Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(=O)([O-])[O-].[Na+].[Na+].CC(C)CC(=O)C.[CH3:14][O:15][CH2:16][C:17]1([N:23]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[C:24](=[O:27])[CH2:25][CH3:26])[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]1.[C:34]1([CH2:44][CH2:45]OS(C2C=CC(C)=CC=2)(=O)=O)[C:43]2[C:38](=[CH:39][CH:40]=[CH:41][CH:42]=2)[CH:37]=[CH:36][CH:35]=1>O>[CH3:14][O:15][CH2:16][C:17]1([N:23]([C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=2)[C:24](=[O:27])[CH2:25][CH3:26])[CH2:22][CH2:21][N:20]([CH2:45][CH2:44][C:34]2[C:43]3[C:38](=[CH:39][CH:40]=[CH:41][CH:42]=3)[CH:37]=[CH:36][CH:35]=2)[CH2:19][CH2:18]1
Reactant: Cc1ccc(S(=O)(=O)OCCc2cccc3ccccc23)cc1
Reactant: CCC(=O)N(c1ccccc1)C1(COC)CCNCC1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)CC(C)C
Product: CCC(=O)N(c1ccccc1)C1(COC)CCN(CCc2cccc3ccccc23)CC1
Temperature: 25 °C
Yield: 43.4 %

Procedure:
A mixture of 6.4 parts of sodium carbonate and 120 parts of 4-methyl-2-pentanone is stirred and refluxed with water-separator. Then there are added 4.1 parts of N-[4-(methoxymethyl)-4-piperidinyl]-N-phenylpropanamide and 5.5 parts of [2-(1-naphthalenyl)ethyl]4-methylbenzenesulfonate and the whole is stirred and refluxed for 20 hours. The reaction mixture is cooled to room temperature and poured onto water. The organic phase is separated, washed with water, dried, filtered and evaporated. The oily residue is purified by column-chromatography over silica gel using a mixture of trichloromethane and 7% of methanol as eluent. The pure fractions are collected and the eluent is evaporated. The oily residue solidifies on triturating in hexane. The product is filtered off and crystallized from a small amount of 2,2'-oxybispropane, yielding 2.8 parts (43.4%) of N-{4-(methoxymethyl)-1-[2-(1-naphthalenyl)ethyl]-4-piperidinyl}-N-phenylpropanamide; mp. 109.8° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[C:12]([CH:14]3[CH2:16][CH2:15]3)[N:11]3[N:17]=[CH:18][C:19]([C:20]#[CH:21])=[C:10]3[N:9]=2)=[CH:4][CH:3]=1.Br[C:23]1[CH:24]=[C:25]([S:29]([NH:32][C:33]([CH3:37])([CH3:36])[CH2:34][OH:35])(=[O:31])=[O:30])[CH:26]=[CH:27][CH:28]=1>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[C:12]([CH:14]3[CH2:16][CH2:15]3)[N:11]3[N:17]=[CH:18][C:19]([C:20]#[C:21][C:23]4[CH:24]=[C:25]([S:29]([NH:32][C:33]([CH3:37])([CH3:36])[CH2:34][OH:35])(=[O:30])=[O:31])[CH:26]=[CH:27][CH:28]=4)=[C:10]3[N:9]=2)=[CH:4][CH:3]=1
Reactant: C#Cc1cnn2c(C3CC3)cc(-c3ccc(Cl)cc3)nc12
Reactant: CC(C)(CO)NS(=O)(=O)c1cccc(Br)c1
Product: CC(C)(CO)NS(=O)(=O)c1cccc(C#Cc2cnn3c(C4CC4)cc(-c4ccc(Cl)cc4)nc23)c1

Procedure:
The title compound was prepared from 5-(4-chloro-phenyl)-7-cyclopropyl-3-ethynyl-pyrazolo[1,5-a]pyrimidine (example C.5) (118 mg, 0.4 mmol) and 3-bromo-N-(2-hydroxy-1,1-dimethyl-ethyl)-benzenesulfonamide (148 mg, 0.48 mmol) (example B.6) according to general procedure II. Obtained as a yellow solid (46 mg, 22%). MS (ISP) 521.5 [(M+H)+]; mp 202-204° C.
Reaction SMILES: [CH3:1][C:2]1[CH2:6][CH:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[NH:4][N:3]=1.N>[Ni].CO>[CH3:1][CH:2]([NH2:3])[CH2:6][CH:5]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[NH2:4]
Reactant: CC1=NNC(c2ccccc2)C1
Agent: [Ni]
Agent: N
Solvent: CO
Product: CC(N)CC(N)c1ccccc1

