Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: N[CH2:2][C:3]1([OH:13])[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH2:6][CH2:5][CH2:4]1.N([O-])=O.[Na+]>C(O)(=O)C.O.C(OCC)(=O)C>[CH:8]1[C:7]2[CH2:6][CH2:5][CH2:4][C:3](=[O:13])[CH2:2][C:12]=2[CH:11]=[CH:10][CH:9]=1
Reactant: NCC1(O)CCCc2ccccc21
Agent: O=N[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Solvent: CCOC(C)=O
Product: O=C1CCCc2ccccc2C1
Reaction time: 2 h
Yield: 54.2 %

Procedure:
To a solution of 1-aminomethyl-1-hydroxy-1,2,3,4-tetrahydronaphthalene (19 g) in 10% acetic acid in water (380 ml) was dropwise added sodium nitrite (11 g) in water (56 ml) at 5° C., and the mixture was stirred at the same temperature for 2 hours. The resulting mixture was diluted with ethyl acetate and separated. The organic layer was successively washed with water, saturated aqueous sodium hydrogencarbonate and brine, dried over anhydrous magnesium sulfate and evaporated in vacuo. The residue was purified by column chromatography on silica gel (hexane-ethyl acetate) to give 5,7,8,9-tetrahydrobenzocyclohepten-6-one (9.3 g).
Reaction SMILES: C([O:3][C:4]([C:6]1[N:7]=[C:8](Br)[N:9]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[N:12]([CH3:19])[C:11](=[O:20])[C:10]=12)=[O:5])C.Cl.[OH-:23].[Na+]>>[OH:23][C:8]1[N:9]2[C:18]3[C:13]([N:12]([CH3:19])[C:11](=[O:20])[C:10]2=[C:6]([C:4]([OH:3])=[O:5])[N:7]=1)=[CH:14][CH:15]=[CH:16][CH:17]=3
Reactant: [OH-]
Reactant: CCOC(=O)c1nc(Br)n2c1c(=O)n(C)c1ccccc12
Agent: Cl
Agent: [Na+]
Product: Cn1c(=O)c2c(C(=O)O)nc(O)n2c2ccccc21
Yield: 81 %

Procedure:
A mixture of 1-bromo-5-methyl-4-oxo-4,5-dihydroimidazo[1,5-a]quinoxaline 3-carboxylic acid ethyl ester (1.5 g) and 0.5 N sodium hydroxide solution (40 ml) was heated on steam bath for 18 hours. After cooling and acidification by concentrated hydrochloric acid, the product precipitated out as a cream colored solid (0.9 g, 81% yield), m.p. >300° C.
Reaction SMILES: Br[CH2:2][C:3]1[C:8]([Cl:9])=[C:7]([Cl:10])[CH:6]=[CH:5][C:4]=1[Cl:11].[SH:12][C:13]1[N:18]=[C:17]([OH:19])[CH:16]=[CH:15][N:14]=1>>[Cl:9][C:8]1[C:7]([Cl:10])=[CH:6][CH:5]=[C:4]([Cl:11])[C:3]=1[CH2:2][S:12][C:13]1[N:18]=[C:17]([OH:19])[CH:16]=[CH:15][N:14]=1
Reactant: Oc1ccnc(S)n1
Reactant: Clc1ccc(Cl)c(CBr)c1Cl
Product: Oc1ccnc(SCc2c(Cl)ccc(Cl)c2Cl)n1
Yield: 89 %

Procedure:
As per procedure from Example 1, this compound was prepared from 2-(bromomethyl)-1,3,4-trichlorobenzene and 2-sulfanylpyrimidin-4-ol to provide the title compound as a white solid (1.04 g, 89% yield); 1H NMR (400 MHz, DMSO-d6): δ 4.72 (s, 2H), 6.21 (bs, 1H), 7.58 (d, J=8.8 Hz 1H), 7.68 (d, J=8.8 Hz 1H), 8.02 (bs, 1H); M+322.8.
Reaction SMILES: [OH:1][C:2]1[C:9]([C:10]([F:13])([F:12])[F:11])=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=[O:5].[Br:14]N1C(=O)CCC1=O>C(#N)C>[Br:14][C:7]1[CH:8]=[C:9]([C:10]([F:11])([F:12])[F:13])[C:2]([OH:1])=[C:3]([CH:6]=1)[CH:4]=[O:5]
Reactant: O=Cc1cccc(C(F)(F)F)c1O
Reactant: O=C1CCC(=O)N1Br
Solvent: CC#N
Product: O=Cc1cc(Br)cc(C(F)(F)F)c1O
Temperature: 0 °C
Reaction time: 1 h
Yield: 76.4 %

