Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][CH:2]1[CH2:28][O:27][C:5]2=[CH:6][CH:7]=[C:8]3[C:12]([N:11]([CH2:13][C@@H:14]([NH:16][C:17](=[O:26])[O:18][CH2:19][C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)[CH3:15])[N:10]=[CH:9]3)=[C:4]2[CH:3]1O.[N-:30]=[N+:31]=[N-:32].[Na+]>CS(C)=O>[N:30]([CH:3]1[C:4]2[C:5](=[CH:6][CH:7]=[C:8]3[C:12]=2[N:11]([CH2:13][C@@H:14]([NH:16][C:17](=[O:26])[O:18][CH2:19][C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH3:15])[N:10]=[CH:9]3)[O:27][CH2:28][CH:2]1[Br:1])=[N+:31]=[N-:32]
Reactant: C[C@@H](Cn1ncc2ccc3c(c21)C(O)C(Br)CO3)NC(=O)OCc1ccccc1
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CS(C)=O
Product: C[C@@H](Cn1ncc2ccc3c(c21)C(N=[N+]=[N-])C(Br)CO3)NC(=O)OCc1ccccc1
Temperature: 80 °C
Yield: 80 %

Procedure:
A mixture of the product from Step A (0.31 g, 0.67 mmol) and sodium azide (0.65 g, 10 mmol) in dimethylsulfoxide (20 mL) was heated at 80° C. for 3 h, cooled to room temperature, and extracted with ethyl acetate. The combined extracts were dried and concentrated to a residue which was purified by chromatography (silica, 30% ethyl acetate in hexane) to give an oil (0.26 g, 68%): LC/MS (+APCI) m/z 423 (M+H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:9]2[CH2:13][CH2:12][CH2:11][NH:10]2)[CH:6]=[CH:7][CH:8]=1.[Cl:14][C:15]1[CH:20]=[CH:19][C:18]([S:21](Cl)(=[O:23])=[O:22])=[CH:17][CH:16]=1>>[Cl:14][C:15]1[CH:20]=[CH:19][C:18]([S:21]([N:10]2[CH2:11][CH2:12][CH2:13][CH:9]2[C:5]2[CH:6]=[CH:7][CH:8]=[C:3]([O:2][CH3:1])[CH:4]=2)(=[O:23])=[O:22])=[CH:17][CH:16]=1
Reactant: O=S(=O)(Cl)c1ccc(Cl)cc1
Reactant: COc1cccc(C2CCCN2)c1
Product: COc1cccc(C2CCCN2S(=O)(=O)c2ccc(Cl)cc2)c1

Procedure:
The title compound, white solid, m.p. 95° C. and MS: m/e=351 (M+) was prepared in accordance with the general method of example 1e from (RS)-2-(3-methoxy-phenyl)-pyrrolidine and 4-chloro-benzenesulfonyl chloride.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[C:8]([NH:10][C:11]2[S:12][CH:13]=[CH:14][N:15]=2)[CH:7]=[CH:6][C:3]=1[C:4]#[N:5].C([O-])([O-])=O.[Cs+].[Cs+].Br[CH2:23][C:24]1[S:25][CH:26]=[CH:27][N:28]=1>CC(C)=O>[C:4]([C:3]1[CH:6]=[CH:7][C:8]([NH:10][C:11]2[S:12][CH:13]=[CH:14][N:15]=2)=[CH:9][C:2]=1[O:1][CH2:23][C:24]1[S:25][CH:26]=[CH:27][N:28]=1)#[N:5]
Reactant: BrCc1nccs1
Reactant: N#Cc1ccc(Nc2nccs2)cc1O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC(C)=O
Product: N#Cc1ccc(Nc2nccs2)cc1OCc1nccs1