Procedure:
160 g (1 mol) of 3-methyl-5-phenyl-2-pyrazoline (according to S. G. Beech et al, J. Chem. Soc. (1952) 4,686-90) are hydrogenated with 20 g of freshly prepared Raney nickel in 400 ml of methanol saturated with NH3 for 6 hours at 80° C./100 atmospheres. The catalyst is separated off, the solvent is removed in a rotary evaporator and the product is distilled under a high vacuum. Fractionation of the distillate in a 25 cm Vigreux column gives 151 g=92% of theory of a colourless oil with a boiling point under 0.03 mm of 90°-91° C. C10H16N2 . (164.24)
Reaction SMILES: [Br:1][C:2]1[C:24]([CH3:25])=[CH:23][C:5]2[N:6]([CH:10]3[CH2:15][CH2:14][N:13](C(OC(C)(C)C)=O)[CH2:12][CH2:11]3)[C:7](=[O:9])[NH:8][C:4]=2[CH:3]=1.FC(F)(F)C(O)=O>ClCCl>[Br:1][C:2]1[C:24]([CH3:25])=[CH:23][C:5]2[N:6]([CH:10]3[CH2:11][CH2:12][NH:13][CH2:14][CH2:15]3)[C:7](=[O:9])[NH:8][C:4]=2[CH:3]=1
Reactant: Cc1cc2c(cc1Br)[nH]c(=O)n2C1CCN(C(=O)OC(C)(C)C)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1cc2c(cc1Br)[nH]c(=O)n2C1CCNCC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 87.9 %

Procedure:
1,1-Dimethylethyl 4-(5-bromo-6-methyl-2-oxo-2,3-dihydro-1H-benzimidazol-1-yl)-1-piperidinecarboxylate (D36) (1.32 mmol, 541 mg) was dissolved in dichloromethane (5 mL), trifluoroacetic acid (5 mL) added and the mixture stirred under argon at room temperature for 1 h. The reaction mixture was concentrated under reduced pressure, Na2CO3 (10% aqueous solution) added and the product extracted with ethyl acetate (×3). The organic layers were combined, dried (MgSO4) and the solvent removed under reduced pressure to afford the product as a yellow solid (1.16 mmol, 359 mg, 88%)
Reaction SMILES: C([O-])(=O)C.C([O-])(=O)C.C([O-])(=O)C.[Cl:13][C:14]1[CH:15]=[C:16]([Pb+3])[CH:17]=[CH:18][C:19]=1[Cl:20].[OH:22][C:23]1[C:32]2[C:27](=[N:28][CH:29]=[CH:30][N:31]=2)[NH:26][C:25](=[O:33])[CH:24]=1>CN(C)C1C=CN=CC=1.CS(C)=O.C(OCC)(=O)C>[Cl:13][C:14]1[CH:15]=[C:16]([C:24]2[C:25](=[O:33])[NH:26][C:27]3=[N:28][CH:29]=[CH:30][N:31]=[C:32]3[C:23]=2[OH:22])[CH:17]=[CH:18][C:19]=1[Cl:20]
Reactant: Clc1ccc([Pb+3])cc1Cl
Reactant: O=c1cc(O)c2nccnc2[nH]1
Agent: CC(=O)[O-]
Agent: CN(C)c1ccncc1
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: O=c1[nH]c2nccnc2c(O)c1-c1ccc(Cl)c(Cl)c1
Temperature: 60 °C
Reaction time: 16 h
Yield: 27.1 %

