Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1(=[O:35])[N:5]([C@H:6]2[C@@H:9](/[CH:10]=[CH:11]/[C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[N:8]([CH2:18][C:19]3[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][C:20]=3[O:27][CH3:28])[C:7]2=[O:29])[C:4](=[O:30])[C:3]2=[CH:31][CH:32]=[CH:33][CH:34]=[C:2]12.[H][H]>O1CCCC1.[Pd]>[C:4]1(=[O:30])[N:5]([C@H:6]2[C@@H:9]([CH2:10][CH2:11][C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=3)[N:8]([CH2:18][C:19]3[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][C:20]=3[O:27][CH3:28])[C:7]2=[O:29])[C:1](=[O:35])[C:2]2=[CH:34][CH:33]=[CH:32][CH:31]=[C:3]12
Reactant: COc1ccc(CN2C(=O)[C@@H](N3C(=O)c4ccccc4C3=O)[C@H]2/C=C/c2ccccc2)c(OC)c1
Reactant: [H][H]
Agent: [Pd]
Solvent: C1CCOC1
Product: COc1ccc(CN2C(=O)[C@@H](N3C(=O)c4ccccc4C3=O)[C@H]2CCc2ccccc2)c(OC)c1
Yield: 95.6 %

Procedure:
In 150 ml of tetrahydrofuran is dissolved 5 g of cis-3-phthalimido-4-(E)-styryl-1-(2,4-dimethoxybenzyl)-2-oxoazetidine, followed by addition of 2.5 g of 10% palladium-on-carbon. The mixture is stirred in a hydrogen atmosphere for 30 minutes. The catalyst is filtered off and the filtrate is concentrated under reduced pressure. The residue is crystallized from ether and recovered by filtration to give 4.8 g of cis-3-phthalimido-4-(2-phenylethyl)-1-(2,4-dimethoxybenzyl)-2-oxoazetidine, m.p. 148°-150° C.
Reaction SMILES: Br[CH2:2][C:3]1[N:4]([CH3:28])[C:5]2[C:10]([N:11]=1)=[C:9]([N:12]1[CH2:17][CH2:16][O:15][CH2:14][CH2:13]1)[N:8]=[C:7]([N:18]1[C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=3[N:20]=[C:19]1[CH3:27])[N:6]=2.[NH2:29][CH:30]1[CH2:35][CH2:34][N:33]([C:36](=[O:38])[CH3:37])[CH2:32][CH2:31]1>>[CH3:28][N:4]1[C:3]([CH2:2][NH:29][CH:30]2[CH2:35][CH2:34][N:33]([C:36](=[O:38])[CH3:37])[CH2:32][CH2:31]2)=[N:11][C:10]2[C:5]1=[N:6][C:7]([N:18]1[C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=3[N:20]=[C:19]1[CH3:27])=[N:8][C:9]=2[N:12]1[CH2:17][CH2:16][O:15][CH2:14][CH2:13]1
Reactant: Cc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(CBr)n(C)c2n1
Reactant: CC(=O)N1CCC(N)CC1
Product: CC(=O)N1CCC(NCc2nc3c(N4CCOCC4)nc(-n4c(C)nc5ccccc54)nc3n2C)CC1

Procedure:
4-(8-(Bromomethyl)-9-methyl-2-(2-methyl-1H-benzo[d]imidazol-1-yl)-9H-purin-6-yl)morpholine (50 mg) was reacted with 1-(4-aminopiperidin-1-yl)ethanone via General Procedure E to give 19.6 mg of 286 following reverse phase purification. MS (Q1) 504.3 (M)+
Reaction SMILES: [C:1]([C:3]1[CH:8]=[C:7]([N+:9]([O-:11])=[O:10])[CH:6]=[CH:5][C:4]=1[N:12]=[CH:13][N:14](C)C)#[N:2].N[C:18]1[CH:19]=[C:20]([C:24]#[CH:25])[CH:21]=[CH:22][CH:23]=1>CC(O)=O>[C:24]([C:20]1[CH:19]=[C:18]([NH:2][C:1]2[C:3]3[C:4](=[CH:5][CH:6]=[C:7]([N+:9]([O-:11])=[O:10])[CH:8]=3)[N:12]=[CH:13][N:14]=2)[CH:23]=[CH:22][CH:21]=1)#[CH:25]
Reactant: CN(C)C=Nc1ccc([N+](=O)[O-])cc1C#N
Reactant: C#Cc1cccc(N)c1
Solvent: CC(=O)O
Product: C#Cc1cccc(Nc2ncnc3ccc([N+](=O)[O-])cc23)c1
Temperature: 100 °C
Reaction time: 3 h
Yield: 92.5 %