Procedure:
Following the general procedure for O-alkylation, Method B, a mixture of 2-hydroxy-4-(thiazol-2-ylamino)benzonitrile (70 mg, 0.32 mmol) and Cs2CO3 (105 mg, 0.32 mmol) in acetone (4.4 mL) was treated with 2-bromomethylthiazole (57 mg, 0.32 mmol) at RT. Reaction control by TLC showed full conversion after 4 h. The title compound was obtained after purification by flash chromatography on silica gel (hexane:EtOAc 4/6) in 8 yield (8 mg).
Reaction SMILES: [CH2:1]([C:5]1[N:6]=[C:7]([CH3:27])[NH:8][C:9](=[O:26])[C:10]=1[CH2:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[C:19]([C:24]#[N:25])=[CH:20][CH:21]=[CH:22][CH:23]=2)=[CH:14][CH:13]=1)[CH2:2][CH2:3][CH3:4].[Cl:28][C:29]1[CH:30]=[C:31](B(O)O)[CH:32]=[CH:33][CH:34]=1.C(N(CC)CC)C.N1C=CC=CC=1>C(Cl)Cl.C(OCC)(=O)C.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[CH2:1]([C:5]1[N:6]=[C:7]([CH3:27])[N:8]([C:33]2[CH:32]=[CH:31][CH:30]=[C:29]([Cl:28])[CH:34]=2)[C:9](=[O:26])[C:10]=1[CH2:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[C:19]([C:24]#[N:25])=[CH:20][CH:21]=[CH:22][CH:23]=2)=[CH:14][CH:13]=1)[CH2:2][CH2:3][CH3:4]
Reactant: OB(O)c1cccc(Cl)c1
Reactant: CCCCc1nc(C)[nH]c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CCCCc1nc(C)n(-c2cccc(Cl)c2)c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1
Reaction time: 48 h

Procedure:
To a suspension of 4′-[(4-butyl-2-methyl-6-oxo-1,6-dihydropyrimidin-5-yl)methyl]biphenyl-2-carbonitrile (1.0 g), 3-chlorophenylboronic acid (1.0 g), triethylamine (2.0 mL), pyridine (1.0 mL) and molecular sieves 4 A (1.0 g) in methylene chloride (15 mL) was added copper(II) acetate (1.0 g), and the mixture was stirred for 2 days. The reaction mixture was diluted with ethyl acetate, the insoluble material was filtered off through celite, and the filtrate was concentrated. The residue was purified by silica gel column chromatography to give the title compound as a pale-yellow viscous substance (0.96 g, 73%).
Reaction SMILES: [C:1]([O:5][C:6](=[O:26])[NH:7][C@H:8]1[C@H:17]([O:18][CH3:19])[CH2:16][C:15]2[C:10](=[CH:11][C:12]([C:20]#[N:21])=[CH:13][CH:14]=2)[C:9]1([CH2:24][CH3:25])[CH2:22][CH3:23])([CH3:4])([CH3:3])[CH3:2].C([OH:29])C.CN(C=O)C>O>[C:1]([O:5][C:6](=[O:26])[NH:7][C@H:8]1[C@H:17]([O:18][CH3:19])[CH2:16][C:15]2[C:10](=[CH:11][C:12]([C:20](=[O:29])[NH2:21])=[CH:13][CH:14]=2)[C:9]1([CH2:22][CH3:23])[CH2:24][CH3:25])([CH3:3])([CH3:4])[CH3:2]
Reactant: CCO
Reactant: CCC1(CC)c2cc(C#N)ccc2C[C@@H](OC)[C@@H]1NC(=O)OC(C)(C)C
Solvent: O
Solvent: CN(C)C=O
Product: CCC1(CC)c2cc(C(N)=O)ccc2C[C@@H](OC)[C@@H]1NC(=O)OC(C)(C)C
Temperature: 80 °C

Procedure:
To a mixture of trans-(7-cyano-1,1-diethyl-3-methoxy-1,2,3,4-tetrahydro-naphthalen-2-yl)-carbamic acid tert-butyl ester (33.0 g, 92 mmol), ethanol (45 mL), DMF (25 mL) and water (7.5 mL) was added hydrido(dimethylphosphoniousacid-kP) [hydrogen bis(dimethylphosphinito-kP)]platinum(II) (0.25 g, 0.58 mmol) and the reaction mixture was heated at 80° C. for 24 h. The reaction was cooled to room temperature and concentrated to dryness under vacuum to give the title compound (36.3 g) which was used without further purification. (m/z): [M+H]+ calcd for C21H32N2O4 377.24; found 377.8. 1H NMR (d6-DMSO, 400 mHz) δ (ppm): 7.92 (s, 1H), 7.64 (m, 2H), 7.26 (s, 1H), 7.14 (d, J=7.9 Hz, 1H), 6.64 (d, J=9.4 Hz) 3.81 (t, J=10.0 Hz), 3.58 (m, 1H), 3.30 (s, 3H), 2.58 (dd, J=16.9 Hz, 9.4 Hz, 1H), 1.82 (m, 1H), 1.56-1.45 (m, 4H), 1.41 (s, 9H), 0.58 (m, 6H).
Reaction SMILES: [CH2:1]1[C@@H:5]([C:6]([OH:8])=[O:7])[NH:4][CH2:3][C@H:2]1[OH:9].[OH2:10]>>[OH:9][C@H:2]([CH2:3][OH:10])[CH2:1][C@@H:5]([C:6]([OH:8])=[O:7])[NH2:4]
Reactant: O=C(O)[C@@H]1C[C@H](O)CN1
Reactant: O
Product: N[C@@H](C[C@H](O)CO)C(=O)O