Procedure:
A mixture of 3,4-dichlorophenyl lead triacetate (1.63 g), 8-hydroxy-5H-pyrido[2,3-b]pyrazin-6-one (0.254 g) and 4-dimethylaminopyridine (DMAP) (0.549 g) in anhydrous dimethylsulfoxide (10 mL) under a nitrogen atmosphere was heated to 60° C. for four hours. The reaction mixture was then allowed to cool to ambient temperature and stored at ambient temperature for 16 hours. The reaction mixture was diluted with ethyl acetate. The mixture was washed with aqueous hydrochloric acid (1M) and water, and the organic layer concentrated to give 7-(3,4-dichlorophenyl)-8-hydroxy-5H-pyrido[2,3-b]pyrazin-6-one (0.13 g) which was used without further purification.
Reaction SMILES: [N+:1]([C:4]1[C:5]([NH:11][CH2:12][C:13]2[S:14][C:15]3[CH:20]=[CH:19][N:18]=[CH:17][C:16]=3[N:21]=2)=[N:6][C:7]([Cl:10])=[CH:8][CH:9]=1)([O-])=O>CO.C1COCC1.[Pd]>[Cl:10][C:7]1[N:6]=[C:5]([NH:11][CH2:12][C:13]2[S:14][C:15]3[CH:20]=[CH:19][N:18]=[CH:17][C:16]=3[N:21]=2)[C:4]([NH2:1])=[CH:9][CH:8]=1
Reactant: O=[N+]([O-])c1ccc(Cl)nc1NCc1nc2cnccc2s1
Agent: [Pd]
Solvent: CO
Solvent: C1CCOC1
Product: Nc1ccc(Cl)nc1NCc1nc2cnccc2s1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
10% Pd/C (20 mg) was added to a solution of 3-nitro-6-chloro-N-(thiazolo[4,5-c]pyridin-2-ylmethyl)pyridin-2-amine (100 mg, 0.31 mmol) in MeOH (2 mL) and THF (10 mL). The mixture was stirred at room temperature under 1 atm of H2 for 1 h, and then filtered. The filtrate was concentrated and purified by chromatography on silica gel to afford the title compound. MS (m/z): 292 (M+1)+.
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:36])=[C:4]([C@@H:8]2[C@:12]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=3[F:22])([C:13]#[N:14])[C@H:11]([CH2:23][C:24]([CH3:27])([CH3:26])[CH3:25])[CH2:10][N:9]2[C:28]([NH:30][CH2:31][CH2:32][C:33]([OH:35])=O)=[O:29])[CH:5]=[CH:6][CH:7]=1.[CH3:37][NH2:38]>>[CH3:37][NH:38][C:33]([CH2:32][CH2:31][NH:30][C:28]([N:9]1[CH2:10][CH:11]([CH2:23][C:24]([CH3:25])([CH3:27])[CH3:26])[C:12]([C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=2[F:22])([C:13]#[N:14])[CH:8]1[C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[C:3]=1[F:36])=[O:29])=[O:35]
Reactant: CC(C)(C)C[C@@H]1CN(C(=O)NCCC(=O)O)[C@H](c2cccc(Cl)c2F)[C@@]1(C#N)c1ccc(Cl)cc1F
Reactant: CN
Product: CNC(=O)CCNC(=O)N1CC(CC(C)(C)C)C(C#N)(c2ccc(Cl)cc2F)C1c1cccc(Cl)c1F
Yield: 69.9 %

Procedure:
In a manner similar to the method described in Example 59, a mixture of rac-3-{[(2S,3S,4S)-2-(3-chloro-2-fluoro-phenyl)-3-(4-chloro-2-fluoro-phenyl)-3-cyano-4-(2,2-dimethyl-propyl)-pyrrolidine-1-carbonyl]-amino}-propionic acid (24 mg, 0.0446 mmole, example 73) was reacted with a solution of methylamine (0.05 mL, 2M in THF, 0.10 mmol, Aldrich) to give rac-(2S,3S,4S)-2-(3-chloro-2-fluoro-phenyl)-3-(4-chloro-2-fluoro-phenyl)-3-cyano-4-(2,2-dimethyl-propyl)-pyrrolidine-1-carboxylic acid (2-methylcarbamoyl-ethyl)-amide (17.2 mg, 70%) as a white solid. HRMS (ES+) m/z Calcd for C27H30Cl2F2N4O2+H [(M+H)+]: 551.1787; Found: 551.1789.
Reaction SMILES: [F:1][C:2]1[CH:22]=[CH:21][C:5]2[S:6][C:7]([C:10]3[N:14]4[N:15]=[C:16]([CH3:19])[CH:17]=[CH:18][C:13]4=[N:12][C:11]=3[CH3:20])=[C:8]([CH3:9])[C:4]=2[CH:3]=1.[CH3:23][O:24][N:25]([CH3:31])[C:26](=O)[O:27]CC.[Li+].CC([N-]C(C)C)C>C1COCC1>[CH3:23][O:24][N:25]([CH3:31])[C:26]([C:18]1[C:13]2[N:14]([C:10]([C:7]3[S:6][C:5]4[CH:21]=[CH:22][C:2]([F:1])=[CH:3][C:4]=4[C:8]=3[CH3:9])=[C:11]([CH3:20])[N:12]=2)[N:15]=[C:16]([CH3:19])[CH:17]=1)=[O:27]
Reactant: CCOC(=O)N(C)OC
Reactant: Cc1ccc2nc(C)c(-c3sc4ccc(F)cc4c3C)n2n1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: CON(C)C(=O)c1cc(C)nn2c(-c3sc4ccc(F)cc4c3C)c(C)nc12
Temperature: -78 °C
Reaction time: 1 h
Yield: 31.7 %