Procedure:
A mixture of N′-(2-cyano-4-nitrophenyl)-N,N-dimethylformamidine (1.00 g, 4.58 mmol) and 3-aminophenylacetylene (0.64 g, 5.49 mmol) in HOAc (15 mL) was stirred at 100° C. for 3 h and cooled to room temperature. The precipitate was filtered, washed with ether, and was dried in vacuo to give 1.23 g (93%) of N-(3-ethynylphenyl)-6-nitroquinazolin-4-amine as a yellow solid.
Reaction SMILES: [N:1]1([C:7]2[NH:11][C:10]3[CH:12]=[C:13]([C:16]([F:19])([F:18])[F:17])[CH:14]=[CH:15][C:9]=3[N:8]=2)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[Cl:20][C:21]1[CH:28]=[CH:27][CH:26]=[C:25]([Cl:29])[C:22]=1[CH2:23]Br.C([O-])(O)=O.[Na+].O>CN(C=O)C>[Cl:20][C:21]1[CH:28]=[CH:27][CH:26]=[C:25]([Cl:29])[C:22]=1[CH2:23][N:4]1[CH2:5][CH2:6][N:1]([C:7]2[NH:11][C:10]3[CH:12]=[C:13]([C:16]([F:19])([F:17])[F:18])[CH:14]=[CH:15][C:9]=3[N:8]=2)[CH2:2][CH2:3]1
Reactant: FC(F)(F)c1ccc2nc(N3CCNCC3)[nH]c2c1
Reactant: Clc1cccc(Cl)c1CBr
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: FC(F)(F)c1ccc2nc(N3CCN(Cc4c(Cl)cccc4Cl)CC3)[nH]c2c1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A mixture of the benzoimidazole from step (a) above (96 mg, 0.36 mmol), 2,6-dichlorobenzyl bromide (86 mg, 0.36 mmol, Aldrich) and NaHCO3 (151 mg, 1.8 mmol) in DMF (2 mL) was stirred at room temperature for 16 h. Water (10 mL) was then added and the mixture was extracted with EtOAc (2×20 mL). The combined organic phases were washed with water (5 mL) and brine (5 mL) then dried over Na2SO4 and filtered. The solvent was removed in vacuo and the residue purified by silica gel chromatography, eluting with 40% EtOAc/hexane. The material was recrystallized from EtOAc/hexanes to give the title compound as a white solid. M.p. 254-256° C. MS (ESI, pos. ion) m/z: 429 (M+1).
Reaction SMILES: C(N1C=CN=C1)([N:3]1C=CN=C1)=O.[CH3:13][N:14]1[C:20](=[O:21])[C:19]2[S:22][CH:23]=[CH:24][C:18]=2[N:17]2[CH:25]=[N:26][C:27]([C:28]([OH:30])=O)=[C:16]2[CH2:15]1.N>CN(C)C=O>[CH3:13][N:14]1[C:20](=[O:21])[C:19]2[S:22][CH:23]=[CH:24][C:18]=2[N:17]2[CH:25]=[N:26][C:27]([C:28]([NH2:3])=[O:30])=[C:16]2[CH2:15]1
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: CN1Cc2c(C(=O)O)ncn2-c2ccsc2C1=O
Agent: N
Solvent: CN(C)C=O
Product: CN1Cc2c(C(N)=O)ncn2-c2ccsc2C1=O
Temperature: 25 °C
Yield: 86.8 %