Procedure:
[α]D21 =-23.9 (c =1.0, water) Further reactions analogously to J. Am. Chem. Soc. 1986, 108, 6041 lead to L-cis-4-hydroxyproline
Reaction SMILES: [CH2:1]1[O:36][C:35]2[CH:34]=[CH:33][C:5]([CH2:6][O:7][C:8](=[O:32])[C@H:9]([NH:18][S:19]([C:22]3[C:27]([CH3:28])=[CH:26][C:25]([O:29][CH3:30])=[CH:24][C:23]=3[CH3:31])(=[O:21])=[O:20])[CH2:10][O:11][CH:12]3[CH2:17][CH2:16][CH2:15][CH2:14][O:13]3)=[CH:4][C:3]=2[O:2]1.[CH2:37]1[O:45][C:44]2[CH:43]=[CH:42][C:41]([CH2:46]O)=[CH:40][C:39]=2[O:38]1.C(P(CCCC)CCCC)CCC.N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O>C1C=CC=CC=1>[CH2:1]1[O:36][C:35]2[CH:34]=[CH:33][C:5]([CH2:6][O:7][C:8](=[O:32])[C@H:9]([N:18]([CH2:46][C:41]3[CH:42]=[CH:43][C:44]4[O:45][CH2:37][O:38][C:39]=4[CH:40]=3)[S:19]([C:22]3[C:27]([CH3:28])=[CH:26][C:25]([O:29][CH3:30])=[CH:24][C:23]=3[CH3:31])(=[O:21])=[O:20])[CH2:10][O:11][CH:12]3[CH2:17][CH2:16][CH2:15][CH2:14][O:13]3)=[CH:4][C:3]=2[O:2]1
Reactant: OCc1ccc2c(c1)OCO2
Reactant: COc1cc(C)c(S(=O)(=O)N[C@H](COC2CCCCO2)C(=O)OCc2ccc3c(c2)OCO3)c(C)c1
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: c1ccccc1
Product: COc1cc(C)c(S(=O)(=O)N(Cc2ccc3c(c2)OCO3)[C@H](COC2CCCCO2)C(=O)OCc2ccc3c(c2)OCO3)c(C)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 90.8 %

Procedure:
To a solution of 2(R)-(4-methoxy-2,6-dimethylbenzenesulfonyl-amino)-3-(tetrahydropyran-2-yloxy)propionic acid 3,4-methylenedioxybenzyl ester (9.0 g, 16.8 mmol) in benzene (150 mL) at 0° C. was added 3,4-methylenedioxyphenyl methanol (3.8 g, 25.2 mmol), tri-n-butylphosphine (5.1 g, 25.2 mmol), followed by 1,1′-[azodicarbonyl]dipiperidine (6.35 g, 25.2 mmol). The reaction mixture was allowed to warm to room temperature over 4 h. After 16 h, the reaction mixture was diluted with an equal volume of hexanes, cooled to 0° C. for 2 h and filtered. The residue was chromatographed (300 g SiO2, 15% ethyl acetate-hexanes) to afford 2(R)-[(3,4-methylenedioxybenzyl)-(4-methoxy-2,6-dimethylbenzenesulfonyl)amino]-3-(tetrahydropyran-2-yloxy)propionic acid 3,4-methylenedioxybenzyl ester (10.0 g) as a pale orange oil.
Reaction SMILES: [CH3:1][C:2]([C:5]1[CH:10]=[CH:9][C:8]2[C:11]3[CH2:16][CH2:15][NH:14][CH2:13][C:12]=3[C:17](=[O:19])[O:18][C:7]=2[CH:6]=1)([CH3:4])[CH3:3].[ClH:20].[Cl:21][CH2:22][CH2:23][N:24]1[CH2:30][CH:29]2[CH2:31][CH2:32][CH:26]([CH2:27][CH2:28]2)[CH2:25]1>>[ClH:21].[ClH:20].[CH:29]12[CH2:31][CH2:32][CH:26]([CH2:27][CH2:28]1)[CH2:25][N:24]([CH2:23][CH2:22][N:14]1[CH2:15][CH2:16][C:11]3[C:8]4[CH:9]=[CH:10][C:5]([C:2]([CH3:1])([CH3:3])[CH3:4])=[CH:6][C:7]=4[O:18][C:17](=[O:19])[C:12]=3[CH2:13]1)[CH2:30]2
Reactant: ClCCN1CC2CCC(CC2)C1
Reactant: CC(C)(C)c1ccc2c3c(c(=O)oc2c1)CNCC3
Agent: Cl
Product: CC(C)(C)c1ccc2c3c(c(=O)oc2c1)CN(CCN1CC2CCC(CC2)C1)CC3
Yield: 48 %