Procedure:
The solution of 3-(5-fluoro-3-methyl-benzo[b]thiophen-2-yl)-2,6-dimethyl-imidazo[1,2-b]pyridazine (2.09 g, 6.73 mmol) in THF (56 mL) is stirred at −78° C. Ethyl N-methoxy-N-methylcarbamate (4.48 g, 33.7 mmol) is added. LDA (10 mL, 20.1 mmol) is added dropwise to maintain reaction temperature at −75° C. The reaction is stirred at −78° C. for 1 hour. The mixture is quenched with H2O, filtered through celite with CH2Cl2. The collect solution is washed with H2O, dried over Na2SO4, filtered and concentrated. The crude is purified by ISCO (50-100% EtOAc/Hexane) to give the title compound (0.85 g, 31%). 1H NMR (CDCl3): δ 7.8 (dd, J=4.8, 8.5 Hz, 1H), 7.5 (dd, J=2.5, 9.7 Hz, 1H), 7.2 (m, 1H), 7.0 (s, 1H), 3.7 (s, 3H), 3.5 (s, 3H), 2.6 (s, 3H), 2.55 (s, 3H), 2.3 (s, 3H) ppm. MS (m/e): 399 (100%, M+1).
Reaction SMILES: [NH2:1][C:2]1[C:11]2[N:12]=[C:13]([CH2:31][CH2:32][O:33][CH3:34])[N:14]([CH2:15][CH2:16][CH2:17][NH:18][CH2:19][C:20]3[CH:25]=[CH:24][C:23]([CH2:26][C:27]([O:29][CH3:30])=[O:28])=[CH:22][CH:21]=3)[C:10]=2[C:9]2[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=2[N:3]=1.[N:35]1([CH2:41][CH2:42][C:43](O)=[O:44])[CH2:40][CH2:39][CH2:38][CH2:37][CH2:36]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CO>CN(C=O)C>[NH2:1][C:2]1[C:11]2[N:12]=[C:13]([CH2:31][CH2:32][O:33][CH3:34])[N:14]([CH2:15][CH2:16][CH2:17][N:18]([CH2:19][C:20]3[CH:21]=[CH:22][C:23]([CH2:26][C:27]([O:29][CH3:30])=[O:28])=[CH:24][CH:25]=3)[C:43](=[O:44])[CH2:42][CH2:41][N:35]3[CH2:40][CH2:39][CH2:38][CH2:37][CH2:36]3)[C:10]=2[C:9]2[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=2[N:3]=1
Reactant: COCCc1nc2c(N)nc3ccccc3c2n1CCCNCc1ccc(CC(=O)OC)cc1
Reactant: O=C(O)CCN1CCCCC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CO
Solvent: CN(C)C=O
Product: COCCc1nc2c(N)nc3ccccc3c2n1CCCN(Cc1ccc(CC(=O)OC)cc1)C(=O)CCN1CCCCC1
Reaction time: 2 h
Yield: 11.5 %