Procedure:
2-hydroxy-3-trifluoromethylbenzaldehyde (59.16 g) was dissolved in acetonitrile (500 mL), and N-bromosuccinimide (57.56 g) was added to the solution, and then the mixture was stirred at 0° C. for 1 hour. The solvent was distilled off under reduced pressure and water was added, and then the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, and then dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure and the obtained crystal was washed with n-hexane (50 mL) to obtain the title compound (63.98 g) as a pale yellow crystal.
Reaction SMILES: [CH3:1][C:2]1O[C:4](=[O:15])[C:5]2[C:11]([N+:12]([O-:14])=[O:13])=[CH:10][CH:9]=[CH:8][C:6]=2[N:7]=1.Cl.[NH2:17][CH:18]1[CH2:23][CH2:22][C:21](=[O:24])[NH:20][C:19]1=[O:25].CCCP1(OP(CCC)(=O)OP(CCC)(=O)O1)=O.O>C(#N)C.C(OCC)(=O)C>[CH3:1][C:2]1[N:17]([CH:18]2[CH2:23][CH2:22][C:21](=[O:24])[NH:20][C:19]2=[O:25])[C:4](=[O:15])[C:5]2[C:6](=[CH:8][CH:9]=[CH:10][C:11]=2[N+:12]([O-:14])=[O:13])[N:7]=1
Reactant: NC1CCC(=O)NC1=O
Reactant: Cc1nc2cccc([N+](=O)[O-])c2c(=O)o1
Agent: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: O
Solvent: CC#N
Product: Cc1nc2cccc([N+](=O)[O-])c2c(=O)n1C1CCC(=O)NC1=O
Temperature: 60 °C
Reaction time: 96 h
Yield: 89 %