Procedure:
Prepared by the method described for Example 1 from 8-(1,1-dimethylethyl)-1,2,3,4-tetrahydro-5H-[1]benzopyrano[3,4-c]-pyridin-5-one (4 g, 0.016 moles) and 3-(2-chloroethyl)-3-azabicyclo(3.2.2)nonane hydrochloride (3.6 g, 0.016 moles). Recrystallization from methanol gave the product (3.7 g), mp 312°-315° C.
Reaction SMILES: C(O)(=O)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC.C1COCC1.[CH2:28]([O:31][C:32]([N:34]1[C@H:38]([CH:39]([OH:48])[C:40]2[N:41]3[CH:47]=[N:46][CH:45]=[C:42]3[S:43][CH:44]=2)[CH2:37][C@H:36]([S:49][C:50]2[C@H:51]([CH3:74])[C@@H:52]3[C@@H:62]([C@H:63]([O:65][Si](C(C)(C)C)(C)C)[CH3:64])[C:61](=[O:73])[N:53]3[C:54]=2[C:55]([O:57][CH2:58][CH:59]=[CH2:60])=[O:56])[CH2:35]1)=[O:33])[CH:29]=[CH2:30]>C1COCC1.C(OCC)(=O)C>[CH2:28]([O:31][C:32]([N:34]1[C@H:38]([CH:39]([OH:48])[C:40]2[N:41]3[CH:47]=[N:46][CH:45]=[C:42]3[S:43][CH:44]=2)[CH2:37][C@H:36]([S:49][C:50]2[C@H:51]([CH3:74])[C@@H:52]3[C@@H:62]([C@H:63]([OH:65])[CH3:64])[C:61](=[O:73])[N:53]3[C:54]=2[C:55]([O:57][CH2:58][CH:59]=[CH2:60])=[O:56])[CH2:35]1)=[O:33])[CH:29]=[CH2:30]
Reactant: C=CCOC(=O)C1=C(S[C@H]2C[C@@H](C(O)c3csc4cncn34)N(C(=O)OCC=C)C2)[C@H](C)[C@@H]2[C@@H]([C@@H](C)O[Si](C)(C)C(C)(C)C)C(=O)N12
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: C=CCOC(=O)C1=C(S[C@H]2C[C@@H](C(O)c3csc4cncn34)N(C(=O)OCC=C)C2)[C@H](C)[C@@H]2[C@@H]([C@@H](C)O)C(=O)N12
Temperature: 25 °C
Reaction time: 38 h
Yield: 66.8 %