Procedure:
To the product from step (v) of example 29 (480 mg, 1.04 mmol) in DMF (5 mL), 3-(piperidin-1-yl)propanoic acid (196 mg, 1.25 mmol) and HATU (475 mg, 1.25 mmol) were added at rt and stirred for 2 hours. After adding 1 mL of methanol, the crude product was purified by RPHPLC and the resulting residue was triturated with diethyl ether: EtOAc (5:1). The suspension was filtered to afford the title compound as a white solid (72 mg).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6](/[C:9](=[N:15]/[O:16][CH2:17][C:18]2[CH:23]=[CH:22][C:21]([O:24][CH2:25][C:26]3[N:27]=[C:28]([C:32]4[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=4)[O:29][C:30]=3[CH3:31])=[CH:20][CH:19]=2)/[C:10]([O:12]CC)=[O:11])=[CH:5][CH:4]=1.Cl>O1CCCC1.CO.[OH-].[Na+]>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6](/[C:9](=[N:15]/[O:16][CH2:17][C:18]2[CH:23]=[CH:22][C:21]([O:24][CH2:25][C:26]3[N:27]=[C:28]([C:32]4[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=4)[O:29][C:30]=3[CH3:31])=[CH:20][CH:19]=2)/[C:10]([OH:12])=[O:11])=[CH:5][CH:4]=1
Reactant: CCOC(=O)/C(=N\OCc1ccc(OCc2nc(-c3ccccc3)oc2C)cc1)c1ccc(OC)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: COc1ccc(/C(=N/OCc2ccc(OCc3nc(-c4ccccc4)oc3C)cc2)C(=O)O)cc1
Yield: 90 %

Procedure:
Ethyl Z-2-(4-methoxyphenyl)-2-[4-(5-methyl-2-phenyl-4-oxazolylmethoxy)benzyloxyimino]acetate (1.20 g) was dissolved in tetrahydrofuran (5 ml)-methanol (10 ml), and 0.5N aqueous solution of sodium hydroxide (10 ml) was added and the mixture was heated under reflux for 1 hour. 1N HCl (5.5 ml) was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated aqueous sodium chloride, dried (MgSO4) and then concentrated. The residual crystal was recrystallized from ethyl acetate to obtain Z-2-(4-methoxyphenyl)-2-[4-(5-methyl-2-phenyl-4-oxazolylmethoxy)benzyloxyimino]acetic acid (1.02 g, yield 90%) as colorless crystals. m.p. 183-184° C.
Reaction SMILES: [Si:1]([O:8][C@@H:9]([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[C:31]1[CH:36]=[CH:35][C:34]([Cl:37])=[CH:33][CH:32]=1)[CH:10]1[CH2:15][CH2:14][N:13]([C:16]2[CH:24]=[CH:23][C:19]([C:20](O)=[O:21])=[CH:18][CH:17]=2)[CH2:12][CH2:11]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[Si:38]([O:55][CH2:56][C@H:57]1[N:62]([CH2:63][CH2:64][C@@H:65]([NH:74][C:75]2[CH:80]=[CH:79][C:78]([S:81]([NH2:84])(=[O:83])=[O:82])=[CH:77][C:76]=2[S:85]([C:88]([F:91])([F:90])[F:89])(=[O:87])=[O:86])[CH2:66][S:67][C:68]2[CH:73]=[CH:72][CH:71]=[CH:70][CH:69]=2)[CH2:61][CH2:60][O:59][CH2:58]1)([C:51]([CH3:54])([CH3:53])[CH3:52])([C:45]1[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=1)[C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1.C(Cl)CCl>C(Cl)Cl.CN(C1C=CN=CC=1)C>[Si:1]([O:8][C@@H:9]([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[C:31]1[CH:36]=[CH:35][C:34]([Cl:37])=[CH:33][CH:32]=1)[CH:10]1[CH2:15][CH2:14][N:13]([C:16]2[CH:24]=[CH:23][C:19]([C:20]([NH:84][S:81]([C:78]3[CH:79]=[CH:80][C:75]([NH:74][C@H:65]([CH2:64][CH2:63][N:62]4[CH2:61][CH2:60][O:59][CH2:58][C@H:57]4[CH2:56][O:55][Si:38]([C:51]([CH3:52])([CH3:53])[CH3:54])([C:45]4[CH:46]=[CH:47][CH:48]=[CH:49][CH:50]=4)[C:39]4[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=4)[CH2:66][S:67][C:68]4[CH:73]=[CH:72][CH:71]=[CH:70][CH:69]=4)=[C:76]([S:85]([C:88]([F:89])([F:90])[F:91])(=[O:86])=[O:87])[CH:77]=3)(=[O:83])=[O:82])=[O:21])=[CH:18][CH:17]=2)[CH2:12][CH2:11]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: CC(C)(C)[Si](OC[C@@H]1COCCN1CC[C@H](CSc1ccccc1)Nc1ccc(S(N)(=O)=O)cc1S(=O)(=O)C(F)(F)F)(c1ccccc1)c1ccccc1
Reactant: CC(C)(C)[Si](C)(C)O[C@@H](c1ccccc1-c1ccc(Cl)cc1)C1CCN(c2ccc(C(=O)O)cc2)CC1
Agent: CN(C)c1ccncc1
Solvent: ClCCCl
Solvent: ClCCl
Product: CC(C)(C)[Si](C)(C)O[C@@H](c1ccccc1-c1ccc(Cl)cc1)C1CCN(c2ccc(C(=O)NS(=O)(=O)c3ccc(N[C@H](CCN4CCOC[C@H]4CO[Si](c4ccccc4)(c4ccccc4)C(C)(C)C)CSc4ccccc4)c(S(=O)(=O)C(F)(F)F)c3)cc2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 253 %