Procedure:
5.66 g (34.9 mmol) of 1,1'-carbonyldiimidazole were added portionwise to a suspension of 8.8 g (33.4 mmol) of 5-methyl-6-oxo-5,6-dihydro-4H-imidazo[1,5-a]thieno[2,3-f][1,4]diazepin-3-carboxylic acid (EP 150 040 A2) in 80 ml of dimethylformamide. The resulting pale brown solution was heated to 50° for 45 minutes. Subsequently, the solution was cooled to room temperature and 8.1 ml of aqueous ammonia solution were added dropwise thereto. After a further 30 minutes the reaction mixture was poured into 100 ml of ice-water and the resulting precipitate was filtered off and rinsed with water, ethanol and subsequently with ether. After drying at 70°/10 Torr there were obtained 7.6 g (86%) of 5-methyl-6-oxo-5,6-dihydro-4H-imidazo[1,5-a]thieno[2,3-f][1,4]diazepin-3-carboxamide as colourless crystals of m.p. 294°-296°.
Reaction SMILES: C([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH:15]2[CH:20]([CH2:21][CH3:22])[CH:19]([CH3:23])[CH:18]([CH2:24][O:25][Si](C)(C)C)[CH2:17][C:16]2([C:31]2[CH:36]=[CH:35][C:34]([O:37][CH2:38][CH2:39][N:40]3[CH2:45][CH2:44][CH2:43][CH2:42][CH2:41]3)=[CH:33][CH:32]=2)O)=[CH:11][CH:10]=1)C1C=CC=CC=1>C(Cl)Cl.C(OCC)(=O)C.Cl[Ti](Cl)(Cl)Cl>[CH2:21]([CH:20]1[C:15]([C:12]2[CH:13]=[CH:14][C:9]([OH:8])=[CH:10][CH:11]=2)=[C:16]([C:31]2[CH:32]=[CH:33][C:34]([O:37][CH2:38][CH2:39][N:40]3[CH2:41][CH2:42][CH2:43][CH2:44][CH2:45]3)=[CH:35][CH:36]=2)[CH2:17][CH:18]([CH2:24][OH:25])[CH:19]1[CH3:23])[CH3:22]
Reactant: CCC1C(C)C(CO[Si](C)(C)C)CC(O)(c2ccc(OCCN3CCCCC3)cc2)C1c1ccc(OCc2ccccc2)cc1
Agent: Cl[Ti](Cl)(Cl)Cl
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CCC1C(c2ccc(O)cc2)=C(c2ccc(OCCN3CCCCC3)cc2)CC(CO)C1C

Procedure:
To a solution of 2-(4-benzyloxy-phenyl)-3-ethyl-4-methyl-1-[4-(2-piperidin-1-yl-ethoxy)-phenyl]-5-trimethylsilanyloxy methyl-cyclohexanol in DCM (1 mL) was added TiCl4 (0.033 mL, 3 eq.) and the mixture stirred until reaction was done. The reaction mixture was diluted with ethyl acetate (10 mL), and washed with 5% NaHCO3 aqueous solution, then brine. The crude products was purified on HPLC to yield 4-{6-ethyl-4-hydroxymethyl-5-methyl-2-[4-(2-piperidin-1-yl-ethoxy)-phenyl]-cyclohex-1-enyl}-phenol.
Reaction SMILES: C(OC([N:11]1[CH2:15][CH:14]2[CH2:16][CH:17]([CH2:19][O:20][C:21]3[CH:30]=[C:29]4[C:24]([C:25]([O:31][C:32]5[CH:37]=[CH:36][C:35]([N+:38]([O-:40])=[O:39])=[CH:34][C:33]=5[F:41])=[CH:26][CH:27]=[N:28]4)=[CH:23][C:22]=3[O:42][CH3:43])[CH2:18][CH:13]2[CH2:12]1)=O)C1C=CC=CC=1.Br>C(O)(=O)C.CCOC(C)=O>[F:41][C:33]1[CH:34]=[C:35]([N+:38]([O-:40])=[O:39])[CH:36]=[CH:37][C:32]=1[O:31][C:25]1[C:24]2[C:29](=[CH:30][C:21]([O:20][CH2:19][CH:17]3[CH2:18][CH:13]4[CH2:12][NH:11][CH2:15][CH:14]4[CH2:16]3)=[C:22]([O:42][CH3:43])[CH:23]=2)[N:28]=[CH:27][CH:26]=1
Reactant: COc1cc2c(Oc3ccc([N+](=O)[O-])cc3F)ccnc2cc1OCC1CC2CN(C(=O)OCc3ccccc3)CC2C1
Agent: Br
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: COc1cc2c(Oc3ccc([N+](=O)[O-])cc3F)ccnc2cc1OCC1CC2CNCC2C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 113 %