Procedure:
Acetic acid (0.26 ml) and 1.52 ml of a 1 M tetra-n-butyl ammonium fluoride/THF solution are added to a solution of 213 mg of allyl(1R,5S,6S)-2-[(3S,5S)-1-allyloxycarbonyl-5-[1-hydroxy-1-(imidazo[5,1-b]thiazol-3-yl)methyl]pyrrolidin-3-yl]thio-6-[(1R)-1-(t-butyldimethylsilyloxy)ethyl]-1-methylcarbapen-2-em-3-carboxylate (stereoisomer B) in 4.5 ml of anhydrous THF, and the mixture is stirred in an argon atmosphere at room temperature for 38 hr. The reaction solution is diluted with 80 ml of ethyl acetate, the diluted solution is successively washed with 40 ml of a 1/15 M phosphate buffer (pH 7.0) and 20 ml of saturated saline, the washed solution is dried over anhydrous magnesium sulfate and filtered, and the solvent is removed by evaporation to give 193 mg of a slightly yellow oil. This oil is successively purified by column chromatography on silica gel (ethyl acetate:methanol=95:5→9:1) and on Sephadex LH-20 (chloroform:methanol=1:1) to give 119.2 mg of allyl(1R,5S,6S)-2-[(3S,5S)-1-allyloxycarbonyl-5-[1-hydroxy-1-(imidazo[5,1-b]thiazol-3-yl)methyl]pyrrolidin-3-yl]thio-6-((1R)-1-hydroxyethyl)-1-methylcarbapen-2-em-3-carboxylate (stereoisomer B) as a milky white amorphous material.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([O:8][CH2:9][CH2:10][N:11]([CH2:14][CH3:15])[CH2:12][CH3:13])[CH:5]=[CH:4][C:3]=1[C:16](=[O:21])[C:17](=[CH2:20])[CH2:18][CH3:19].Cl[C:23]1C=C(OCCN2CCCCC2)C=CC=1C(=O)CCC>>[Cl:1][C:2]1[CH:7]=[C:6]([O:8][CH2:9][CH2:10][N:11]2[CH2:12][CH2:13][CH2:23][CH2:15][CH2:14]2)[CH:5]=[CH:4][C:3]=1[C:16](=[O:21])[C:17](=[CH2:20])[CH2:18][CH3:19]
Reactant: CCCC(=O)c1ccc(OCCN2CCCCC2)cc1Cl
Reactant: C=C(CC)C(=O)c1ccc(OCCN(CC)CC)cc1Cl
Product: C=C(CC)C(=O)c1ccc(OCCN2CCCCC2)cc1Cl

Procedure:
This compound is prepared by essentially the same procedure as described in Example 1 Step B except that the 1-[2-chloro-4-(2-diethylaminoethoxy)phenyl]-1-butanone of Example 1 Step B is replaced by an equimolecular quantity of 1-[2-chloro-4-(2-piperidinoethoxy)phenyl]-1-butanone. The product is obtained as a yellow oil upon distillation in vacuo (0.3 m.).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:17][C@:16]([C:19]2[CH:24]=[C:23]([F:25])[CH:22]=[C:21]([F:26])[CH:20]=2)([CH3:18])[N:15]([CH2:27][C:28]([OH:30])=[O:29])[C:14](=[O:31])[C:9]21[CH2:13][CH2:12][CH2:11][CH2:10]2)=[O:7])([CH3:4])([CH3:3])[CH3:2].FC(F)(F)C(O[C:37]1[C:42]([F:43])=[C:41]([F:44])[C:40]([F:45])=[C:39]([F:46])[C:38]=1[F:47])=O>CN(C=O)C>[F:25][C:23]1[CH:24]=[C:19]([C@@:16]2([CH3:18])[N:15]([CH2:27][C:28](=[O:30])[O:29][C:37]3[C:38]([F:47])=[C:39]([F:46])[C:40]([F:45])=[C:41]([F:44])[C:42]=3[F:43])[C:14](=[O:31])[C:9]3([CH2:10][CH2:11][CH2:12][CH2:13]3)[N:8]([C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])[CH2:17]2)[CH:20]=[C:21]([F:26])[CH:22]=1
Reactant: O=C(Oc1c(F)c(F)c(F)c(F)c1F)C(F)(F)F
Reactant: CC(C)(C)OC(=O)N1C[C@@](C)(c2cc(F)cc(F)c2)N(CC(=O)O)C(=O)C12CCCC2
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1C[C@@](C)(c2cc(F)cc(F)c2)N(CC(=O)Oc2c(F)c(F)c(F)c(F)c2F)C(=O)C12CCCC2
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a stirred solution of [(8R)-6-(tert-butoxycarbonyl)-8-(3,5-difluorophenyl)-8-methyl-10-oxo-6,9-diazaspiro[4.5]dec-9-yl]acetic acid (254 mg, 0.579 mmol, described in Intermediate 21) in DMF (2 mL) was added pentafluorophenyl trifluoroacetate (0.7 mL, 4.07 mmol). The reaction mixture was stirred for 4 h at ambient temperature, then partitioned between saturated aqueous NaHCO3 (30 mL) and EtOAc (50 mL). The organic layer was dried over Na2SO4, filtered, and concentrated in vacuo. The crude product was purified on silica gel, eluting with a gradient of hexanes:EtOAc—100:0 to 0:100, to provide the title compound.
Reaction SMILES: [F:1][C:2]1[CH:25]=[CH:24][C:5]2[N:6]=[C:7]([NH:9][C:10]3[CH:15]=[CH:14][C:13]([C:16]4[CH:20]=[C:19]([C:21]([NH2:23])=O)[O:18][N:17]=4)=[CH:12][CH:11]=3)[S:8][C:4]=2[CH:3]=1.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:35])=CC=1>O1CCOCC1>[F:1][C:2]1[CH:25]=[CH:24][C:5]2[N:6]=[C:7]([NH:9][C:10]3[CH:15]=[CH:14][C:13]([C:16]4[CH:20]=[C:19]([C:21](=[S:35])[NH2:23])[O:18][N:17]=4)=[CH:12][CH:11]=3)[S:8][C:4]=2[CH:3]=1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: NC(=O)c1cc(-c2ccc(Nc3nc4ccc(F)cc4s3)cc2)no1
Solvent: C1COCCO1
Product: NC(=S)c1cc(-c2ccc(Nc3nc4ccc(F)cc4s3)cc2)no1
Yield: 81 %