Procedure:
A slurry of compound 2 was treated with 3-aminopiperidine-2,6-dione hydrochloride 3 (1.1 equiv.) in acetonitrile and a solution of 1-propanephosphonic acid cyclic anhydride (“T3P”) (2 equiv.) in ethyl acetate at 75-80° C. After 3 to 5 days, the total of compounds 1a and 2 was less than 1% area normalized (typically 0.05% area normalized). The reaction mixture was cooled to 55 to 65° C. Water was charged over 30 min, maintaining the temperature at 60° C. throughout the addition. During the first portion of water addition, an exotherm was observed. The mixture was further cooled to 20 to 30° C. over 1 hr. The resulting solid was filtered and washed with a mixture of acetonitrile and water (1:1). The solid was transferred back to the reactor and was agitated with a mixture of acetonitrile and water (1:1) between 20 to 30° C. for 1 hr. The mixture was filtered and the filter cake was washed with a mixture of acetonitrile and water (1:1). The filter cake was dried in a vacuum oven to afford compound 4 as a white solid: HPLC purity: 98.9 to 99.2%; yield: 89 to 93%; MS (m/e): 317 (M+1).
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[CH:11][C:7]([C:8](Cl)=[O:9])=[CH:6][CH:5]=1)([O-:3])=[O:2].[OH:13][CH:14]1[C:18]2[N:19]=[CH:20][N:21]=[C:22]([N:23]3[CH2:28][CH2:27][N:26]([C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[CH2:25][CH2:24]3)[C:17]=2[C@H:16]([CH3:36])[CH2:15]1.CCN(CC)CC.C([O-])(O)=O.[Na+]>C(Cl)Cl>[CH3:36][C@H:16]1[C:17]2[C:22]([N:23]3[CH2:28][CH2:27][N:26]([C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[CH2:25][CH2:24]3)=[N:21][CH:20]=[N:19][C:18]=2[C@H:14]([O:13][C:8](=[O:9])[C:7]2[CH:6]=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:12][CH:11]=2)[CH2:15]1.[CH3:36][C@H:16]1[C:17]2[C:22]([N:23]3[CH2:28][CH2:27][N:26]([C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[CH2:25][CH2:24]3)=[N:21][CH:20]=[N:19][C:18]=2[C@@H:14]([O:13][C:8](=[O:9])[C:7]2[CH:6]=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:12][CH:11]=2)[CH2:15]1
Reactant: C[C@@H]1CC(O)c2ncnc(N3CCN(C(=O)OC(C)(C)C)CC3)c21
Reactant: O=C(Cl)c1ccc([N+](=O)[O-])cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C[C@@H]1C[C@@H](OC(=O)c2ccc([N+](=O)[O-])cc2)c2ncnc(N3CCN(C(=O)OC(C)(C)C)CC3)c21
Product: C[C@@H]1C[C@H](OC(=O)c2ccc([N+](=O)[O-])cc2)c2ncnc(N3CCN(C(=O)OC(C)(C)C)CC3)c21
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
4-Nitrobenzoyl chloride (15.78 g, 85.03 mmol) was added to a 0° C. solution of (R)-tert-butyl 4-(7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazine-1-carboxylate (25.85 g, 77.30 mmol) and NEt3 (11.73 g, 16.16 mL, 115.9 mmol) in DCM (400 mL). The reaction mixture was stirred for 5 minutes. The mixture was then warmed to room temperature and stirred overnight (17 hours), after which saturated NaHCO3 was added. The reaction mixture was stirred for 10 minutes and transferred to a separatory funnel. The organic layers were collected, and the aqueous extracts were washed with DCM (2×). The combined organic extracts were dried (Na2SO4), filtered, and concentrated. The crude was flashed on silica loaded with 7:1 hexanes:ethyl acetate (gradient 5:1 hexanes:ethyl acetate to 2:1 hexanes:ethyl acetate to 1:1 hexanes:ethyl acetate). Some clean tert-butyl 4-((5R,7R)-5-methyl-7-(4-nitrobenzoyloxy)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazine-1-carboxylate, some clean tert-butyl 4-((5R,7S)-5-methyl-7-(4-nitrobenzoyloxy)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazine-1-carboxylate and some mixed fractions were isolated. The mixed fractions were recolumned and combined with the previously isolated material to give tert-butyl 4-((5R,7R)-5-methyl-7-(4-nitrobenzoyloxy)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazine-1-carboxylate (14.27 g, 38%) and tert-butyl 4-((5R,7S)-5-methyl-7-(4-nitrobenzoyloxy)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazine-1-carboxylate (12.58 g, 34%). The use of 4-bromobenzoyl chloride has been shown to offer slightly better separation of the isomers.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][C:5]2([CH2:12][CH2:11][NH:10][CH2:9][CH2:8]2)[CH2:4][CH2:3]1.Br[C:14]1[CH:19]=[CH:18][C:17]([Cl:20])=[C:16]([Cl:21])[CH:15]=1>>[Cl:21][C:16]1[CH:15]=[C:14]([N:10]2[CH2:9][CH2:8][C:5]3([CH2:4][CH2:3][N:2]([CH3:1])[CH2:7][CH2:6]3)[CH2:12][CH2:11]2)[CH:19]=[CH:18][C:17]=1[Cl:20]
Reactant: Clc1ccc(Br)cc1Cl
Reactant: CN1CCC2(CCNCC2)CC1
Product: CN1CCC2(CC1)CCN(c1ccc(Cl)c(Cl)c1)CC2

Procedure:
Was prepared according to method A from 3-methyl-3,9-diaza-spiro[5.5]undecane and 1-bromo-3,4-dichlorobenzene as a yellow oil. LC-ESI−HRMS of [M+H]+ shows 313.1238 Da. Calc. 313.123829 Da, dev. −0.1 ppm.
Reaction SMILES: [NH2:1][C:2]1[CH:13]=[CH:12][CH:11]=[CH:10][C:3]=1[C:4]([NH:6][CH2:7][CH2:8][CH3:9])=[O:5].[CH2:14]([NH2:17])[CH2:15]C.[C:18]12[C:24](=CC=CC=1)[NH:23]C(=O)OC2=O>>[NH:17]1[CH2:14][CH2:15][N:23]=[C:24]1[CH2:18][NH:1][C:2]1[CH:13]=[CH:12][CH:11]=[CH:10][C:3]=1[C:4]([NH:6][CH2:7][CH2:8][CH3:9])=[O:5]
Reactant: CCCNC(=O)c1ccccc1N
Reactant: O=c1[nH]c2ccccc2c(=O)o1
Reactant: CCCN
Product: CCCNC(=O)c1ccccc1NCC1=NCCN1