Procedure:
To a round bottom flask equipped with a magnetic stir bar was added 5-[4-(2-Fluoro-4-nitro-phenoxy)-6-methoxy-quinolin-7-yloxymethyl]-hexahydrocyclopenta-[c]pyrrole-2-carboxylic acid benzyl ester (2.5 g, 4.1 mmol, 1.0 eq), 33% HBr in acetic acid (5 ml) and acetic acid (5 ml). The mixture was stirred at room temperature for 1 hour and diluted with EtOAc to give a pale orange solid. The solid was filtered, washed with EtOAc and dried, giving 4-(2-Fluoro-4-nitro-phenoxy)-6-methoxy-7-(octahydro-cyclopenta[c]pyrrol-5-ylmethoxy)-quinoline (2.1 g, 95% yield). 1H NMR (400 MHz, CDCl3): 8.83 (d, 1H), 8.32 (m, 2H), 8.02 (s, 1H), 7.76 (t, 1H), 7.65 (s, 1H), 6.89 (d, 1H), 5.3 (d, 2H), 4.11 (m, 3H), 3.26 (m, 4H), 2.95 (m, 2H), 2.68 (m, 3H), 2.36 (m, 2H), 1.68 (m, 2H); MS (EI) for C24H24FN3O5: 454 (M+H+).
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[O:7][C:8]([CH3:42])=[C:9]([CH2:11][O:12][C:13]2[CH:39]=[CH:38][C:16]([CH2:17][O:18][C:19]3[C:23](/[CH:24]=[C:25]4/[C:26](=[O:31])[NH:27][C:28](=[O:30])[S:29]/4)=[CH:22][N:21]([C:32]4[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=4)[N:20]=3)=[CH:15][C:14]=2[O:40][CH3:41])[N:10]=1.[CH3:43]N(C)C=O.[H-].[Na+].CI>O>[O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[O:7][C:8]([CH3:42])=[C:9]([CH2:11][O:12][C:13]2[CH:39]=[CH:38][C:16]([CH2:17][O:18][C:19]3[C:23](/[CH:24]=[C:25]4/[C:26](=[O:31])[N:27]([CH3:43])[C:28](=[O:30])[S:29]/4)=[CH:22][N:21]([C:32]4[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=4)[N:20]=3)=[CH:15][C:14]=2[O:40][CH3:41])[N:10]=1
Reactant: CN(C)C=O
Reactant: COc1cc(COc2nn(-c3ccccc3)cc2/C=C2\SC(=O)NC2=O)ccc1OCc1nc(-c2ccco2)oc1C
Agent: [H-]
Agent: [Na+]
Solvent: CI
Solvent: O
Product: COc1cc(COc2nn(-c3ccccc3)cc2/C=C2\SC(=O)N(C)C2=O)ccc1OCc1nc(-c2ccco2)oc1C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 92 %

Procedure:
To a mixture of (5Z)-5-({3-[(4-{[2-(2-furyl)-5-methyl-1,3-oxazol-4-yl]methoxy}-3-methoxybenzyl)oxy]-1-phenyl-1H-pyrazol-4-yl}methylene)-1,3-thiazolidine-2,4-dione (0.50 g) and N,N-dimethylformamide (10 mL) was added sodium hydride (60% in oil, 0.040 g) at room temperature. After stirring the reaction mixture at room temperature for 30 min, methyl iodide (0.16 g) was added, and the mixture was further stirred at room temperature for 30 hrs. The reaction mixture was poured into water, and the precipitated crystals were collected by filtration to give (5Z)-5-({3-[(4-{[2-(2-furyl)-5-methyl-1,3-oxazol-4-yl]methoxy}-3-methoxybenzyl)oxy]-1-phenyl-1H-pyrazol-4-yl}methylene)-3-methyl-1,3-thiazolidine-2,4-dione as yellow crystals (0.47 g, yield 92%). Recrystallization from tetrahydrofuran-hexane gave yellow prism crystals. melting point: 215-216° C.
Reaction SMILES: C1(O[C:8]2[CH:9]=[C:10]3[C:14](=[CH:15][CH:16]=2)[NH:13][CH:12]=[C:11]3[CH2:17][C@H:18]2[CH2:22][CH2:21][CH2:20][N:19]2[CH3:23])CCCCC1.[CH2:24](OC(N1CCC[C@@H]1C(C1C2C(=CC=C(OC3CCCCC3)C=2)NC=1)=O)=O)C1C=CC=CC=1>>[CH3:24][C:8]1[CH:9]=[C:10]2[C:14](=[CH:15][CH:16]=1)[NH:13][CH:12]=[C:11]2[CH2:17][C@H:18]1[CH2:22][CH2:21][CH2:20][N:19]1[CH3:23]
Reactant: O=C(c1c[nH]c2ccc(OC3CCCCC3)cc12)[C@H]1CCCN1C(=O)OCc1ccccc1
Reactant: CN1CCC[C@@H]1Cc1c[nH]c2ccc(OC3CCCCC3)cc12
Product: Cc1ccc2[nH]cc(C[C@H]3CCCN3C)c2c1

