Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]([CH3:12])[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([CH3:13])[CH:8]=2)[N:3]=1.[Br:14]N1C(=O)CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(Cl)(Cl)Cl.C(OCC)(=O)C>[Br:14][CH2:13][C:7]1[CH:8]=[C:9]2[C:4](=[CH:5][CH:6]=1)[N:3]=[C:2]([Cl:1])[CH:11]=[C:10]2[CH3:12]
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1ccc2nc(Cl)cc(C)c2c1
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)Cl
Solvent: CCOC(C)=O
Product: Cc1cc(Cl)nc2ccc(CBr)cc12
Temperature: 70 °C
Reaction time: 1 h
Yield: 42.7 %

Procedure:
To a solution of 2-chloro-4,6-dimethylquinoline (1.31 g) in chloroform (20 mL) was added N-bromosuccinimide (1.24 g) at room temperature. The reaction solution was heated at 70° C., and benzoyl peroxide (0.25 g) was divided into 5 portions and added at intervals of a few tens of min. The mixture was stirred at the same temperature for 1 h. The reaction solution was cooled to room temperature and diluted with ethyl acetate, then the organic layer was washed with a mixed solution of saturated aqueous sodium thiosulfate and saturated brine and saturated brine. The organic layer was dried with anhydrous magnesium sulfate, then the desiccant was removed by filtration, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (ethyl acetate/hexane=10:1) to obtain 6-bromomethyl-2-chloro-4-methylquinoline (0.79 g).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[S:10][C:11]([C:15]([OH:17])=O)=[C:12]([CH3:14])[N:13]=2)=[CH:5][CH:4]=1.[NH2:18][C:19]1[NH:23][N:22]=[N:21][N:20]=1>CN(C)C=O>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[S:10][C:11]([C:15]([NH:18][C:19]3[NH:23][N:22]=[N:21][N:20]=3)=[O:17])=[C:12]([CH3:14])[N:13]=2)=[CH:5][CH:4]=1
Reactant: COc1ccc(-c2nc(C)c(C(=O)O)s2)cc1
Reactant: Nc1nnn[nH]1
Solvent: CN(C)C=O
Product: COc1ccc(-c2nc(C)c(C(=O)Nc3nnn[nH]3)s2)cc1
Yield: 64.4 %

Procedure:
A solution of 300 mg (1.20 mmol) of 2-(4-methoxyphenyl)-4-methyl-5-thiazolecarboxylic acid and 292.7 mg (1.81 mmol) of N,N'-carbonyldiimidazole (CDI) in dry dimethylformamide (8 ml) was stirred at room temperature for 1 hour. Under the same conditions, a solution of 5-aminotetrazole (122.8 mg, 1.44 mmol) in dry dimethylformamide (1 ml) was added thereto and allowed to react at 70° C. for 3 hours. After the solvent was distilled off from the reaction mixture, the residue was treated with water under ice-cooling and acidified with 2N-HCl to pH 2. The produced solids were filtered with suction, suspended in 100 ml of water and made alkaline with 1N potassium hydroxide (pH=11). After the impurities were removed from the alkaline solution by extracting with ethyl acetate, the aqueous phase was acidified with 2N-HCl to pH 2 and the deposited solids were filtered with suction, washed with water and recrystallized from methanol-THF-water to give 244.4 mg (yield 64 %) of 2-(4-methoxyphenyl)-4-methyl-N-(1H-tetrazole-5-yl)-5-thiazolecarboxamide as white crystals, m.p. 275°-278° C.
Reaction SMILES: [O:1]=[CH:2][C@@H:3]([C@H:5]([C@H:7]([CH2:9][OH:10])[OH:8])[OH:6])[OH:4]>C(O)C>[O:1]=[CH:2][C@H:3]([C@@H:5]([C@@H:7]([CH2:9][OH:10])[OH:8])[OH:6])[OH:4]
Reactant: O=C[C@H](O)[C@@H](O)[C@@H](O)CO
Solvent: CCO
Product: O=C[C@@H](O)[C@H](O)[C@H](O)CO

