylate (340 mg). NMR Spectrum: (DMSOd6) 1.41 (s, 9H), 1.73 (dd, 1H), 1.78 (dd, 1H), 1.96-1.05 (m, 2H), 2.89 (bs, 2H), 2.95 (s, 3H), 2.87 (s, 3H), 3.92-4.10 (m, 2H), 4.33-4.44 (m, 1H), 8.15 (s, 1H); Mass spectrum: M+H+ 401-403
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([CH:9]=[C:10]([I:14])[C:11]=1[O:12][CH3:13])[NH2:8])([CH3:4])([CH3:3])[CH3:2].[N:15]([CH2:18][CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21])=[C:16]=[O:17]>>[C:1]([C:5]1[CH:6]=[C:7]([NH:8][C:16](=[O:17])[NH:15][CH2:18][CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21])[CH:9]=[C:10]([I:14])[C:11]=1[O:12][CH3:13])([CH3:4])([CH3:2])[CH3:3]
Reactant: COc1c(I)cc(N)cc1C(C)(C)C
Reactant: CCOC(=O)CCN=C=O
Product: CCOC(=O)CCNC(=O)Nc1cc(I)c(OC)c(C(C)(C)C)c1
Yield: 83 %

Procedure:
3-tert-Butyl-5-iodo-4-methoxyaniline (305 mg, 1 mmol) and ethyl 3-isocyanatopropionate were reacted in the same manner as Example 15 Part A and purified on an Isco 40 g silica cartridge eluting with ethyl acetate/hexane (0% to 25%) to give the title compound (373 mg, 83%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10]([C:19]3[CH:24]=[CH:23][C:22]4[O:25][CH2:26][O:27][C:21]=4[CH:20]=3)[O:11][C:12]=2[CH2:13][CH2:14][C:15]([O:17]C)=[O:16])=[CH:4][CH:3]=1.[OH-].[K+].CO.Cl>O1CCCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:9]=[C:10]([C:19]3[CH:24]=[CH:23][C:22]4[O:25][CH2:26][O:27][C:21]=4[CH:20]=3)[O:11][C:12]=2[CH2:13][CH2:14][C:15]([OH:17])=[O:16])=[CH:6][CH:7]=1
Reactant: COC(=O)CCc1oc(-c2ccc3c(c2)OCO3)nc1-c1ccc(Cl)cc1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: O=C(O)CCc1oc(-c2ccc3c(c2)OCO3)nc1-c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 98.1 %

Procedure:
A mixture of methyl 3-[4-(4-chlorophenyl)-2-[3,4-(methylenedioxy)phenyl]-5-oxazolyl]propionate (1.29 g), potassium hydroxide (0.44 g), methanol (20 mL) and tetrahydrofuran (15 mL) was stirred at room temperature for 2 hrs. The reaction mixture was poured into dilute hydrochloric acid, and extracted with ethyl acetate. The organic layer was washed with water, dried over anhydrous magnesium sulfate, and concentrated to give 3-[4-(4-chlorophenyl)-2-[3,4-(methylenedioxy)phenyl]-5-oxazolyl]propionic acid (1.22 g, 98%) as a colorless powder. Recrystallization from ethyl acetate-hexane gave colorless prism crystals. melting point: 199–200° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:20]([C:21](=[O:23])[CH3:22])=[C:11]3[CH:12]=[CH:13][C:14]([C:16]([F:19])([F:18])[F:17])=[CH:15][N:10]3[N:9]=2)=[CH:4][CH:3]=1.CO[CH:26](OC)[N:27]([CH3:29])[CH3:28]>>[CH3:26][N:27]([CH3:29])/[CH:28]=[CH:22]/[C:21]([C:20]1[C:8]([C:5]2[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=2)=[N:9][N:10]2[CH:15]=[C:14]([C:16]([F:19])([F:18])[F:17])[CH:13]=[CH:12][C:11]=12)=[O:23]
Reactant: CC(=O)c1c(-c2ccc(F)cc2)nn2cc(C(F)(F)F)ccc12
Reactant: COC(OC)N(C)C
Product: CN(C)/C=C/C(=O)c1c(-c2ccc(F)cc2)nn2cc(C(F)(F)F)ccc12
Temperature: 25 °C