Procedure:
2-Amino-N-propylbenzamide (prepared from propylamine and isatoic anhydride, using, the methods described in Example 17) and CMI were reacted using conditions described in the general procedure for CMI coupling to give 2-[(4,5-dihydro-1H-imidazol-2-ylmethyl)amino]-N-propylbenzamide, isolated as the hydrochloride salt.
Reaction SMILES: N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O.[F:19][C:20]1[CH:21]=[C:22]2[C:26](=[CH:27][CH:28]=1)[NH:25][C:24]([C:29]([O:31][CH2:32][CH3:33])=[O:30])=[CH:23]2.[N:34]1[CH:39]=[CH:38][CH:37]=[C:36]([CH2:40][CH2:41]O)[CH:35]=1.C(P(CCCC)CCCC)CCC>O1CCCC1>[F:19][C:20]1[CH:21]=[C:22]2[C:26](=[CH:27][CH:28]=1)[N:25]([CH2:41][CH2:40][C:36]1[CH:35]=[N:34][CH:39]=[CH:38][CH:37]=1)[C:24]([C:29]([O:31][CH2:32][CH3:33])=[O:30])=[CH:23]2
Reactant: CCOC(=O)c1cc2cc(F)ccc2[nH]1
Reactant: OCCc1cccnc1
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: C1CCOC1
Product: CCOC(=O)c1cc2cc(F)ccc2n1CCc1cccnc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 41.3 %

Procedure:
A solution of 0.365 g (1.44 mmol) of 1,1′-(azodicarbonyl)dipiperidine in 10 ml of tetrahydrofuran is added dropwise to a solution of 0.2 g (0.97 mmol) of ethyl 5-fluoro-1H-indole-2-carboxylate, 0.178 g (1.45 mmol) of 2-(pyrid-3-yl)ethanol and 0.36 ml (1.44 mmol) of tributylphosphine in 30 ml of tetrahydrofuran. The reaction mixture is stirred overnight at room temperature and then concentrated under reduced pressure and taken up in 50 ml of cyclohexane. The suspension is then filtered and the filtrate is chromatographed on a column of silica (eluent: dichloromethane/methanol). 0.125 g of the expected product is obtained.
Reaction SMILES: [Br-].[CH:2]([C:4]1C=CC=CC=1[P+](C)(C1C=CC=CC=1)C1C=CC=CC=1)=[O:3].[C:24]([C:28]1[CH:35]=[CH:34][C:31]([CH:32]=O)=[CH:30][CH:29]=1)([O:26][CH3:27])=[O:25].C(OCC)(=O)C>C1(C)C=CC=CC=1>[C:24]([C:28]1[CH:35]=[CH:34][C:31]([CH:32]=[CH:4][CH:2]=[O:3])=[CH:30][CH:29]=1)([O:26][CH3:27])=[O:25]
Reactant: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1C=O
Reactant: COC(=O)c1ccc(C=O)cc1
Agent: [Br-]
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: COC(=O)c1ccc(C=CC=O)cc1