Procedure:
FIG. 5A shows that strain IMS0002 is capable of fermenting 20 gl−1 L-arabinose to ethanol during an anaerobic batch fermentation of approximately 70 hours. The specific growth rate under anaerobic conditions with L-arabinose as sole carbon source was 0.05±0.001 h−1. Taking into account the ethanol evaporation during the batch fermentation, the ethanol yield from 20 gl−1 arabinose was 0.43±0.003 g g−1. Without evaporation correction the ethanol yield was 0.35±0.01 g g−1 of arabinose. No formation of arabinitol was observed during anaerobic growth on arabinose. In FIG. 5B, the ethanolic fermentation of a mixture of 20 gl−1 glucose and 20 g l−1 L-arabinose by strain IMS0002 is shown. L-arabinose consumption started after glucose depletion. Within 70 hours, both the glucose and L-arabinose were completely consumed. The ethanol yield from the total of sugars was 0.42±0.003 g g−1.
Reaction SMILES: [N+:1]([C:4]1[CH:26]=[CH:25][C:7]([C:8]([N:10]2[CH2:16][C:15]3[CH:17]=[CH:18][CH:19]=[CH:20][C:14]=3[CH2:13][C:12]3[CH:21]=[CH:22][CH:23]=[CH:24][C:11]2=3)=[O:9])=[CH:6][C:5]=1[CH3:27])([O-])=O.NN>[Pd].C(O)C>[NH2:1][C:4]1[CH:26]=[CH:25][C:7]([C:8]([N:10]2[CH2:16][C:15]3[CH:17]=[CH:18][CH:19]=[CH:20][C:14]=3[CH2:13][C:12]3[CH:21]=[CH:22][CH:23]=[CH:24][C:11]2=3)=[O:9])=[CH:6][C:5]=1[CH3:27]
Reactant: Cc1cc(C(=O)N2Cc3ccccc3Cc3ccccc32)ccc1[N+](=O)[O-]
Agent: [Pd]
Agent: NN
Solvent: CCO
Product: Cc1cc(C(=O)N2Cc3ccccc3Cc3ccccc32)ccc1N
Yield: 78.7 %

Procedure:
A mixture of 1.11 g of 5-(4-nitro-3-methylbenzoyl)-6,11-dihydro-5H-dibenz[b,e]azepine, 50 ml of ethanol, 0.30 g of anhydrous hydrazine and 0.27 g palladium-on-carbon is refluxed 1 hour, and then filtered through diatomaceous earth. The filtrate is evaporated and the residue recrystallized from dichloromethane-hexane to give 0.80 g of crystals, m.p. 203°-204° C.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7]([CH3:23])=[N:8][C:9]2[C:10](=[CH:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH2:11][CH2:12][CH2:13][C:14]=2[CH:15]=1)=[O:5])[CH3:2].[H][H]>C(OCC)(=O)C.[Pd]>[CH2:1]([O:3][C:4]([C:6]1[C:7]([CH3:23])=[N:8][C:9]2[CH:10]([CH2:16][C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=3)[CH2:11][CH2:12][CH2:13][C:14]=2[CH:15]=1)=[O:5])[CH3:2]
Reactant: [H][H]
Reactant: CCOC(=O)c1cc2c(nc1C)C(=Cc1ccccc1)CCC2
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CCOC(=O)c1cc2c(nc1C)C(Cc1ccccc1)CCC2
Yield: 95.8 %

Procedure:
A solution of 5,6,7,8-tetrahydro-2-methyl-8-(phenylmethylene)-3-quinolinecarboxylic acid ethyl ester (3.4 g) in ethyl acetate (150 ml) is treated with 10 percent palladium on carbon (0.70 g) and reduced at 40 p.s.i. hydrogen pressure for 3 hours. Catalyst is filtered and the filtrate is evaporated to yield 5,6,7,8-tetrahydro-2-methyl-8-(phenylmethyl)-3-quinolinecarboxylic acid ethyl ester (3.28 g) as an oil.
Reaction SMILES: [C:1]1([C:7]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[C:8]2[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][C:20]#[N:21])[CH2:10][CH2:9]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-]>>[NH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][N:11]1[CH2:10][CH2:9][C:8](=[C:7]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[CH2:13][CH2:12]1
Reactant: N#CCCCCCCN1CCC(=C(c2ccccc2)c2ccccc2)CC1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Product: NCCCCCCCN1CCC(=C(c2ccccc2)c2ccccc2)CC1
Yield: 91 %