Procedure:
A mixture of 1-[2-(4-Fluorophenyl)-6-(trifluoromethyl)pyrazolo[1,5-α]pyridin-3-yl]ethanone (11.85 g), 36.77 mmol) and N,N-dimethylformamide dimethyl acetal (100 mL) was stirred at reflux for 17 hours. The mixture was cooled to room temperature and then to 0° C. The resulting orange precipitate was collected by filtration, washed with cold hexanes, and dried under vacuum to afford the title compound as an orange solid, 10.17 g (73qb). 1H NMR (DMSO-d6): δ 9.44 (s, 1H), 8.22 (d, 1H, J=9.4Hz), 7.75 (m, 2H), 7.65 (d, 1H, J=9.5 Hz), 7.56 (d, 1H, J=12.4 Hz), 7.35 (m, 2H), 5.05 (d, 1H, J=12.3 Hz), 3.04 (s, 3H), 2.56 (s, 3H). MS (+ve ion electrospray) 377 (80), (M+).
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[C:5]([CH:18]=[CH:19][C:20]=1[OH:21])[O:6][CH2:7][C:8]1[CH:17]=[CH:16][C:11]([C:12]([O:14]C)=[O:13])=[CH:10][CH:9]=1)=[O:2]>CCO.[OH-].[Na+].O>[CH:1]([C:3]1[CH:4]=[C:5]([CH:18]=[CH:19][C:20]=1[OH:21])[O:6][CH2:7][C:8]1[CH:17]=[CH:16][C:11]([C:12]([OH:14])=[O:13])=[CH:10][CH:9]=1)=[O:2]
Reactant: COC(=O)c1ccc(COc2ccc(O)c(C=O)c2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: O=Cc1cc(OCc2ccc(C(=O)O)cc2)ccc1O
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 99.7 %

Procedure:
A suspension of compound 40 (0.50 g, 1.75 mmol) in a mixture of EtOH (5 mL) and 1N aq NaOH was stirred at room temperature for 2.5 h to give a light yellow solution. The reaction mixture was diluted with water (50 mL), washed with EtOAc (25 mL) and acidified with conc HCl (˜1 mL). The off-white precipitate that formed was collected, washed with water, and dried under high vacuum to give 0.475 g (100%) of 4-[(3-formyl-4-hydroxyphenoxy)methyl]benzoic acid (isotucaresol; III) as a cream-colored powder: mp 222-224° C. (dec); Rf 0.46 (10% MeOH-EtOAc); 1H NMR (300 MHz, acetone-d6) δ10.62 (br s, 1 H, OH), 10.00 (s, 1H, CHO), 8.06 (d, 2H, J=8 Hz, H-2,6), 7.62 (d, 2H, J=8 Hz, H-3,5), 7.43 (d, 1H, J=3 Hz, H-2′), 7.33 (dd, J=3, 8.9 Hz, H-6′), 6.95 (d, 2H, J=8.9 Hz, H-5′), 2.44 (br s, 1H, OH); 13C NMR (75 MHz, acetone-d6) δ197.2, 167.2, 156.7, 152.6, 143.3, 130.9, 130.6, 128.1, 126.5, 121.6, 119.1, 117.6, 70.7; HRMS calcd. for M+NH4+ 290.1028, found 290.1037; Anal. calcd. for C15H12O5.0.25 H2O: C, 65.09; H, 4.55. Found: C, 65.46; H, 4.56.
Reaction SMILES: Cl[C:2]1[CH:17]=[C:6]2[C:7]3[C:12]([CH2:13][CH2:14][N:5]2[C:4](=[O:18])[N:3]=1)=[CH:11][C:10]([O:15][CH3:16])=[CH:9][CH:8]=3.[Cl:19][C:20]1[CH:26]=[CH:25][CH:24]=[CH:23][C:21]=1[NH2:22]>>[Cl:19][C:20]1[CH:26]=[CH:25][CH:24]=[CH:23][C:21]=1[NH:22][C:2]1[CH:17]=[C:6]2[C:7]3[C:12]([CH2:13][CH2:14][N:5]2[C:4](=[O:18])[N:3]=1)=[CH:11][C:10]([O:15][CH3:16])=[CH:9][CH:8]=3
Reactant: Nc1ccccc1Cl
Reactant: COc1ccc2c(c1)CCn1c-2cc(Cl)nc1=O
Product: COc1ccc2c(c1)CCn1c-2cc(Nc2ccccc2Cl)nc1=O