Procedure:
A solution of 27.3 g (0.09 mole) of formyl methyltriphenyl phosphonium bromide and 14.8 g (0.09 mole) of p-carbomethoxybenzaldehyde in 900 ml of dry toluene was refluxed under nitrogen for 24 hr. After evaporating toluene under reduced pressure, the residue was chromatographed over silica column with 5% ethyl acetate in petroleum ether as eluant. The second fraction obtained by using 10% ethyl acetate in petroleum ether gave 4-carbomethoxycinnamaldehyde. Recrystallization from benzene gave 12.5 g 4-carbomethoxycinnamaldehyde, yield 73% m.p. 99°-101° C. The infrared spectrum showed absorption at 1720 cm-1 ##STR8## 1680 cm-1 (CHO), and 1620 cm-1 (--CH=CH--). NMR (CDCl3) showed δ3.8 (s, --COOCH3, 3) 6.5-7.1 (m,=CH--CHO, l), 7.3-7.6 (m, aromatic, 4), 7.9-8.1 (d, --CH=, l), and 9.8 (d, --CHO, l). Analysis calculated for C11H10O3 : C, 69.42%, H, 5.2%. Found: C, 68.69%, H, 5.25%.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH2:9][CH2:10][CH2:11][OH:12])[CH:6]=[CH:7][CH:8]=1)#[CH:2].Br[C:14]1[CH:15]=[C:16]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH:17]=[CH:18][CH:19]=1>>[C:16]1([C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH:17]=[CH:18][CH:19]=[C:14]([C:2]#[C:1][C:3]2[CH:4]=[C:5]([CH2:9][CH2:10][CH2:11][OH:12])[CH:6]=[CH:7][CH:8]=2)[CH:15]=1
Reactant: Brc1cccc(-c2ccccc2)c1
Reactant: C#Cc1cccc(CCCO)c1
Product: OCCCc1cccc(C#Cc2cccc(-c3ccccc3)c2)c1

Procedure:
Coupling of alcohol 50 with 3-bromobiphenyl was conducted following the method described in Example 21 to give 3-(3-(biphenyl-3-ylethynyl)phenyl)propan-1-ol. Purification by flash chromatography (5% EtOAc-hexanes) gave a brown oil. Yield (0.560 g, 67%): 1H NMR (400 MHz, CDCl3) δ 7.78 (br s, 1H), 7.61 (d, J=7.2 Hz, 2H), 7.56 (d, J=7.6 Hz, 1H), 7.51 (d, J=8.0 Hz, 1H), 7.37-7.48 (m, 6H), 7.29 (d, J=7.6 Hz, 1H), 7.19 (d, J=7.6 Hz, 1H), 3.70 (dt, J=6.2, 5.2 Hz, 2H), 2.73 (t, J=7.6 Hz, 2H), 1.92 (quint, J=6.8 Hz, 2H), 1.27 (t, J=5.2 Hz, 1H).
Reaction SMILES: [CH2:1]([N:4]1[C:13](=[O:14])[C:12]([OH:15])=[C:11]2[C:6]([CH2:7][CH2:8][N:9]([CH2:17][C:18]3[CH:23]=[CH:22][C:21]([F:24])=[C:20]([Cl:25])[CH:19]=3)[C:10]2=[O:16])=[C:5]1[C:26]([O:28][CH3:29])=[O:27])[CH:2]=[CH2:3].[C:30](=O)([O-])[O-].[Cs+].[Cs+].IC>CN(C=O)C>[CH2:1]([N:4]1[C:13](=[O:14])[C:12]([O:15][CH3:30])=[C:11]2[C:6]([CH2:7][CH2:8][N:9]([CH2:17][C:18]3[CH:23]=[CH:22][C:21]([F:24])=[C:20]([Cl:25])[CH:19]=3)[C:10]2=[O:16])=[C:5]1[C:26]([O:28][CH3:29])=[O:27])[CH:2]=[CH2:3]
Reactant: O=C([O-])[O-]
Reactant: C=CCn1c(C(=O)OC)c2c(c(O)c1=O)C(=O)N(Cc1ccc(F)c(Cl)c1)CC2
Agent: [Cs+]
Solvent: CI
Solvent: CN(C)C=O
Product: C=CCn1c(C(=O)OC)c2c(c(OC)c1=O)C(=O)N(Cc1ccc(F)c(Cl)c1)CC2
Temperature: 40 °C