Procedure:
(R)-5-Cyclohexyloxy-3-(1-methyl-2-pyrrolidinylmethyl)-1H-indole: from (R)-3-[(N-benzyloxycarbonylpyrrolidin-2-yl)carbonyl]-5-cyclohexyloxy-1H-indole (Example 2g).
Reaction SMILES: Br[CH2:2][C:3]1[C:8]2[N:9]=[C:10]([C:12]3[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=3)[S:11][C:7]=2[CH:6]=[C:5]([O:20][CH3:21])[CH:4]=1.[C-:22]#[N:23].[K+]>C(O)C.O>[C:22]([CH2:2][C:3]1[C:8]2[N:9]=[C:10]([C:12]3[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=3)[S:11][C:7]=2[CH:6]=[C:5]([O:20][CH3:21])[CH:4]=1)#[N:23]
Reactant: COc1ccc(-c2nc3c(CBr)cc(OC)cc3s2)cc1
Reactant: [C-]#N
Agent: [K+]
Solvent: CCO
Solvent: O
Product: COc1ccc(-c2nc3c(CC#N)cc(OC)cc3s2)cc1
Temperature: 25 °C
Yield: 72.4 %

Procedure:
To a solution of 4-bromomethyl-6-methoxy-2-(4-methoxy-phenyl)-benzothiazole (0.47 g, 1.29 mmol) in ethanol (6 mL) was added a solution of potassium cyanide (0.1 g, 1.54 mmol) in water (0.5 mL). The mixture was refluxed for 1.5 h, then cooled to room temperature. Ethanol was evaporated and the mixture was extracted with ethylacetate. After chromatographic purification gave 4-cyanomethyl-6-methoxy-2-(4-methoxy-phenyl)-benzothiazole as a yellow solid (0.29 g, 73% yield). Mass spec: MH+=311.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]2[CH:18]=[C:17]3[C:12]([C:13]([OH:26])=[C:14]([C:21]([O:23]CC)=O)[C:15](=[O:20])[N:16]3[CH3:19])=[N:11][CH:10]=2)=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH3:34][S:35]([C:38]1[CH:43]=[CH:42][C:41]([CH2:44][CH2:45][NH2:46])=[CH:40][CH:39]=1)(=[O:37])=[O:36]>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][C:9]2[CH:18]=[C:17]3[C:12]([C:13]([OH:26])=[C:14]([C:21]([NH:46][CH2:45][CH2:44][C:41]4[CH:40]=[CH:39][C:38]([S:35]([CH3:34])(=[O:37])=[O:36])=[CH:43][CH:42]=4)=[O:23])[C:15](=[O:20])[N:16]3[CH3:19])=[N:11][CH:10]=2)=[CH:6][CH:7]=1
Reactant: CCOC(=O)c1c(O)c2ncc(Cc3ccc(F)cc3)cc2n(C)c1=O
Reactant: CS(=O)(=O)c1ccc(CCN)cc1
Solvent: CCN(CC)CC
Product: Cn1c(=O)c(C(=O)NCCc2ccc(S(C)(=O)=O)cc2)c(O)c2ncc(Cc3ccc(F)cc3)cc21
Yield: 25.7 %

Procedure:
In a similar manner to that described in example 196, from ethyl 7-[(4-fluorophenyl)methyl]-4-hydroxy-1-methyl-2-oxo-1,2-dihydro-1,5-naphthyridine-3-carboxylate (30 mg, 0.084 mmol) described in example 92, triethylamine (0.5 mL, 4.08 mmol), and {2-[4-(methylsulfonyl)phenyl]ethyl}amine (250 mg, 1.25 mmol), was prepared 7-[(4-fluorophenyl)methyl]-4-hydroxy-1-methyl-N-{2-[4-(methylsulfonyl)phenyl]ethyl}-2-oxo-1,2-dihydro-1,5-naphthyridine-3-carboxamide (11 mg, 26% yield) as a white solid after purification by reverse phase HPLC. 1H NMR (CDCl3) δ 10.28 (br s, 1 H), 8.56 (s, 1 H), 7.87 (d, J=8 Hz, 2 H), 7.44 (d, J=8 Hz, 2 H), 7.38 (s, 1 H), 7.16-7.14 (m, 2 H), 7.04-6.99 (m, 2 H), 4.13 (s, 2 H), 3.72 (m, 2 H), 3.56 (s, 3 H), 3.06-3.02 (m, 5 H); HRMS m/z calcd for: C26H25FN3O5S: 510.1493. Found: 510.1498.
Reaction SMILES: [N:1]([CH2:4][CH2:5][C:6]1[C:14]2[C:9](=[CH:10][C:11]([Cl:16])=[C:12]([CH3:15])[CH:13]=2)[NH:8][C:7]=1[Si](CC)(CC)CC)=[N+]=[N-].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>CO.[F-].C([N+](CCCC)(CCCC)CCCC)CCC.C1COCC1>[Cl:16][C:11]1[CH:10]=[C:9]2[C:14]([C:6]([CH2:5][CH2:4][NH2:1])=[CH:7][NH:8]2)=[CH:13][C:12]=1[CH3:15]
Reactant: CC[Si](CC)(CC)c1[nH]c2cc(Cl)c(C)cc2c1CCN=[N+]=[N-]
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CO
Solvent: C1CCOC1
Product: Cc1cc2c(CCN)c[nH]c2cc1Cl