Procedure:
The title compound was prepared from 2-chloro-9-methoxy-6,7-dihydro-pyrimido[6,1-a]isoquinolin-4-one (4) and 2-chloro-aniline as in Example 1 d. 1H-NMR (400 MHz, d6-DMSO) δ 9.10 (br, 1H), 7.91 (brd, 1H), 7.70 (brd, 1H), 7.53 (dd, 1H), 7.37 (t, 1H), 7.21 (t, 1H), 7.05-6.95 (2H), 6.55 (br, 1H), 3.97 (t, 2H), 3.84 (s, 3H) and 2.96 (t, 2H); MS (ESI) (M+H)+ 354.
Reaction SMILES: [ClH:1].[NH2:2][C:3]1[N:8]=[C:7]([NH2:9])[N:6]([O:10]CC2C=CC=CC=2)[C:5]([CH3:19])([CH3:18])[N:4]=1.O>C(O)C.[Pd]>[ClH:1].[NH2:2][C:3]1[N:8]=[C:7]([NH2:9])[N:6]([OH:10])[C:5]([CH3:19])([CH3:18])[N:4]=1
Reactant: CC1(C)N=C(N)N=C(N)N1OCc1ccccc1
Agent: [Pd]
Agent: Cl
Solvent: CCO
Solvent: O
Product: CC1(C)N=C(N)N=C(N)N1O
Yield: 69.4 %

Procedure:
A solution of 10.0 grams (0.035 mole) of 4,6-diamino-1,2-dihydro-1-phenylmethoxy-2,2-dimethyl-1,3,5-triazine hydrochloride and 20 ml of water in 30 ml of ethanol was hydrogenated in the presence of 1.0 gram of 5% palladium on charcoal using a Parr hydrogenator. Upon completion of the uptake of the theoretical amount of hydrogen, the reaction mixture was filtered. The filtrate was concentrated under reduced pressure to a residual solid. The solid was recrystallized from ethanol, yielding 4.7 grams of 4,6-diamino-1,2-dihydro-1-hydroxy-2,2-dimethyl-1,3,5-triazine hydrochloride, m.p. 241° C. (dec.). The NMR spectrum was consistent with the proposed structure. The reaction was repeated several times to provide sufficient material for the next step.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:12](=[CH:13][CH:14]=1)[NH:11][C:10]1[CH:9]([NH2:15])[CH2:8][CH2:7][CH2:6][C:5]2=1.[C:16]1([N:22]=[C:23]=[O:24])[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>>[Cl:1][C:2]1[CH:3]=[C:4]2[C:12](=[CH:13][CH:14]=1)[NH:11][C:10]1[CH:9]([NH:15][C:23]([NH:22][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)=[O:24])[CH2:8][CH2:7][CH2:6][C:5]2=1
Reactant: O=C=Nc1ccccc1
Reactant: NC1CCCc2c1[nH]c1ccc(Cl)cc21
Product: O=C(Nc1ccccc1)NC1CCCc2c1[nH]c1ccc(Cl)cc21

Procedure:
N-(6-Chloro-2,3,4,9-tetrahydro-1H-carbazol-1-yl)-N′-phenylurea was prepared from 6-chloro-2,3,4,9-tetrahydro-1H-carbazol-1-amine and phenyl isocyanate in a similar manner as described above to give a white solid (74% yield). 1H-NMR (DMSO-d6): δ 10.93 (s, 1H), 8.30 (s, 1H), 7.41-7.36 (m, 3H), 7.28 (d, 1H), 7.21 (m, 2H), 7.00 (dd, 1H), 6.88 (m, 1H), 6.57 (d, 1H), 4.95 (m, 1H), 2.59 (m, 2H), 1.98 (m, 1H), 1.88-1.70 (m, 3H); MS m/z 338 (M−1).
Reaction SMILES: [CH2:1]1[CH2:10][O:9][CH:8]2[CH:3]([C@:4]3([CH2:23][CH2:22][C@H:21]4[C@@H:11]([CH:12]=[CH:13][C:14]5[C@:19]4([CH3:20])[CH:18]=[CH:17][C:16](=[O:24])[CH:15]=5)[C@@H:6]3[CH2:7]2)[CH3:5])[O:2]1.[OH-:25].[Na+].OO.O>CO>[CH2:1]1[CH2:10][O:9][C:3]2([CH2:8][CH2:7][C@H:6]3[C@H:11]4[C@H:21]([CH2:22][CH2:23][C@:4]23[CH3:5])[C@:19]2([CH3:20])[C:14](=[CH:15][C:16](=[O:24])[C@@H:17]3[O:25][C@@H:18]32)[CH:13]=[CH:12]4)[O:2]1
Reactant: C[C@]12C=CC(=O)C=C1C=C[C@@H]1[C@@H]2CC[C@]2(C)C3OCCOC3C[C@@H]12
Reactant: [OH-]
Agent: OO
Agent: [Na+]
Solvent: O
Solvent: CO
Product: C[C@@]12C(=CC(=O)[C@@H]3O[C@@H]31)C=C[C@@H]1[C@@H]2CC[C@@]2(C)[C@H]1CCC21OCCO1
Temperature: 25 °C
Reaction time: 4.5 h
Yield: 75 %