Procedure:
A mixture of methyl 2-(allyl)-6-(3-chloro-4-fluorobenzyl)-4-hydroxy-3,5-dioxo-2,3,5,6,7,8-hexahydro-2,6-naphthyridine-1-carboxylate (6.08 g, 14.92 mmol), cesium carbonate (6.08 g, 18.65 mmol), and iodomethane (2.79 mL, 44.77 mmol) in DMF (20 mL) was heated at 40° C. overnight. The reaction mixture was filtered and concentrated under vacuum. The residue was subjected to column chromatography on silica gel. Collection and concentration of appropriate fractions provided the title compound. (ES MS M+1=435.2)
Reaction SMILES: [Br:1][C:2]1[S:6][C:5]([C:7]([OH:9])=O)=[CH:4][CH:3]=1.[NH2:10][C:11]1[CH:12]=[C:13]([CH:18]=[CH:19][C:20]=1[CH3:21])[C:14]([O:16][CH3:17])=[O:15]>>[Br:1][C:2]1[S:6][C:5]([C:7]([NH:10][C:11]2[CH:12]=[C:13]([CH:18]=[CH:19][C:20]=2[CH3:21])[C:14]([O:16][CH3:17])=[O:15])=[O:9])=[CH:4][CH:3]=1
Reactant: O=C(O)c1ccc(Br)s1
Reactant: COC(=O)c1ccc(C)c(N)c1
Product: COC(=O)c1ccc(C)c(NC(=O)c2ccc(Br)s2)c1
Yield: 88 %

Procedure:
Compound a was prepared by coupling 5-bromothiophene-2-carboxylic acid with commercially available methyl 3-amino-4-methylbenzoate using the method described in Example 128 to afford a white solid in 88% yield. HPLC Ret time=3.25 min. LCMS [M+H]+ 355.2.
Reaction SMILES: [Br:1][CH2:2][C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[O:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=O.[NH2:19][C:20]([NH2:22])=[S:21]>CO>[BrH:1].[CH2:12]([O:11][C:6]1[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=1[C:3]1[N:19]=[C:20]([NH2:22])[S:21][CH:2]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: O=C(CBr)c1ccccc1OCc1ccccc1
Reactant: NC(N)=S
Solvent: CO
Product: Br
Product: Nc1nc(-c2ccccc2OCc2ccccc2)cs1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
A solution of 21.7 g of 2-bromo-1-(2-benzyloxy-phenyl)-ethanone in 150 ml of methanol was treated at room temperature with 7.6 g of thiourea and boiled for 1 hour. The reaction mixture was concentrated to a volume of 60 ml. 20.7 g of 4-(2-benzyloxy-phenyl)-thiazol-2-ylamine hydrobromide separated as colorless crystals upon cooling to 0° C. and after the addition of 250 ml of diethyl ether.
Reaction SMILES: O[CH2:2][CH:3]([CH2:5]O)O.[CH2:7]([O:9][C:10]([C:12]1[CH:18]=[CH:17][C:15](O)=[CH:14][CH:13]=1)=[O:11])[CH3:8]>O>[CH2:8]([CH:7]1[C:18]2[C:12](=[CH:13][CH:14]=[CH:15][CH:17]=2)[C:10](=[O:11])[O:9]1)[CH2:2][CH2:3][CH3:5]
Reactant: CCOC(=O)c1ccc(O)cc1
Reactant: OCC(O)CO
Solvent: O
Product: CCCCC1OC(=O)c2ccccc21
Temperature: 75 °C
Reaction time: 1.5 h

Procedure:
1000 g of gelatin, 300 g of glycerin, 1300 g of water and 2000 mg of ethylparaben are used. An appropriate amount of water is added into the gelatin, allowing it to absorb water and swell. Glycerin, ethylparaben and residual water are placed into a tank and heated to a temperature of 70 to 80° C., and homogeneously mixed. The swollen gelatin is added with agitation, melted, incubated for 1 to 2 hrs, and kept rest for foams to float up. The floating foams are then scraped, the remainder is filtered through a clean white cloth and kept warm for further use. The viscosity of the resulting gum liquid is generally 2.8 to 3.2 degree.
Reaction SMILES: [S-:1][C:2]#[N:3].[K+].[CH3:5][O:6][C:7]1[N:12]=[CH:11][C:10]([NH2:13])=[CH:9][CH:8]=1.BrBr.O>C(O)(=O)C>[CH3:5][O:6][C:7]1[N:12]=[C:11]2[S:1][C:2]([NH2:3])=[N:13][C:10]2=[CH:9][CH:8]=1
Reactant: COc1ccc(N)cn1
Reactant: N#C[S-]
Agent: BrBr
Agent: [K+]
Solvent: O
Solvent: CC(=O)O
Product: COc1ccc2nc(N)sc2n1
Temperature: 25 °C
Yield: 33.2 %