Procedure:
2-(6-chloro-5-methyl-1H-indol-3-yl)ethanamine was prepared according to method D Step V with 3-(2-azidoethyl)-6-chloro-5-methyl-2-(triethylsilyl)-1H-indole (0.654 g; 1.87 mmol) and triphenylphosphine (0.737 g; 2.81 mmol) in methanol (10 mL) and tetrabutylamonium fluoride (5.62 mL 1M) in THF (stirred for 36 hours).
Reaction SMILES: [CH:1]1([C:7]2[CH:28]=[CH:27][C:10]([C:11]([N:13]3[C:19]4[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=4[CH2:17][N:16]4[CH:24]=[CH:25][CH:26]=[C:15]4[CH2:14]3)=[O:12])=[CH:9][CH:8]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[Cl:29][C:30]([Cl:35])([Cl:34])[C:31](Cl)=[O:32]>ClCCl>[Cl:29][C:30]([Cl:35])([Cl:34])[C:31]([C:24]1[N:16]2[C:15]([CH2:14][N:13]([C:11](=[O:12])[C:10]3[CH:27]=[CH:28][C:7]([CH:1]4[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]4)=[CH:8][CH:9]=3)[C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=3[CH2:17]2)=[CH:26][CH:25]=1)=[O:32]
Reactant: O=C(Cl)C(Cl)(Cl)Cl
Reactant: O=C(c1ccc(C2CCCCC2)cc1)N1Cc2cccn2Cc2ccccc21
Solvent: ClCCl
Product: O=C(c1ccc(C2CCCCC2)cc1)N1Cc2ccc(C(=O)C(Cl)(Cl)Cl)n2Cc2ccccc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 58.2 %

Procedure:
To a solution of 10-(4-cyclohexylbenzoyl)-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine of Example 4 (1.85 g) in dichloromethane (50 mL) was added trichloroacetyl chloride (1 g). After stirring overnight at room temperature, the mixture was washed with saturated aqueous sodium bicarbonate, dried over anhydrous sodium sulfate, and filtered through a short column of Magnesol®. After eluting with several additional volumes of dichloromethane, the eluate was combined and refluxed with gradual addition of hexane until crystallization was observed. The title compound (1.5 g) was obtained upon cooling, as colorless crystals, m.p. 172–174° C.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][N:3]=1.[CH2:12]([NH:19][C:20]([C:22]1[S:26][C:25](Br)=[N:24][C:23]=1[CH3:28])=[O:21])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>>[CH2:12]([NH:19][C:20]([C:22]1[S:26][C:25]([N:3]2[CH:4]=[C:5]([C:8]([F:9])([F:11])[F:10])[CH:6]=[CH:7][C:2]2=[O:1])=[N:24][C:23]=1[CH3:28])=[O:21])[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: Oc1ccc(C(F)(F)F)cn1
Reactant: Cc1nc(Br)sc1C(=O)NCc1ccccc1
Product: Cc1nc(-n2cc(C(F)(F)F)ccc2=O)sc1C(=O)NCc1ccccc1
Yield: 60 %