Procedure:
To a solution of 3-[4-(6-fluoro-benzothiazol-2-ylamino)-phenyl]-isoxazole-5-carboxylic acid amide (3.54 g; 10 mmol) in dioxane (25 ml), was added Lawesson's reagent (4.11 g; 10 mmol) and the resulting reaction mixture was refluxed for 45 min. The pH of the reaction mixture was adjusted to near neutral, the solvent was removed and the residue was diluted with water (20 ml) and extracted with EtOAc (3×30 ml). The EtOAc layer was washed with water (3×10 ml) followed by brine (10 ml), and dried over anhydrous Na2SO4. The solvent was removed, and the residue was triturated with dichloromethane, filtered and dried to afford 3.0 g (80%) of the title compound. Mass (ES−), 369 (M−1); IR (KBr): 3282 (br), 3142 (br), 1651, 1608, 1588, 1555, 1441 (br); 1H NMR (DMSO-d6) δ: 7.18 (m, 1H), 7.58 (s, 1H), 7.65 (m, 1H), 7.77 (m, 1H), 7.88-7.94 (br, 4H), 7.97, 10.33 (2×br, 2H), 10.79 (s, 1H).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Br:8][C:9]1[CH:10]=[CH:11][CH:12]=[C:13]2[C:18]=1[N:17]=[C:16](Cl)[CH:15]=[CH:14]2.[Li+].C[Si]([N-][Si](C)(C)C)(C)C>C1COCC1>[Br:8][C:9]1[CH:10]=[CH:11][CH:12]=[C:13]2[C:18]=1[N:17]=[C:16]([NH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[CH:15]=[CH:14]2
Reactant: Nc1ccccc1
Reactant: Clc1ccc2cccc(Br)c2n1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: Brc1cccc2ccc(Nc3ccccc3)nc12
Temperature: 25 °C
Reaction time: 1 h
Yield: 75.8 %

Procedure:
To a solution of aniline (0.76 g, 8.16 mmol) and 8-bromo-2-chloroquinoline (Biofine International, Vancouver, BC; 1.1 g, 4.54 mmol) in THF (7 mL) at 0° C. was added LiHMDS (1.0 M solution in THF, 13.61 mL, 13.61 mmol) drop wise via a syringe. The resulting brown mixture was stirred at RT for 1 h, and then quenched with sat. NH4Cl solution (15 mL) and extracted with EtOAc (2×50 mL). The combined organic solution was concentrated and the residue was purified on a silica gel column (25-45% EtOAc in hexanes) to afford 8-bromo-N-phenylquinolin-2-amine (Ex. 165c, 1.03 g, 3.44 mmol, 76% yield) as a brown crystalline solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 9.69 (1H, s), 8.21 (2H, d, J=7.8 Hz), 8.10 (1H, d, J=8.8 Hz), 7.94 (1H, m), 7.77 (1H, d, J=7.0 Hz), 7.35 (2H, t, J=7.8 Hz), 7.21 (1H, t, J=7.7 Hz), 7.13 (1H, d, J=9.0 Hz), 6.98 (1H, t, J=7.3 Hz). m/z (ESI, +ve) 299/301 (M+H)+.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[CH2:7]([NH:11][CH2:12][CH:13]([CH3:15])[CH3:14])[CH:8]([CH3:10])[CH3:9].[CH:16](=O)[CH2:17][CH2:18][CH3:19]>>[CH:16](/[N:11]([CH2:12][CH:13]([CH3:15])[CH3:14])[CH2:7][CH:8]([CH3:10])[CH3:9])=[CH:17]\[CH2:18][CH3:19]
Reactant: CC(C)CNCC(C)C
Reactant: CCCC=O
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CC/C=C/N(CC(C)C)CC(C)C
Temperature: -7 °C
Reaction time: 0.17 h
Yield: 74.2 %