Procedure:
To a solution of (R)-4-(4-((tert-butyldimethylsilyloxy)(4′-chlorobiphenyl-2-yl)methyl)piperidin-1-yl)benzoic acid (INTERMEDIATE 13, 183 mg, 0.34 mmol) in DCM (3 ml) were added sequentially DMAP (125 mg, 1.02 mmol), 4-((R)-4-((S)-3-((tert-butyldiphenylsilyloxy)methyl)morpholino)-1-(phenylthio)butan-2-ylamino)-3-(trifluoromethylsulfonyl)benzenesulfonamide (INTERMEDIATE 105, 280 mg, 0.34 mmol) and EDC (131 mg, 0.68 mmol). The resulting solution was stirred at room temperature overnight. Evaporation of the volatiles under reduced pressure gave a residue which was purified by column chromatography (ISCO, 27 g silica gel column, eluting with 0→20% EtOAc/hexanes) to give 4-(4-((R)-(tert-butyldimethylsilyloxy)(4′-chlorobiphenyl-2-yl)methyl)piperidin-1-yl)-N-(4-((R)-4-((S)-3-((tert-butyldiphenylsilyloxy)methyl)morpholino)-1-(phenylthio)butan-2-ylamino)-3-(trifluoromethylsulfonyl)phenylsulfonyl)benzamide (EXAMPLE 24, STEP 1,153 mg) which was used in the preparation of EXAMPLE 24, STEP 2 without further purification.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][N:5]=[CH:4][C:3]=1[C:8]1[S:9][CH:10]=[C:11]([C:13]2[CH:14]=[C:15]([CH:19]=[CH:20][CH:21]=2)[C:16]([OH:18])=O)[N:12]=1.S(Cl)(Cl)=O.[CH2:26]([NH2:28])[CH3:27]>>[CH2:26]([NH:28][C:16](=[O:18])[C:15]1[CH:19]=[CH:20][CH:21]=[C:13]([C:11]2[N:12]=[C:8]([C:3]3[CH:4]=[N:5][CH:6]=[CH:7][C:2]=3[CH3:1])[S:9][CH:10]=2)[CH:14]=1)[CH3:27]
Reactant: Cc1ccncc1-c1nc(-c2cccc(C(=O)O)c2)cs1
Reactant: CCN
Solvent: O=S(Cl)Cl
Product: CCNC(=O)c1cccc(-c2csc(-c3cnccc3C)n2)c1

Procedure:
By the reaction in the same manner as in Example 60 using 3-[2-(4-methylpyridin-3-yl)-1,3-thiazol-4-yl]benzoic acid (259 mg), thionyl chloride (0.09 ml) and aqueous ethylamine solution (70%, 5 ml), the title compound (215 mg) was obtained as pale-brown powder crystals.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7]2[S:13][C:12]3[CH:14]=[CH:15][CH:16]=[CH:17][C:11]=3[NH:10][C:9](=O)[C:8]=2[CH:19]=1)([O-:3])=[O:2].P12(SP3(SP(SP(S3)(S1)=S)(=S)S2)=S)=[S:21].O>C1(C)C=CC=CC=1>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]2[S:13][C:12]3[CH:14]=[CH:15][CH:16]=[CH:17][C:11]=3[NH:10][C:9](=[S:21])[C:8]=2[CH:19]=1)([O-:3])=[O:2]
Reactant: O=C1Nc2ccccc2Sc2ccc([N+](=O)[O-])cc21
Reactant: S=P12SP3(=S)SP(=S)(S1)SP(=S)(S2)S3
Solvent: O
Solvent: Cc1ccccc1
Product: O=[N+]([O-])c1ccc2c(c1)C(=S)Nc1ccccc1S2
Reaction time: 8 h
Yield: 154.2 %