Procedure:
The title compound was prepared in a yield of 91% in a similar manner to that described in Preparation 41' by reacting 4-(diphenylmethylene)-1-(6-cyanohexyl)-piperidine (prepared as described in Preparation 40') and lithium aluminum hydride.
Reaction SMILES: [OH:1][C:2]([C:5]1([NH:9][C:10]([C:12]2[C:20]3[C:15](=[N:16][CH:17]=[C:18]([C:21]4[C:29]5[C:24](=[CH:25][C:26]([F:30])=[CH:27][CH:28]=5)[N:23]([CH3:31])[N:22]=4)[N:19]=3)[N:14](COCC[Si](C)(C)C)[CH:13]=2)=[O:11])[CH2:8][CH2:7][CH2:6]1)([CH3:4])[CH3:3].FC(F)(F)C(O)=O.C(N)CN>ClCCl>[OH:1][C:2]([C:5]1([NH:9][C:10]([C:12]2[C:20]3[C:15](=[N:16][CH:17]=[C:18]([C:21]4[C:29]5[C:24](=[CH:25][C:26]([F:30])=[CH:27][CH:28]=5)[N:23]([CH3:31])[N:22]=4)[N:19]=3)[NH:14][CH:13]=2)=[O:11])[CH2:6][CH2:7][CH2:8]1)([CH3:4])[CH3:3]
Reactant: Cn1nc(-c2cnc3c(n2)c(C(=O)NC2(C(C)(C)O)CCC2)cn3COCC[Si](C)(C)C)c2ccc(F)cc21
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Solvent: NCCN
Product: Cn1nc(-c2cnc3[nH]cc(C(=O)NC4(C(C)(C)O)CCC4)c3n2)c2ccc(F)cc21
Temperature: 25 °C
Reaction time: 3 h
Yield: 66.1 %

Procedure:
In a 10 ml round-bottomed flask, 2-(6-fluoro-1-methyl-1H-indazol-3-yl)-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid [1-(1-hydroxy-1-methyl-ethyl)-cyclobutyl]-amide (140 mg, 0.24 mmol) was dissolved in dichloromethane (1.2 ml) and trifluoroacetic acid (0.75 ml, 9.7 mmol) was added. The orange reaction mixture was stirred at room temperature for 3 h then concentrated. The residue was dissolved in dichloromethane (1.2 ml) and ethylenediamine (1.0 ml, 14.8 mmol) was added. The reaction was stirred at room temperature for 1 h then quenched with water and diluted with ethyl acetate. The resulting suspension was filtered and washed with hot water and ethyl acetate then dried under high vacuum to provide 67 mg (63%) of 2-(6-fluoro-1-methyl-1H-indazol-3-yl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid [1-(1-hydroxy-1-methyl-ethyl)-cyclobutyl]-amide as a light yellow powder. MS: (M+Na)+=445; 1H NMR (DMSO-d6, 300 MHz): δ (ppm) 9.11 (s, 1H), 8.53 (dd, J=8.9, 5.5 Hz, 1H), 8.41 (s, 1H), 8.31 (s, 1H), 7.68 (dd, J=9.8, 2.3 Hz, 1H), 7.08-7.23 (m, 1H), 4.99 (br. s., 1H), 4.15 (s, 3H), 2.38-2.62 (m, 4H), 1.84-2.02 (m, 1H), 1.66-1.83 (m, 1H), 1.23 (s, 6H).
Reaction SMILES: [O:1]=[C:2]1[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:4][CH2:3]1.[CH:15]1([CH2:20][C:21](Cl)=[O:22])[CH2:19][CH2:18][CH2:17][CH2:16]1>>[CH:15]1([CH2:20][C:21]([CH:7]2[C:2](=[O:1])[CH2:3][CH2:4][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:6]2)=[O:22])[CH2:19][CH2:18][CH2:17][CH2:16]1
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Reactant: O=C(Cl)CC1CCCC1
Product: CC(C)(C)OC(=O)N1CCC(=O)C(C(=O)CC2CCCC2)C1
Yield: 59 %