Procedure:
In a 500 ml, 3-neck flask equipped with a mechanical stirrer, dropping funnel and thermometer, acetic acid (100 mL) was added and cooled in an ice bath. Potassium thiocyanate (40 g, 412 mmol) and 6-methoxypyridin-3-amine (6.2 g, 49.9 mmol) were added to the reaction mixture. The reaction was cooled in an ice-salt bath until the reaction temperature reached <0° C. A solution of bromine (8 mL, 156 mmol) in acetic acid (30.0 mL) was added dropwise over 2 hours at a rate that maintained the reaction temperature <0° C. Mechanical stirring was required. After the addition was complete, the mixture was left to stir and allowed to slowly warm to room temperature overnight. Water (30 mL) was then added and the mixture was heated to 85° C. in an oil bath. This mixture was then filtered while still hot. The orange filter cake was returned to the reaction flask, and an additional 50 ml acetic acid was added. The mixture was heated again to 85° C., and then filtered while still hot once more. The combined filtrates were cooled in an ice bath and neutralized to pH 8 with conc. ammonium hydroxide. A purple precipitate formed which was then collected by filtration to afford 5 g of crude material. This crude material was recrystallized from methanol (40 mL) to yield 5-methoxythiazolo[5,4-b]pyridin-2-amine (3 g, 16.55 mmol, 33.1% yield) as purple crystals. 1H NMR (300 MHz, DMSO-d6) δ ppm 7.60 (1H, d, J=8.42 Hz), 7.41 (2H, s), 6.67 (1H, d, J=8.78 Hz), 3.81 (3H, s).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](Cl)=[C:8]([C:11]([NH2:13])=[O:12])[CH:7]=[N:6][N:5]2[CH:14]=1.[CH2:15]([NH2:18])[CH2:16][CH3:17].C(N(C(C)C)CC)(C)C.O>CN1CCCC1=O>[Br:1][C:2]1[CH:3]=[C:4]2[C:9]([NH:18][CH2:15][CH2:16][CH3:17])=[C:8]([C:11]([NH2:13])=[O:12])[CH:7]=[N:6][N:5]2[CH:14]=1
Reactant: NC(=O)c1cnn2cc(Br)cc2c1Cl
Reactant: CCCN
Solvent: CN1CCCC1=O
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: CCCNc1c(C(N)=O)cnn2cc(Br)cc12
Temperature: 105 °C
Reaction time: 1 h
Yield: 76.4 %

Procedure:
A mixture of 6-bromo-4-chloropyrrolo[1,2-b]pyridazine-3-carboxamide (Preparation 5, 137 mg, 0.5 mmol), n-propylamine (123 mL, 1.500 mmol) and diisopropylethylamine (0.349 mL, 2.000 mmol) in N-methylpyrrolidinone (1.5 mL) was heated to 105° C. for 0.75 hr. After cooling to rt, water (15 ml) was added and the resulting suspension was stirred at rt for 1 hr. The suspension was filtered and the filter cake was dried. The filter cake was rinsed with hexane and dried to afford the title compound (120 mg, 0.382 mmol, 76% yield) as a tan solid. HPLC (condition M): retention time=2.56 min.; LCMS (ES+) m/z: 297.00/299.00; 1H NMR (400 MHz, MeOD) δ ppm 1.09 (t, J=7.4 Hz, 3 H), 1.72-1.83 (m, 2 H), 3.70 (t, J=6.9 Hz, 2 H), 7.01 (d, J=1.8 Hz, 1 H), 7.60 (d, J=1.8 Hz, 1 H), 8.09 (s, 1 H).
Reaction SMILES: [BH4-].[Na+].[CH3:3][C@H:4]1[CH2:13][C:12](=[O:14])[CH2:11][C:6]2([CH2:10][CH2:9][CH2:8][CH2:7]2)[C@H:5]1[C:15]([O:17][CH2:18][CH3:19])=[O:16].Cl>CO>[OH:14][C@@H:12]1[CH2:11][C:6]2([CH2:7][CH2:8][CH2:9][CH2:10]2)[C@@H:5]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[C@@H:4]([CH3:3])[CH2:13]1.[OH:14][C@H:12]1[CH2:11][C:6]2([CH2:7][CH2:8][CH2:9][CH2:10]2)[C@@H:5]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[C@@H:4]([CH3:3])[CH2:13]1
Reactant: CCOC(=O)[C@H]1[C@@H](C)CC(=O)CC12CCCC2
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CCOC(=O)[C@H]1[C@@H](C)C[C@@H](O)CC12CCCC2
Product: CCOC(=O)[C@H]1[C@@H](C)C[C@H](O)CC12CCCC2
Temperature: 20 °C
Reaction time: 4 h
Yield: 22 %
Yield: 37 %