Procedure:
2-Nitro-10,11-dihydrodibenzo[b,f][1,4]thiazepin-11-one (0.27 g) was dissolved in toluene (20 ml). Phosphorus pentasulphide (0.22 g) was added to the solution and the whole was stirred under reflux for 4 hours, then cooled and left overnight. Addition of water (40 ml) and separation of the phases gave, after evaporation of the dried organic layer, a yellow solid which was purified by column chromatography on silica gel and recrystallisation from ethanol to give the product as yellow needles (0.22 g, m/s. M+ =288).
Reaction SMILES: [O:1]1[CH2:17][CH:2]1[CH2:3][O:4][C:5]1[C:14]2[CH2:13][CH2:12][CH2:11][CH2:10][C:9]=2[C:8]([CH:15]=[O:16])=[CH:7][CH:6]=1.[C:18]([NH2:22])([CH3:21])([CH3:20])[CH3:19]>>[C:18]([NH:22][CH2:17][CH:2]([OH:1])[CH2:3][O:4][C:5]1[C:14]2[CH2:13][CH2:12][CH2:11][CH2:10][C:9]=2[C:8]([CH:15]=[O:16])=[CH:7][CH:6]=1)([CH3:21])([CH3:20])[CH3:19]
Reactant: CC(C)(C)N
Reactant: O=Cc1ccc(OCC2CO2)c2c1CCCC2
Product: CC(C)(C)NCC(O)COc1ccc(C=O)c2c1CCCC2
Temperature: 45 °C

Procedure:
To 4-(2,3-epoxypropoxy)-5,6,7,8-tetrahydronapthaldehyde (2.4 gms) is added tert.-butylamine (15 ml.). The resulting solution is heated at 45° C. for 15 hours. The excess tert.-butylamine is removed at reduced pressure (20 mm). To the residue is added 30 ml. 6 N hydrochloride acid, and the resulting mixture is refluxed for three hours. The acidic mixture is poured into a saturated solution of sodium carbonate which is heated on a steam bath with nitrogen bubbling through it. The basic mixture is extracted with chloroform, which is dried over anhydrous sodium sulfate, filtered and concentrated to give 2.3 g of 4-(3-tert.butylamino-2-hydroxypropoxy)-5,6,7,8-tetrahydronapthaldehyde as an oil.
Reaction SMILES: [CH:1]([N:4]1[CH2:15][CH2:14][C:7]2([O:12][CH2:11][C:10](=O)[NH:9][CH2:8]2)[CH2:6][CH2:5]1)([CH3:3])[CH3:2].[F-].[Na+].O>C1COCC1>[CH:1]([N:4]1[CH2:5][CH2:6][C:7]2([O:12][CH2:11][CH2:10][NH:9][CH2:8]2)[CH2:14][CH2:15]1)([CH3:3])[CH3:2]
Reactant: CC(C)N1CCC2(CC1)CNC(=O)CO2
Agent: [F-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)N1CCC2(CC1)CNCCO2
Temperature: 25 °C
Reaction time: 1 h