Procedure:
Following the procedure as described in Example 3, making variations only as required to use 2-hydroxy-5-(trifluoromethyl)pyridine in place of 4-aminopyridin-2(1H)-one to react with N-benzyl-2-bromo-4-methylthiazole-5-carboxamide, the title compound was obtained as a white solid in 60% yield: mp 148-149° C.; 1H NMR (300 MHz, CDCl3) δ 9.19 (br s, 1H), 7.53 (dd, J=9.6, 2.7 Hz, 1H), 7.37-7.25 (m, 5H), 6.78 (d, J=9.6 Hz, 1H), 6.27 (t, J=5.7 Hz, 1H), 4.58 (d, J=5.7 Hz, 2H), 2.69 (s, 3H); 13C NMR (75 MHz, CDCl3) δ 161.7, 159.6, 152.4, 151.9, 137.6, 135.2, 131.1, 128.8, 127.9, 124.6, 124.5, 122.1, 121.1, 111.8, 44.2, 17.2; MS (ES+) m/z 394.2 (M+1).
Reaction SMILES: [NH2:1][C:2]1[C:3]([O:18][CH3:19])=[CH:4][C:5]2[CH2:11][N:10]([CH2:12][CH3:13])[CH2:9][C:8](=[O:14])[N:7]([CH2:15][CH3:16])[C:6]=2[CH:17]=1.Cl[C:21]1[N:26]=[C:25]([NH:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=2[S:34]([N:37]([CH3:39])[CH3:38])(=[O:36])=[O:35])[C:24]([Cl:40])=[CH:23][N:22]=1>>[Cl:40][C:24]1[C:25]([NH:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=2[S:34]([N:37]([CH3:39])[CH3:38])(=[O:36])=[O:35])=[N:26][C:21]([NH:1][C:2]2[C:3]([O:18][CH3:19])=[CH:4][C:5]3[CH2:11][N:10]([CH2:12][CH3:13])[CH2:9][C:8](=[O:14])[N:7]([CH2:15][CH3:16])[C:6]=3[CH:17]=2)=[N:22][CH:23]=1
Reactant: CCN1CC(=O)N(CC)c2cc(N)c(OC)cc2C1
Reactant: CN(C)S(=O)(=O)c1ccccc1Nc1nc(Cl)ncc1Cl
Product: CCN1CC(=O)N(CC)c2cc(Nc3ncc(Cl)c(Nc4ccccc4S(=O)(=O)N(C)C)n3)c(OC)cc2C1

Procedure:
The title compound was prepared from 8-Amino-1,4-diethyl-7-methoxy-1,3,4,5-tetrahydro-benzo[e][1,4]diazepin-2-one and 2-(2,5-Dichloro-pyrimidin-4-ylamino)-N,N-dimethyl-benzenesulfonamide in an analogous manner to example 730 (0.042 g, 34%). Mp 195-197° C.; LCMS (m/e) 574 (M); 1H-NMR (DMSO, 400 MHz) δ 9.27 (s, 1H), 8.30 (s, 2H), 7.86 (s, 1H), 7.80-7.78 (d, 1H, J=7.83 Hz), 7.50-7.43 (t, 1H, J=9.18 Hz), 7.30-7.26 (t, 1H, J=7.58 Hz), 7.07 (s, 1H), 3.84 (s, 1H), 3.51 (s, 3H), 2.96 (s, 2H), 2.65 (s, 1H), 2.59-2.53 (q, 2H, J=7.08 Hz), 1.08-1.05 (t, 3H, J=7.33 Hz), 0.90-0.86 (t, 3H, J=6.83 Hz).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([C:13]2[S:17][C:16]([C:18]3[C:19]([CH2:34][CH3:35])=[C:20]([CH2:24][CH2:25][N:26]4[CH2:29][CH:28]([C:30]([O:32]C)=[O:31])[CH2:27]4)[CH:21]=[CH:22][CH:23]=3)=[N:15][N:14]=2)[CH:6]=[CH:7][C:8]=1[CH2:9][CH:10]([CH3:12])[CH3:11])#[N:2].[OH-].[Na+].Cl>C(O)(C)C.O>[C:1]([C:3]1[CH:4]=[C:5]([C:13]2[S:17][C:16]([C:18]3[C:19]([CH2:34][CH3:35])=[C:20]([CH2:24][CH2:25][N:26]4[CH2:29][CH:28]([C:30]([OH:32])=[O:31])[CH2:27]4)[CH:21]=[CH:22][CH:23]=3)=[N:15][N:14]=2)[CH:6]=[CH:7][C:8]=1[CH2:9][CH:10]([CH3:11])[CH3:12])#[N:2]
Reactant: CCc1c(CCN2CC(C(=O)OC)C2)cccc1-c1nnc(-c2ccc(CC(C)C)c(C#N)c2)s1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC(C)O
Product: CCc1c(CCN2CC(C(=O)O)C2)cccc1-c1nnc(-c2ccc(CC(C)C)c(C#N)c2)s1
Temperature: 25 °C
Reaction time: 1 h
Yield: 29.7 %