Procedure:
tert-Butyl 3-(2-cyclopentylacetyl)-4-oxopiperidine-1-carboxylate (311 mg, 59%) was synthesised from tert-butyl 4-oxopiperidine-1-carboxylate and 2-cyclopentylacetyl chloride according to the general procedure for the preparation of diketones. MS (ES−) m/z 308.1 (M−H)−
Reaction SMILES: C(OC1C=C(OC2CC3C(C(=O)N(C)CCCCC=CC4C(C(O)=O)(NC3=O)C4)C2)C2C(=C(C)C=CC=2)N=1)C.[CH2:40]([O:42][C:43]1[CH:52]=[C:51]([O:53][CH:54]2[CH2:71][CH:70]3[CH:56]([C:57](=[O:83])[N:58]([CH3:82])[CH2:59][CH2:60][CH2:61][CH2:62][CH:63]=[CH:64][CH:65]4[C:67]([C:73]([NH:75][S:76]([CH:79]5[CH2:81][CH2:80]5)(=[O:78])=[O:77])=[O:74])([NH:68][C:69]3=[O:72])[CH2:66]4)[CH2:55]2)[C:50]2[C:45](=[C:46]([CH3:86])[C:47](OC)=[CH:48][CH:49]=2)[N:44]=1)[CH3:41]>>[CH2:40]([O:42][C:43]1[CH:52]=[C:51]([O:53][CH:54]2[CH2:71][CH:70]3[CH:56]([C:57](=[O:83])[N:58]([CH3:82])[CH2:59][CH2:60][CH2:61][CH2:62][CH:63]=[CH:64][CH:65]4[C:67]([C:73]([NH:75][S:76]([CH:79]5[CH2:81][CH2:80]5)(=[O:77])=[O:78])=[O:74])([NH:68][C:69]3=[O:72])[CH2:66]4)[CH2:55]2)[C:50]2[C:45](=[C:46]([CH3:86])[CH:47]=[CH:48][CH:49]=2)[N:44]=1)[CH3:41]
Reactant: CCOc1cc(OC2CC3C(=O)NC4(C(=O)NS(=O)(=O)C5CC5)CC4C=CCCCCN(C)C(=O)C3C2)c2ccc(OC)c(C)c2n1
Agent: CCOc1cc(OC2CC3C(=O)NC4(C(=O)O)CC4C=CCCCCN(C)C(=O)C3C2)c2cccc(C)c2n1
Product: CCOc1cc(OC2CC3C(=O)NC4(C(=O)NS(=O)(=O)C5CC5)CC4C=CCCCCN(C)C(=O)C3C2)c2cccc(C)c2n1

Procedure:
The title compound (13) was prepared from 17-[2-ethoxy-8-methylquinolin-4-yloxy]-13-methyl-2,14-dioxo-3,13-diazatricyclo[13.3.0.04,6]octadec-7-ene-4-carboxylic acid (12) following the procedure reported for synthesis of N-[17-[2-ethoxy-7-methoxy-8-methylquinolin-4-yloxy]-13-methyl-2,14-dioxo-3,13-diazatricyclo-[13.3.0.04,6]octadec-7-ene-4-carbonyl](cyclopropyl)sulfonamide (3): m/z=639 (M+H)+.
Reaction SMILES: [C:1]([CH2:4][C:5]1[CH:13]=[CH:12][CH:11]=[CH:10][C:6]=1[C:7](O)=[O:8])(O)=[O:2].[NH4+:14].[OH-]>>[C:7]1(=[O:8])[C:6]2[C:5](=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH2:4][C:1](=[O:2])[NH:14]1
Reactant: O=C(O)Cc1ccccc1C(=O)O
Reactant: [NH4+]
Agent: [OH-]
Product: O=C1Cc2ccccc2C(=O)N1
Temperature: 200 °C
Reaction time: 8 h
Yield: 74 %

Procedure:
2-(Carboxymethyl)benzoic acid (10 g, 55.6 mmol) was dissolved in concentrated NH4OH (15 mL) and then was evaporated to dryness under reduced pressure. The process was repeated with additional NH4OH (5 mL). The resulting residue was treated with 1,2-dichlorobenzene (20 mL) and heated with stirring at 200° C. without a condenser allowing the solvent to evaporate. The concentrated mixture was allowed to cool to room temperature, diluted with methanol (20 mL), and allowed to stand overnight. The precipitate was collected by filtration, washed with methanol, and dried under reduced pressure to provide the title compound as tan needles (6.6 g, 74%).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:10]([O:14][CH3:15])[C:11]([OH:13])=O)[CH:5]=[CH:6][C:7]=1[O:8][CH3:9].[NH2:16][CH2:17][C:18]1[CH:25]=[CH:24][C:21]([C:22]#[N:23])=[CH:20][CH:19]=1>>[C:17]([C:18]1[CH:25]=[CH:24][C:21]([CH2:22][NH:23][C:11](=[O:13])[CH:10]([C:4]2[CH:5]=[CH:6][C:7]([O:8][CH3:9])=[C:2]([OH:1])[CH:3]=2)[O:14][CH3:15])=[CH:20][CH:19]=1)#[N:16]
Reactant: COc1ccc(C(OC)C(=O)O)cc1O
Reactant: N#Cc1ccc(CN)cc1
Product: COc1ccc(C(OC)C(=O)NCc2ccc(C#N)cc2)cc1O