Procedure:
A solution of 1.0 g of 17, 17-ethylenedioxy-androsta-1,4,6-trien-3-one in 40 ml of methanol is treated at room temperature with 0.28 ml of 10% methanolic sodium hydroxide and 1.8 ml of 30% hydrogen peroxide and stirred at room temperature for 4.5 hours. 50 ml of water are added dropwise to the solution, the separated product is collected by suction and chromatographed on 30 g of silica gel. Elution with hexane/ether (3:2) yields 0.793 g (75%) of crystalline 17,17-ethylenedioxy-1α,2α-epoxy-androsta-4,6-dien-3-one. The analytical sample is prepared by recrystallisation from ether; melting point 181°-186° C.; [α]D25 =+167° (c=0.5 in dioxan); UV (ethanol): λmax 291 nm (ε=19270).
Reaction SMILES: [CH:1]([NH2:4])([CH3:3])[CH3:2].C(=O)=O.Cl.[N-:9]([C:12]#[N:13])[C:10]#[N:11].[Na+]>C(O)CCC.CC(C)=O>[C:10]([NH:9][C:12]([NH:4][CH:1]([CH3:3])[CH3:2])=[NH:13])#[N:11]
Reactant: N#C[N-]C#N
Reactant: CC(C)N
Agent: Cl
Agent: O=C=O
Agent: [Na+]
Solvent: CCCCO
Solvent: CC(C)=O
Product: CC(C)NC(=N)NC#N
Temperature: 25 °C
Yield: 97.2 %

Procedure:
All the above-named compounds except N-[1-(9,10 dihydro-9,10 dioxo)anthracenyl]-N'-(1-methylethyl)imido dicarbonimidic diamide hydrochloride are commercially available. N-[1-(9,10 dihydro-9,10 dioxo)anthracenyl]-N'-(1-methylethyl)imido dicarbonimidic diamide hydrochloride, however, is a novel compound and was synthesized as follows: A three liter round bottomed flask was charged with 18.2 g (3.09 mole) of isopropyl amine. After cooling the flask to -70° C. in a dry ice and acetone bath, 304.5 g of concentrated (37%) hydrochloric acid (3.09 mole) was added. The mixture was warmed to room temperature and water was removed with a rotary evaporator at aspirator pressure. To the dry residue was added 275.3 g (3.09 mole) of sodium dicyanamide and 760 ml of 1-butanol. The mixture was heated under reflux for three hours and then the butanol was removed with a rotary evaporator at aspirator pressure. To the residue in the flask was added 1800 ml of 1,4-dioxane. A slightly sticky precipitate was formed which was filtered and recrystallized from four liters of 1,4-dioxane to yield 379 g of N-cyano-N'-isopropylguanidine as a co-precipitate with some NaCl, 1,4-dioxane, and isopropylamine. Calc. for C5H10N4 (NaCl)0.1(C4H8O2)0.1(C3H9N)0.15 Calc: C 46.94; H 8.18; N 38.83; C12.37 Found: C 46.85; H 8.27; N 38.42; Cl 2.44
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([SH:8])[CH:5]=[CH:6][CH:7]=1.Br[CH2:10][CH2:11][OH:12]>>[Br:1][C:2]1[CH:3]=[C:4]([S:8][CH2:10][CH2:11][OH:12])[CH:5]=[CH:6][CH:7]=1
Reactant: Sc1cccc(Br)c1
Reactant: OCCBr
Product: OCCSc1cccc(Br)c1