Procedure:
To a solution of methyl 1-[2-(3-{5-[3-cyano-4-(2-methylpropyl)phenyl]-1,3,4-thiadiazol-2-yl}-2-ethylphenyl)ethyl]-3-azetidinecarboxylate (D32) (59 mg) in isopropanol (3 mL) and water (3 mL) was added sodium hydroxide (50 mg). The reaction mixture was stirred at room temperature for 1 h. The reaction mixture was neutralized with 1 M HCl solution. The solvent was removed in vacuo. The residue was dissolved in THF, and filtered. The filtrate was purified by Mass Directed AutoPrep to give 1-[2-(3-{5-[3-cyano-4-(2-methylpropyl)phenyl]-1,3,4-thiadiazol-2-yl}-2-ethylphenyl)ethyl]-3-azetidinecarboxylic acid (E10) (17 mg) as an off-white solid. δH (DMSO-d6, 400 MHz): 0.93 (6H, d), 1.11 (3H, t), 1.99 (1H, m), 2.85 (6H, m), 3.38 (2H, m), 3.61 (1H, m), 4.27 (4H, m), 7.40 (1H, m), 7.51 (2H, t), 7.68 (1H, d), 8.31 (1H, dd), 8.46 (1H, d), 13.04 (1H, br s). MS (ES): C27H30N4O2S requires 474. found 475.2 (M+H+).
Reaction SMILES: [Cl:1][C:2]1[CH:19]=[CH:18][C:5]([C:6]([NH:8][C:9]2[S:10][CH:11]=[C:12]([CH2:14][C:15]([OH:17])=O)[N:13]=2)=[O:7])=[CH:4][CH:3]=1.Cl.Cl.[NH:22]1[CH2:27][CH2:26][CH:25]([O:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][N:30]=2)[CH2:24][CH2:23]1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([NH:8][C:9]2[S:10][CH:11]=[C:12]([CH2:14][C:15](=[O:17])[N:22]3[CH2:27][CH2:26][CH:25]([O:28][C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][N:30]=4)[CH2:24][CH2:23]3)[N:13]=2)=[O:7])=[CH:18][CH:19]=1
Reactant: O=C(O)Cc1csc(NC(=O)c2ccc(Cl)cc2)n1
Reactant: c1ccc(OC2CCNCC2)nc1
Agent: Cl
Product: O=C(Nc1nc(CC(=O)N2CCC(Oc3ccccn3)CC2)cs1)c1ccc(Cl)cc1

Procedure:
In analogy to example 1.3, [2-(4-chloro-benzoylamino)-thiazol-4-yl]-acetic acid (example 1.2) was coupled with 2-(piperidin-4-yloxy)-pyridine dihydrochloride (CAS 313490-36-7) to give 4-chloro-N-(4-{2-oxo-2-[4-(pyridin-2-yloxy)-piperidin-1-yl]-ethyl}-thiazol-2-yl)-benzamide, using general procedure C. White amorphous solid. MS 457.6 ([M+H]+)
Reaction SMILES: [CH:1]1([O:7][C:8]2[CH:9]=[C:10]([C@@H:14]([NH:16]C(=O)OC(C)(C)C)[CH3:15])[CH:11]=[CH:12][CH:13]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.O1CCOCC1.[ClH:30]>>[CH:1]1([O:7][C:8]2[CH:9]=[C:10]([C@@H:14]([NH2:16])[CH3:15])[CH:11]=[CH:12][CH:13]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[ClH:30]
Reactant: C[C@H](NC(=O)OC(C)(C)C)c1cccc(OC2CCCCC2)c1
Agent: Cl
Solvent: C1COCCO1
Product: C[C@H](N)c1cccc(OC2CCCCC2)c1
Reaction time: 1 h

Procedure:
(S)-tert-butyl 1-(3-(cyclohexyloxy)phenyl)ethylcarbamate (74.1 mg, 0.232 mmol) was dissolved in 4M HCl in dioxane (1 ml, 4.00 mmol) and the resulting mixture was allowed to sit for 1 hour, then concentrated to yield (S)-1-(3-(cyclohexyloxy)phenyl)ethanamine as an HCl salt (yield assumed quantitative). LCMS m/z 220.1 (M+H)+, Rt 0.66 min.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][C:14]([OH:16])=[O:15])=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.[CH2:18](N=C=NCCCN(C)C)C>C(Cl)(Cl)Cl.CO.CN(C)C1C=CN=CC=1>[C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][C:14]([O:16][CH3:18])=[O:15])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)NCCCCCC(=O)O
Reactant: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClC(Cl)Cl
Solvent: CO
Product: COC(=O)CCCCCNC(=O)OC(C)(C)C
Reaction time: 2 h

Procedure:
1.28 Grams of 6-{(tert-butoxycarbonyl)amino}hexanoic acid was dissolved in a liquid mixture of 9 ml of chloroform and 3 ml of methanol. To the solution 1.27 g of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide monohydrochloride and 7 mg of 4-dimethylaminopyridine were successively added at room temperature, followed by 2 hours' stirring at the same temperature. The reaction liquid was diluted with chloroform, washed successively with saturated aqueous sodium bicarbonate solution and saturated aqueous ammonium chloride solution, and dried over anhydrous sodium sulfate. Distilling the solvent off under reduced pressure, 1.03 g of the title compound was obtained.