Procedure:
(RS)-(3-Hydroxy-4-methoxy-phenyl)-methoxy-acetic acid was coupled with 4-aminomethyl benzonitrile according to general procedure C to give (RS)-N-(4-cyano-benzyl)-2-(3-hydroxy-4-methoxy-phenyl)-2-methoxy-acetamide. White foam.
Reaction SMILES: N[C:2]1[C:3]([C:11]([O:13][CH3:14])=[O:12])=[N:4][C:5]([CH:8]2[CH2:10][CH2:9]2)=[CH:6][N:7]=1.[Br:15]C(Br)C.N(OCCC(C)C)=O.C[Si](C)(C)Br.C([O-])(O)=O.[Na+]>>[Br:15][C:2]1[C:3]([C:11]([O:13][CH3:14])=[O:12])=[N:4][C:5]([CH:8]2[CH2:10][CH2:9]2)=[CH:6][N:7]=1
Reactant: CC(Br)Br
Reactant: COC(=O)c1nc(C2CC2)cnc1N
Agent: CC(C)CCON=O
Agent: C[Si](C)(C)Br
Agent: O=C([O-])O
Product: COC(=O)c1nc(C2CC2)cnc1Br
Reaction time: 8 h

Procedure:
To a solution of methyl 3-amino-6-cyclopropylpyrazine-2-carboxylate (1 g, 5.18 mmol, intermediate A-10, step 2) in dibromethane (16.0 ml, 229 mmol) at 0° under an argon atmosphere was added isoamyl nitrite (1.49 ml, 11.1 mmol) and trimethylbromosilane (2.03 ml, 15.7 mmol). The mixture was stirred at 0° for 10 min and at r.t overnight. The reaction mixture was poured onto ice, neutralized with solid NaHCO3, extracted with dichloromethane, dried over MgSO4, filtered and evaporated. The title compound was obtained after silica gel chromatography using a heptane/ethylacetate gradient as viscous oil (450 mg, 34%).
Reaction SMILES: [S:1]([N:11]1[C:15]2=[N:16][CH:17]=[CH:18][CH:19]=[C:14]2[C:13](C=O)=[CH:12]1)([C:4]1[CH:10]=[CH:9][C:7]([CH3:8])=[CH:6][CH:5]=1)(=[O:3])=[O:2].ClC1C=CC=C(C(OO)=[O:30])C=1>C(Cl)Cl>[S:1]([N:11]1[C:15]2=[N:16][CH:17]=[CH:18][CH:19]=[C:14]2[C:13](=[O:30])[CH2:12]1)([C:4]1[CH:10]=[CH:9][C:7]([CH3:8])=[CH:6][CH:5]=1)(=[O:3])=[O:2]
Reactant: Cc1ccc(S(=O)(=O)n2cc(C=O)c3cccnc32)cc1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)N2CC(=O)c3cccnc32)cc1
Temperature: 25 °C
Yield: 9.2 %