Procedure:
At 5° C., NaBH4 (0.26 g, 6.5 mmol) in methanol (25 ml) was treated with a solution of crude cis-ethyl 7-methyl-9-oxospiro[4.5]decane-6-carboxylate (2.2 g, 9.2 mmol) in methanol (10 ml). The resulting mixture was stirred at 20° C. for 4 h, poured into 2N aqueous HCl (30 ml) and ice/water (50 ml), and extracted twice with MTBE (50 ml). The combined organic phases were washed with water (50 ml), with a saturated aqueous solution of NaCl (50 ml), dried (MgSO4) and concentrated. FC (180 g SiO2, hexane/MTBE 2:1) of the crude product (2.07 g, cis,cis/cis,trans 39:61) gave rel-(6S,7S,9S)-ethyl 9-hydroxy-7-methylspiro[4.5]decane-6-carboxylate (cis,trans; 0.82 g, 37%) and rel-(6S,7S,9R)-ethyl 9-hydroxy-7-methylspiro[4.5]decane-6-carboxylate (cis,cis; 0.49 g, 22%).
Reaction SMILES: [Cl:1][C:2]1[CH:13]=[C:12]([F:14])[C:11]([N:15]2[C:20](=[O:21])[C:19]3[CH2:22][CH2:23][CH2:24][C:18]=3[NH:17][C:16]2=[O:25])=[CH:10][C:3]=1[C:4]([O:6][CH:7]([CH3:9])[CH3:8])=[O:5].[H-].[Na+].[C:28](Cl)(=[O:30])[CH3:29]>CN(C)C=O.C(OCC)(=O)C>[Cl:1][C:2]1[CH:13]=[C:12]([F:14])[C:11]([N:15]2[C:20](=[O:21])[C:19]3[CH2:22][CH2:23][CH2:24][C:18]=3[N:17]([C:28](=[O:30])[CH3:29])[C:16]2=[O:25])=[CH:10][C:3]=1[C:4]([O:6][CH:7]([CH3:9])[CH3:8])=[O:5]
Reactant: CC(C)OC(=O)c1cc(-n2c(=O)[nH]c3c(c2=O)CCC3)c(F)cc1Cl
Reactant: CC(=O)Cl
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(=O)n1c2c(c(=O)n(-c3cc(C(=O)OC(C)C)c(Cl)cc3F)c1=O)CCC2
Reaction time: 2 h

Procedure:
A solution of 3.6 g of isopropyl 2-chloro-4-fluoro-5-(1,2,4,5,6,7-hexahydro-2,4-dioxo-3H-cyclopenta[d]pyrimidin-3-yl)-benzoate in 50 ml of absolute dimethylformamide is stirred at room temperature for 2 hours with 0.43 g of a 55% sodium hydride dispersion. A solution of 0.93 g of acetyl chloride in 10 ml of absolute dimethylformamide is subsequently added dropwise during 10 minutes and the mixture is stirred for 2 hours. The reaction mixture is dissolved in 100 ml of ethyl acetate and the solution is washed thoroughly with water. The organic phase is dried over anhdrous sodium sulphate and evaporated to dryness. The residue is purified by chromatography on a silica gel column using methylene chloride/ethyl acetate (3:1) as the eluent. There is obtained isopropyl 2-chloro-4-fluoro-5-(1,2,4,5,6,7-hexahydro-1-acetyl-2,4-dioxo-3H-cyclopenta[d]pyrimidin-3-yl)-benzoate, 1H--NMR (CDCl3, 400 MHz) 7.86 ppm (d, 1H), 7.37 ppm (d, 1H), 5.24 ppm (m, 1H), 3.13 ppm (m, 2H), 2.75 ppm (m, 2H), 2.68 ppm (s, 3H), 2.12 ppm (m, 2H), 1.36 ppm (d, 6H).