Procedure:
Potassium carbonate (4.8 g, 35 mmol) was added to diisobutylamine (17.5 mL, 0.10 mol) under a nitrogen atmosphere, and the mixture was then cooled to −7° C. Butanal (9.0 mL, 0.10 mol) was added dropwise thereto over 10 minutes. The reaction mixture was gradually heated to room temperature and stirred for 19 hours. Insoluble matter was filtered off, and the filtrate was then concentrated under reduced pressure to obtain the title compound (13.6 g, yield: 74%) as a colorless oil substance.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[CH:7][C:4]=1[CH:5]=[O:6].[CH3:14][Al](C)C.O>C1(C)C=CC=CC=1.CCCCCC>[CH3:1][O:2][C:3]1[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[CH:7][C:4]=1[CH:5]([OH:6])[CH3:14]
Reactant: C[Al](C)C
Reactant: COc1ccc([N+](=O)[O-])cc1C=O
Solvent: O
Solvent: Cc1ccccc1
Solvent: CCCCCC
Product: COc1ccc([N+](=O)[O-])cc1C(C)O
Temperature: 25 °C
Reaction time: 1 h
Yield: 79 %

Procedure:
To a solution of 2-methoxy-5-nitrobenzaldehyde (450 mg) in toluene (30 ml), a solution of trimethylaluminum in hexane (3.0 ml) was added dropwise under ice cooling. After stirring at room temperature for 1 h, water was added to the reaction mixture, which was extracted with ethyl acetate. The organic layer was washed successively with water and a saturated aqueous sodium chloride solution, dried with anhydrous sodium sulfate and the solvent was distilled off under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent, n-hexane:ethyl acetate=2:1) to give 385 mg of the titled compound (yield, 79%).
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)(=O)[CH3:2].[Cl:10][C:11]1[CH:17]=[CH:16][CH:15]=[CH:14][C:12]=1[NH2:13].C1C=CC=CC=1>O>[Cl:10][C:11]1[CH:17]=[CH:16][CH:15]=[CH:14][C:12]=1[N:13]=[C:1]([CH3:2])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: Nc1ccccc1Cl
Reactant: CC(=O)c1ccccc1
Solvent: c1ccccc1
Solvent: O
Product: CC(=Nc1ccccc1Cl)c1ccccc1

Procedure:
A solution of acetophenone (130 ml), 2-chloroaniline (130 ml) and benzene (200 ml) was refluxed in the presence of molecular sieve with continuous removal of water. o-Chloro-N-(α-methyl benzylidene) aniline (XXI) was obtained by fractional distillation. XXI had a boiling point of 111° C. at 0.1 millimeter.
Reaction SMILES: [CH3:1][C:2]1([CH3:15])[CH2:11][CH2:10][CH2:9][C:8]2[CH:7]=[C:6]([C:12](Cl)=[O:13])[CH:5]=[CH:4][C:3]1=2.[OH:16][C:17]1[CH:26]=[C:25]([C:27]#[C:28][Si](C)(C)C)[CH:24]=[CH:23][C:18]=1[C:19]([O:21][CH3:22])=[O:20]>>[OH:16][C:17]1[CH:26]=[C:25]([C:27]#[C:28][C:12](=[O:13])[C:6]2[CH:5]=[CH:4][C:3]3[C:2]([CH3:15])([CH3:1])[CH2:11][CH2:10][CH2:9][C:8]=3[CH:7]=2)[CH:24]=[CH:23][C:18]=1[C:19]([O:21][CH3:22])=[O:20]
Reactant: CC1(C)CCCc2cc(C(=O)Cl)ccc21
Reactant: COC(=O)c1ccc(C#C[Si](C)(C)C)cc1O
Product: COC(=O)c1ccc(C#CC(=O)c2ccc3c(c2)CCCC3(C)C)cc1O