Procedure:
1-Tosyl-1H-pyrrolo[2,3-b]pyridine-3-carbaldehyde (5 g, 16.65 mmol) was dissolved in DCM (165 mL) and chilled to 0° C. m-Chloroperbenzoic acid (“m-CPBA”; 4.85 g, 21.64 mmol, 77% by weight) was added, and the mixture was allowed to gradually warm to room temperature over a 16 hour period. The mixture was then washed with 10% aqueous sodium sulfite solution, dried over sodium sulfate and concentrated. Flash 65 Biotage (5% ethyl acetate/DCM) afforded 1-tosyl-1H-pyrrolo[2,3-b]pyridin-3 (2H)-one (441 mg, 9%). 1H NMR (400 MHz, CDCl3) δ 8.61-8.66 (m, 1H), 8.00-8.05 (m, 2H), 7.92-7.97 (m, 1H), 7.29-7.34 (m, 2H), 7.06-7.12 (m, 1H), 4.38 (s, 2H), 2.41 (s, 3H).
Reaction SMILES: [ClH:1].[CH2:2]1[C:14]2[C:13]3[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=3[N:7]([CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17])[C:6]=2[CH2:5][CH2:4][NH:3]1.C1(NN)C=CC=CC=1>>[ClH:1].[Cl:1][C:9]1[C:8]2[N:7]([CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17])[C:6]3[CH2:5][CH2:4][NH:3][CH2:2][C:14]=3[C:13]=2[CH:12]=[CH:11][CH:10]=1
Reactant: CCOC(=O)Cn1c2c(c3ccccc31)CNCC2
Agent: Cl
Solvent: NNc1ccccc1
Product: CCOC(=O)Cn1c2c(c3cccc(Cl)c31)CNCC2

Procedure:
The title compound is prepared using a procedure analogous to Intermediate 1, substituting 2-chlorophenylhydrazine for phenylhydrazine in Step 1a).
Reaction SMILES: C[O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH2:9][NH:8][CH2:7][CH:6]2[C:13]1[CH:18]=[CH:17][C:16]([O:19]C)=[C:15]([O:21]C)[CH:14]=1.[BrH:23]>>[BrH:23].[OH:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH2:9][NH:8][CH2:7][CH:6]2[C:13]1[CH:18]=[CH:17][C:16]([OH:19])=[C:15]([OH:21])[CH:14]=1
Reactant: COc1ccc2c(c1)C(c1ccc(OC)c(OC)c1)CNC2
Agent: Br
Product: Oc1ccc2c(c1)C(c1ccc(O)c(O)c1)CNC2

Procedure:
To 790 mg of 6-methoxy-4-(3,4-dimethoxyphenyl)-1,2,3,4-tetrahydroisoquinoline, was added 16 ml of 48% hydrobromic acid, and the mixture was heated under reflux for 3 hours under an argon stream. The reaction solution was cooled, and precipitates which separated out were collected by filtration, giving 630 mg of 6-hydroxy-4-(3,4-dihydroxyphenyl)-1,2,3,4-tetrahydroisoquinoline hydrobromide.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][N:5]=[C:4]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[C:3]=1[CH3:13].[CH3:14][NH:15][CH3:16].C1COCC1.C(N(C(C)C)CC)(C)C>O1CCOCC1.O>[CH3:14][N:15]([CH3:16])[C:2]1[N:7]=[CH:6][N:5]=[C:4]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[C:3]=1[CH3:13]
Reactant: CCOC(=O)c1ncnc(Cl)c1C
Reactant: CNC
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Solvent: O
Product: CCOC(=O)c1ncnc(N(C)C)c1C
Temperature: 80 °C

Procedure:
To a solution of ethyl 6-chloro-5-methylpyrimidine-4-carboxylate (35) (0.9 g, 4.48 mmol) dissolved in dioxane (20 ml) were added dimethyl amine in THF (1M. 22.43 ml, 22.43 mmol) and diisopropyl ethylamine (3 ml, 22.43 mmol). The reaction mixture was heated to 80° C. for 16 h. Then the mixture is cooled to room temperature, diluted with water, and extracted with EtOAc (2×50 mL). The combined organic layer was washed with water, brine, dried over sodium sulfate, and concentrated at reduced pressure to yield ethyl 6-(dimethylamino)-5-methylpyrimidine-4-carboxylate (23) as a light yellow liquid; 0.4 g (43%).
Reaction SMILES: O[C:2]1([C:23]2[CH:28]=[CH:27][CH:26]=[C:25]([CH3:29])[CH:24]=2)[C:6]2[CH:7]=[C:8]([NH:13][C:14](=[O:20])[CH2:15][C:16]([CH3:19])([CH3:18])[CH3:17])[C:9]([CH3:12])=[C:10]([CH3:11])[C:5]=2[O:4][C:3]1([CH3:22])[CH3:21]>C(OCC)(=O)C.CCCCCC>[CH3:17][C:16]([CH3:19])([CH3:18])[CH2:15][C:14]([NH:13][C:8]1[C:9]([CH3:12])=[C:10]([CH3:11])[C:5]2[O:4][C:3]([CH3:21])([CH3:22])[CH:2]([C:23]3[CH:28]=[CH:27][CH:26]=[C:25]([CH3:29])[CH:24]=3)[C:6]=2[CH:7]=1)=[O:20]
Reactant: Cc1cccc(C2(O)c3cc(NC(=O)CC(C)(C)C)c(C)c(C)c3OC2(C)C)c1
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: Cc1cccc(C2c3cc(NC(=O)CC(C)(C)C)c(C)c(C)c3OC2(C)C)c1
Yield: 87 %