Procedure:
Alkylation of 3-bromobenzenethiol with 2-bromoethanol according to the method used in Example 18, gave 2-(3-bromophenylthio)ethanol (125) as a yellow oil without purification. Yield (3.6 g, 97%): 1H NMR (400 MHz, CDCl3) δ 7.49 (t, J=2.0 Hz, 1H), 7.31 (ddd, J=0.8, 1.6, 8.0 Hz, 1H), 7.27 (ddd, J=0.8, 1.6, 8.0 Hz, 1H), 7.13 (t, J=7.6 Hz, 1H), 3.75 (t, J=6.4 Hz, 2H), 3.10 (t, J=6.4 Hz, 2H), 2.18 (brs, 1H).
Reaction SMILES: [N+:1]([C:4]1[CH:14]=[CH:13][C:7]2[NH:8][CH2:9][CH2:10][CH2:11][CH2:12][C:6]=2[CH:5]=1)([O-:3])=[O:2].[C:15](=O)([O-])[O-].[K+].[K+].IC.[H-].[Na+]>CN(C=O)C>[CH3:15][N:8]1[CH2:9][CH2:10][CH2:11][CH2:12][C:6]2[CH:5]=[C:4]([N+:1]([O-:3])=[O:2])[CH:14]=[CH:13][C:7]1=2
Reactant: O=[N+]([O-])c1ccc2c(c1)CCCCN2
Reactant: O=C([O-])[O-]
Agent: [H-]
Agent: [K+]
Agent: [Na+]
Solvent: CI
Solvent: CN(C)C=O
Product: CN1CCCCc2cc([N+](=O)[O-])ccc21
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 99.9 %

Procedure:
A solution of 7-Nitro-2,3,4,5-tetrahydro-1H-benzo[b]azepine (192 mg, 1.0 mmol) in DMF (10 mL) was treated with potassium carbonate (345 mg, 2.5 eq), and iodomethane (0.08 mL, 1.25 eq) and stirred at room temperature for 30 min. Sodium hydride was added (1.5 eq) and the mixture stirred for 30 min, quenched with water and extracted with ether. The organic layers washed with brine and dried (MgSO4), filtered and concentrated to give 1-Methyl-7-nitro-2,3,4,5-tetrahydro-1H-benzo[b]azepine (206 mg, 100%) as a yellow solid. MP: 52-54° C.; 1H-NMR (CDCl3) δ 7.97 (s, 1H), 7.89 (dd, J=2.6, 8.7 Hz, 1H), 6.61 (d, J=8.7 Hz, 1H), 4.42 (br s, 1H), 2.88-2.84 (m, 2H), 1.89-1.78 (m, 4H); LC/MS (ESI+): 207.04 (M+H).
Reaction SMILES: CCN(C1C=CC2C3(C4C(OC=2C=1)=CC(C)=C(NC1C=CC=CC=1)C=4)OC(=[O:20])C1C3=CC=CC=1)CC.P([O-])([O-])([O-])=O.[CH3:42][C@@H:43]([C@@H:50]1[C@@:54]2([CH3:69])[CH2:55][CH2:56][CH2:57]/[C:58](=[CH:59]\[CH:60]=[C:61]3\[CH2:62][C@@H:63]([OH:68])[CH2:64][CH2:65][C:66]\3=[CH2:67])/[C@@H:53]2[CH2:52][CH2:51]1)[CH2:44][CH2:45][CH2:46][CH:47]([CH3:49])[CH3:48].C(Cl)Cl>C(O)C>[CH3:42][C@@H:43]([C@@H:50]1[C@@:54]2([CH3:69])[CH2:55][CH2:56][CH2:57]/[C:58](=[CH:59]\[CH:60]=[C:61]3\[CH2:62][C@@H:63]([OH:68])[CH2:64][CH2:65][C:66]\3=[CH2:67])/[C@@H:53]2[CH2:52][CH2:51]1)[CH2:44][CH2:45][CH2:46][C:47]([OH:20])([CH3:48])[CH3:49]
Reactant: CCN(CC)c1ccc2c(c1)Oc1cc(C)c(Nc3ccccc3)cc1C21OC(=O)c2ccccc21
Reactant: C=C1CC[C@H](O)C/C1=C/C=C1\CCC[C@]2(C)[C@@H]([C@H](C)CCCC(C)C)CC[C@@H]12
Agent: O=P([O-])([O-])[O-]
Solvent: CCO
Solvent: ClCCl
Product: C=C1CC[C@H](O)C/C1=C/C=C1\CCC[C@]2(C)[C@@H]([C@H](C)CCCC(C)(C)O)CC[C@@H]12
Reaction time: 48 h