Procedure:
In a similar manner to Example 14(a), by reaction of 4.7 g (21 mmol) of 5,5-dimethyl-5,6,7,8-tetrahydro-2-naphthoyl chloride with 5.7 g (22.8 mmol) of methyl 2-hydroxy-4-trimethylsilylethynylbenzoate (prepared in Example 5(a) of patent EP 0,661,258), 5.14 g (68.5%) of the expected methyl ester are obtained, with a melting point of 89-90° C.
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6](=[O:22])[N:7]3[C:14]4[CH:15]=[C:16]([O:19][CH2:20][CH3:21])[CH:17]=[CH:18][C:13]=4[NH:12][C:8]3=[N:9]2)=[CH:4][CH:3]=1.Br[CH2:24][CH2:25][CH2:26][C:27]([O:29][CH2:30][CH3:31])=[O:28]>>[C:27]([CH2:26][CH2:25][CH2:24][N:12]1[C:8]2=[N:9][C:10]3[C:5]([C:6](=[O:22])[N:7]2[C:14]2[CH:15]=[C:16]([O:19][CH2:20][CH3:21])[CH:17]=[CH:18][C:13]1=2)=[CH:4][CH:3]=[C:2]([CH3:1])[CH:11]=3)([O:29][CH2:30][CH3:31])=[O:28]
Reactant: CCOC(=O)CCCBr
Reactant: CCOc1ccc2[nH]c3nc4cc(C)ccc4c(=O)n3c2c1
Product: CCOC(=O)CCCn1c2ccc(OCC)cc2n2c(=O)c3ccc(C)cc3nc12

Procedure:
6-(Carboethoxypropyl)-3-methyl-9-ethoxybenzimidazo[2,1-b]quinazolin-12(6H)one is prepared with 3-methyl-9-ethoxybenzimidazo[2,1-b]quinazolin-12(6H)one and ethyl 4-bromobutyrate.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][N:6]=[C:5]([S:9][C:10]2[CH:11]=[C:12]([CH:16]=[CH:17][CH:18]=2)[C:13](O)=[O:14])[CH:4]=1)#[N:2].[BH4-].[Na+].O>S(Cl)(Cl)=O.O1CCOCC1>[OH:14][CH2:13][C:12]1[CH:11]=[C:10]([S:9][C:5]2[CH:4]=[C:3]([CH:8]=[CH:7][N:6]=2)[C:1]#[N:2])[CH:18]=[CH:17][CH:16]=1
Reactant: N#Cc1ccnc(Sc2cccc(C(=O)O)c2)c1
Agent: [BH4-]
Agent: [Na+]
Solvent: O=S(Cl)Cl
Solvent: O
Solvent: C1COCCO1
Product: N#Cc1ccnc(Sc2cccc(CO)c2)c1
Temperature: 50 °C
Reaction time: 2 h
Yield: 43.5 %

Procedure:
Dissolve 3-(4-cyano-pyridin-2-ylsulfanyl)-benzoic acid (920 mg, 3.59 mmol) in thionyl chloride (50 mL) and stir. Heat to reflux. After 2 hours, concentrate under reduced pressure to give a residue. Dissolve residue in dioxane (100 mL) and add sodium borohydride (1.36 g, 35.9 mmol). Heat to 50° C. After 2 hours, cool to ambient temperature and add water. Extract with ethyl acetate, combine organic layers, dry with sodium sulfate, filter and concentrate to give the title compound as a yellow oil (378 mg, 44%): 1H NMR (DMSO-d6) δ 4.56 (d, 2H), 5.31 (t, 1H), 7.38 (m, 1H), 7.48 (m, 3H), 7.55 (m, 1H), 7.59 (dd, 1H), 8.62 (dd, 1H).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]1[C:10]([CH3:11])=[N:9]1>C1(C)C(C)=CC=CC=1>[Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]2[C:3]=1[CH:8]=[C:10]([CH3:11])[NH:9]2
Reactant: CC1=NC1c1ccccc1Br
Solvent: Cc1ccccc1C
Product: Cc1cc2c(Br)cccc2[nH]1
Yield: 75.4 %

Procedure:
The solution of 2-(2-bromophenyl)-3-methyl-2H-azirine (758 mg, 3.61 mmol) in xylene (20 mL) was stirred at 160° C. for 7 d. The reaction mixture was concentrated in vacuo. The residue was purified by SiO2 chromatography eluting with petroleum ether/EtOAc (10:1) to afford 4-bromo-2-methyl-1H-indole as yellow oil (572 mg, 75.5%). MS (ESI): m/z=210.1 [M+1]+.