Procedure:
Using N-(3-hydroxy-2,2,6,7-tetramethyl-3-(3-methylphenyl)-2,3-dihydro-1-benzofuran-5-yl)-3,3-dimethylbutanamide obtained in Example 239, the title compound was synthesized in the same manner as in Example 271. Yield: 87%. Melting point: 156-157° C. (ethyl acetate-hexane).
Reaction SMILES: [CH:1]1([N:7]([C@H:19]2[CH2:23][CH2:22][N:21]([C:24](=[O:26])[CH3:25])[CH2:20]2)[C:8]([NH:10][C:11]2[S:12][C:13]([S:16]C#N)=[CH:14][N:15]=2)=[O:9])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.SC[C@@H]([C@@H](CS)O)O.Cl[CH2:36][CH2:37][N:38]1[CH2:43][CH2:42][O:41][CH2:40][CH2:39]1>>[C:24]([N:21]1[CH2:22][CH2:23][C@H:19]([N:7]([CH:1]2[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]2)[C:8]([NH:10][C:11]2[S:12][C:13]([S:16][CH2:36][CH2:37][N:38]3[CH2:43][CH2:42][O:41][CH2:40][CH2:39]3)=[CH:14][N:15]=2)=[O:9])[CH2:20]1)(=[O:26])[CH3:25]
Reactant: ClCCN1CCOCC1
Reactant: CC(=O)N1CC[C@H](N(C(=O)Nc2ncc(SC#N)s2)C2CCCCC2)C1
Agent: O[C@H](CS)[C@@H](O)CS
Product: CC(=O)N1CC[C@H](N(C(=O)Nc2ncc(SCCN3CCOCC3)s2)C2CCCCC2)C1

Procedure:
Prepared as described in general procedure (H) using 1-cyclohexyl-3-(5-thiocyanato-thiazol-2-yl)-1-[1-(acetyl)-pyrrolidin-3(S)-yl]-urea, dithioerythritol and N-(2-chloroethyl)morpholine
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[C:3]1[CH:10]=[C:9]([N+:11]([O-:13])=[O:12])[CH:8]=[CH:7][C:4]=1[CH:5]=O.[CH3:16][C:17](=[O:22])[CH2:18][C:19](=[O:21])[CH3:20].C(O)(=O)C.N1CCCCC1>ClCCl>[N+:11]([C:9]1[CH:8]=[CH:7][C:4]([CH:5]=[C:18]([C:17](=[O:22])[CH3:16])[C:19](=[O:21])[CH3:20])=[C:3]([C:2]([F:15])([F:14])[F:1])[CH:10]=1)([O-:13])=[O:12]
Reactant: O=Cc1ccc([N+](=O)[O-])cc1C(F)(F)F
Reactant: CC(=O)CC(C)=O
Solvent: ClCCl
Solvent: C1CCNCC1
Solvent: CC(=O)O
Product: CC(=O)C(=Cc1ccc([N+](=O)[O-])cc1C(F)(F)F)C(C)=O

Procedure:
1 g (4.56 mmol) of 2-trifluoromethyl-4-nitrobenzaldehyde, 0.51 ml (5.02 mmol) of 2,4-pentanedione, 0.4 ml (6.85 mmol) of acetic acid and 90 μl (0.91 mmol) of piperidine in 20 ml of anhydrous dichloromethane are stirred under reflux with a water trap for 24 h. After cooling, the reaction solution is washed successively with saturated sodium bicarbonate solution and saturated sodium chloride solution. The organic phase is dried over magnesium sulfate and concentrated. The residue (1.28 g) is reacted in the next stage without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[C:6](=O)[C:7]3[C:12]([S:13][C:14]=2[CH:15]=1)=[C:11]([O:16][CH3:17])[CH:10]=[CH:9][CH:8]=3.B#B>O1CCCC1.O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[CH2:6][C:7]3[C:12]([S:13][C:14]=2[CH:15]=1)=[C:11]([O:16][CH3:17])[CH:10]=[CH:9][CH:8]=3
Reactant: COc1cccc2c(=O)c3ccc(Cl)cc3sc12
Agent: B#B
Solvent: O
Solvent: C1CCOC1
Product: COc1cccc2c1Sc1cc(Cl)ccc1C2