Procedure:
Nocardia autotrophica N-102 in the same BG medium (100 ml/500 ml-Erlenmeyer flask) as used in Example 1 was cultured at 28° C. under the aerobic conditions for 48 hours. To the culture solution were added 10 ml of a 5% PMCD (made by Mercian Co.) solution (0.01 M phosphate buffer, pH 7.0) and a solution of 2% vitamin D3 in 1 ml of ethanol (in the amount of 7 mol of PMCD relative to 1 mol of vitamin D3), and cultivation was continued for a further 96 hours. After completion of the cultivation, 200 ml of methylene chloride was added to the flask, and the mixture was extracted. The methylene chloride layer was concentrated to dryness under reduced pressure, and immediately after the residue was dissolved in 3 ml of 2-propanol:n-hexane (1:9) and allowed to stand at -20° C. for 2 hours. The resulting insolubles were removed by centrifugation. The supernatant was concentrated under reduced pressure and applied to HPLC on Zorbax SIL column (4.6 mm×25 cm) with n-hexane-2-propanol (86:14) as a mobile phase at a flow rate of 1.5 ml/min. The peak fraction at 3.8 minutes was collected, and concentrated to dryness at 40° C. or below under reduced pressure with a nitrogen gas replacement to give 25-hydroxyvitamin D3, which was strictly identical to the authentic sample of the commercially available 25-hydroxyvitamin D3 (made by Duphar Co., Holland) in terms of the retention time of HPLC, the UV absorption spectrum and mass spectrum cleavage pattern.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8]C)=[O:7])=[CH:4][N:3]=1.Cl[CH2:13][C:14](=O)[CH3:15]>C(O)C>[CH3:15][C:14]1[N:1]=[C:2]2[CH:11]=[CH:10][C:5]([C:6]([OH:8])=[O:7])=[CH:4][N:3]2[CH:13]=1
Reactant: COC(=O)c1ccc(N)nc1
Reactant: CC(=O)CCl
Solvent: CCO
Product: Cc1cn2cc(C(=O)O)ccc2n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 71.1 %

Procedure:
A mixture of methyl 6-aminonicotinate (510 mg), chloroacetone (620 mg) and ethanol (10 ml) was refluxed for 10 hours. After the solvent was removed, ethanol (5 ml) and water (5 ml) was added to the residue. To the solution containing methyl 2-methylimidazo[1,2-a]pyridine-6-carboxylate was added sodium hydroxide (536 mg) and the mixture was stirred for 1 hour at ambient temperature. Ethanol was evaporated and the resulting crystal was collected. A suspension of the obtained crystal in water (3 ml) was adjusted to pH 3.5 with hydrochloric acid, and the residual crystal was collected and dried to give 2-methylimidazo[1,2-a]pyridine-6-carboxylic acid (0.42 g).
Reaction SMILES: FC(F)(F)S(O[C:7]1[CH:8]=[CH:9][C:10]2[N:11]([N:13]=[CH:14][C:15]=2[C:16]2[CH:21]=[CH:20][N:19]=[C:18]([NH:22][CH:23]3[CH2:25][CH2:24]3)[N:17]=2)[N:12]=1)(=O)=O.[C:28]1([SH:34])[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1.CC([O-])(C)C.[Na+].O>CS(C)=O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH:23]1([NH:22][C:18]2[N:17]=[C:16]([C:15]3[CH:14]=[N:13][N:11]4[C:10]=3[CH:9]=[CH:8][C:7]([S:34][C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)=[N:12]4)[CH:21]=[CH:20][N:19]=2)[CH2:24][CH2:25]1
Reactant: O=S(=O)(Oc1ccc2c(-c3ccnc(NC4CC4)n3)cnn2n1)C(F)(F)F
Reactant: Sc1ccccc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: CC(C)(C)[O-]
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: c1ccc(Sc2ccc3c(-c4ccnc(NC5CC5)n4)cnn3n2)cc1
Temperature: 100 °C
Yield: 35.5 %

Procedure:
To a solution of 3-[2-(cyclopropylamino)-4-pyrimidinyl]pyrazolo[1,5-b]pyridazin-6-yl trifluoromethanesulfonate (250 mg, 0.625 mmol) in DMSO (8 mL) was added Pd(PPh3)4 (29 mg, 0.025 mmol), benzene thiol (0.064 mL, 0.625 mmol), and NaOtBu (120 mg, 1.31 mmol). The reaction mixture was heated at an oil bath temperature of 100° C. for about 2 hours. The mixture was cooled to RT and water (40 mL) was added. The aqueous layer was washed with EtOAc (3×60 mL). The combined organic layers were dried (MgSO4) and concentrated in vacuo and purified by silica-gel column chromatography (gradient 50-100% EtOAc in hexanes) to give the title compound as a yellow solid (80 mg, 36%). 1H-NMR (400 MHz, CDCl3) δ 8.90 (d, 1H, J=9.1 Hz), 8.34 (s, 1H), 8.29 (bs, 1H), 7.67 (m, 2H), 7.47 (m, 3H), 6.92 (d, 1H, J=5.3 Hz), 6.88 (d, 1H, J=9.4 Hz), 5.38 (s, 1H), 2.82 (m, 1H), 0.85 (m, 2H), 0.61 (m, 2H); MS (ESI) (M+H)+ 361.
Reaction SMILES: [C:1]([O:5][C@@H:6]([C:12]1[C:28]([CH3:29])=[CH:27][C:15]2[N:16]=[C:17]([C:19]3[CH:24]=[C:23](Cl)[N:22]=[C:21]([Cl:26])[CH:20]=3)[S:18][C:14]=2[C:13]=1[C:30]1[CH:35]=[CH:34][C:33]([Cl:36])=[CH:32][CH:31]=1)[C:7]([O:9][CH2:10][CH3:11])=[O:8])([CH3:4])([CH3:3])[CH3:2].[CH3:37][N:38]1[CH2:43][CH2:42][NH:41][CH2:40][CH2:39]1.CC(N(C)C)=O>C(O)C>[C:1]([O:5][C@@H:6]([C:12]1[C:28]([CH3:29])=[CH:27][C:15]2[N:16]=[C:17]([C:19]3[CH:24]=[C:23]([N:41]4[CH2:42][CH2:43][N:38]([CH3:37])[CH2:39][CH2:40]4)[N:22]=[C:21]([Cl:26])[CH:20]=3)[S:18][C:14]=2[C:13]=1[C:30]1[CH:35]=[CH:34][C:33]([Cl:36])=[CH:32][CH:31]=1)[C:7]([O:9][CH2:10][CH3:11])=[O:8])([CH3:3])([CH3:4])[CH3:2]
Reactant: CN1CCNCC1
Reactant: CCOC(=O)[C@@H](OC(C)(C)C)c1c(C)cc2nc(-c3cc(Cl)nc(Cl)c3)sc2c1-c1ccc(Cl)cc1
Solvent: CCO
Solvent: CC(=O)N(C)C
Product: CCOC(=O)[C@@H](OC(C)(C)C)c1c(C)cc2nc(-c3cc(Cl)nc(N4CCN(C)CC4)c3)sc2c1-c1ccc(Cl)cc1
Temperature: 100 °C

Procedure:
A solution of (S)-ethyl 2-tert-butoxy-2-(7-(4-chlorophenyl)-2-(2,6-dichloropyridin-4-yl)-5-methylbenzo[d]thiazol-6-yl)acetate (10 mg), N-methylpiperazine (10 mg), and DMA (250 μL) were combined in a microwave tube and heated to 100° C. for 30 min. Reaction was cooled to 23° C. and diluted with absolute ethanol and was purified by reverse phase HPLC, eluting by 5-100% acetonitrile in H2O with 0.1% TFA to give the title compound. LCMS-ESI+: calc'd for C32H36Cl2N4O3S: 627.2, 629.2 (M+H+); Found: 627.2, 629.2 (M+H+).