Procedure:
A stirred suspension of 3-chloro-5-methoxythioxanth-9-one (13.8 g.) in dry tetrahydrofuran (140 ml.) is treated dropwise with a solution of diborane in tetrahydrofuran (1M, 40 ml.) at ambient temperature and in an atmosphere of argon. The mixture is heated at reflux for 1.25 hours, cooled, diluted carefully with water and extracted with ether (× 3). The combined ether extracts are washed with brine, dried over MgSO4 and then evaporated, to give 3-chloro-5-methoxythioxanthene, m.p. 72°-74° C. on recrystallisation from methanol.
Reaction SMILES: Cl[C:2]1[N:3]=[N:4][CH:5]=[C:6]2[C:10]([CH3:11])=[C:9]([CH3:12])[N:8]([CH2:13][CH:14]=[CH2:15])[C:7]=12.[F:16][C:17]1[CH:18]=[C:19]([CH:22]=[CH:23][CH:24]=1)[CH2:20][OH:21]>>[F:16][C:17]1[CH:18]=[C:19]([CH:22]=[CH:23][CH:24]=1)[CH2:20][O:21][C:2]1[N:3]=[N:4][CH:5]=[C:6]2[C:10]([CH3:11])=[C:9]([CH3:12])[N:8]([CH2:13][CH:14]=[CH2:15])[C:7]=12
Reactant: OCc1cccc(F)c1
Reactant: C=CCn1c(C)c(C)c2cnnc(Cl)c21
Product: C=CCn1c(C)c(C)c2cnnc(OCc3cccc(F)c3)c21
Yield: 71.4 %

Procedure:
The title compound was prepared as white cottony crystals in 71.4% yield in a similar procedure to that described in Example 1 by using 7-chloro-2,3-dimethyl-1-(2-propenyl)pyrrolo[2,3-d]pyridazine and 3-fluorobenzyl alcohol.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1.C([Li])CCC.CON(C)[C:16]([C:18]1[N:19]=[CH:20][N:21]([C:23]2[CH:24]=[C:25]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[CH:26]=[CH:27][CH:28]=2)[CH:22]=1)=[O:17].[Cl-].[NH4+]>C1COCC1>[C:25]1([C:29]2[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=2)[CH:26]=[CH:27][CH:28]=[C:23]([N:21]2[CH:22]=[C:18]([C:16]([C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=3)=[O:17])[N:19]=[CH:20]2)[CH:24]=1
Reactant: Brc1ccccn1
Reactant: CON(C)C(=O)c1cn(-c2cccc(-c3ccccc3)c2)cn1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Product: O=C(c1ccccn1)c1cn(-c2cccc(-c3ccccc3)c2)cn1
Temperature: -78 °C
Reaction time: 0.75 h
Yield: 28.8 %

Procedure:
A solution of 2-bromopyridine (1.0 g, 6.5 mmol) in THF (20 ml) was stirred at −78° C. in a nitrogen atmosphere. n-Butyllithium (8.1 ml 1.6M solution in hexanes, 13.0 mmol) was added and stirring at −78° C. was continued for 45 min. The resultant mixture was allowed to warm to 0° C. for two hours, in order to ensure completion of anion formation. The mixture was again cooled to −78° C. and compound 12a (0.5 g, 1.6 mmol) was added. After 30 min. the mixture was allowed to warm to 0° C. and saturated, aqueous ammonium chloride was added. The mixture was extracted with ethyl acetate. The combined extracts were dried over magnesium sulfate and concentrated under reduced pressure. The concentrate was purified by column chromatography on silica gel using a mixture of petroleum ether and ethyl acetate (9:1) as the eluent. This afforded the desired product (0.15 g, 22%) as a yellowish gum. HRMS (ESI+): m/z=326.1305 [M+H]