Procedure:
9-Isopropyl-1-oxa-4,9-diaza-spiro[5.5]undecan-3-one was dissolved in THF and LiA1H4 (5 equivalents) was added. The reaction was heated at reflux for 4 hours and then cooled to room temperature. NaF (20 equivalents) and water (5 equivalents) were added and the reaction was stirred vigorously for 1 hour. The resulting precipitate was filtered away and the filtrate was concentrated to provide the title compound as a colorless oil. GC/MS (m/z) 198, Rt=12.57 minutes.
Reaction SMILES: O=[C:2]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[N:6]2[CH:13]=[N:14][C:15]([C:16]([O:18][CH2:19][CH3:20])=[O:17])=[C:5]2[C@@H:4]2[CH2:21][CH2:22][CH2:23][N:3]12.COC1C=CC(P2(=S)SP(=S)(C3C=CC(OC)=CC=3)[S:33]2)=CC=1>C1(C)C=CC=CC=1>[S:33]=[C:2]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[N:6]2[CH:13]=[N:14][C:15]([C:16]([O:18][CH2:19][CH3:20])=[O:17])=[C:5]2[C@@H:4]2[CH2:21][CH2:22][CH2:23][N:3]12
Reactant: CCOC(=O)c1ncn2c1[C@@H]1CCCN1C(=O)c1ccccc1-2
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Solvent: Cc1ccccc1
Product: CCOC(=O)c1ncn2c1[C@@H]1CCCN1C(=S)c1ccccc1-2

Procedure:
A mixture of 5.0 g (0.0161 mol) of ethyl (S)-11,12,13,13a-tetrahydro-9-oxo-9H-imidazo[1,5-a]pyrrolo[2,1-c][1,4]benzodiazepine-1-carboxylate and 3.46 g (0.0086 mol) of 2,4-bis(p-methoxyphenyl)-1,3,2,4-dithiadiphosphetane-2,4-disulphide is heated to boiling under reflux for 1.5 hours with 30 ml of toluene. This solution is chromatographed on silica gel using ethyl acetate for the elution. There is obtained ethyl (S)-11,12,13,13a-tetrahydro-9-thioxo-9H-imidazo[1,5-a]pyrrolo[2,1-c][1,4]benzodiazepine-1-carboxylate which is recrystallised from 180 ml of ethyl acetate and then melts at 227°-229° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([C:9](=[O:11])[CH3:10])=[C:4]([CH3:12])[CH:3]=1.[Br-:13].[Br-].[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.C([N+](CCCC)(CCCC)CCCC)CCC.C([N+](CCCC)(CCCC)CCCC)CCC>C(#N)C>[Br:13][CH2:10][C:9]([C:5]1[C:4]([CH3:12])=[CH:3][C:2]([Cl:1])=[CH:7][C:6]=1[CH3:8])=[O:11]
Reactant: CC(=O)c1c(C)cc(Cl)cc1C
Reactant: [Br-]
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Solvent: CC#N
Product: Cc1cc(Cl)cc(C)c1C(=O)CBr
Temperature: 25 °C
Reaction time: 8 h
Yield: 102 %

Procedure:
To a solution of 1-(4-chloro-2,6-dimethylphenyl)ethanone (5.0 g, 27 mmol) in acetonitrile (54.8 mL) was added tetrabutylammoniumtribromide (TBABr3, 13.2 g, 27.4 mmol). The reaction was stirred at room temperature overnight. The solution was concentrated under reduced pressure, added with water, and extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous MgSO4(s), and concentrated under reduced pressure to give 2-bromo-1-(4-chloro-2,6-dimethylphenyl)ethanone (7.2 g), which was used directly for the next step without further purification.
Reaction SMILES: [Br:1][C:2]1[C:8]([Br:9])=[CH:7][C:5]([NH2:6])=[C:4]([N+:10]([O-])=O)[CH:3]=1.[H][H]>[Ni].C(O)C>[Br:1][C:2]1[C:8]([Br:9])=[CH:7][C:5]([NH2:6])=[C:4]([NH2:10])[CH:3]=1
Reactant: Nc1cc(Br)c(Br)cc1[N+](=O)[O-]
Reactant: [H][H]
Agent: [Ni]
Solvent: CCO
Product: Nc1cc(Br)c(Br)cc1N
Reaction time: 0.42 h

Procedure:
Five grams of 4,5-dibromo-2-nitroaniline were suspended in 200 ml. of anhydrous ethanol to which was added about 10 g. of Raney Nickel. The hydrogenation mixture was placed in a low pressure hydrogenation apparatus at a hydrogen pressure of 55 psi. A rapid uptake of hydrogen occurred which ceased after about 25 minutes, at which time the deep yellow color originally present was discharged indicating complete reduction of the nitro group to an amine group. The hydrogenation was continued for another half hour and the hydrogenation mixture was then worked up by filtering off the catalyst, washing the filtered catalyst, and stripping the volatile constituents from the filtrate. A yield of 4.1 g. of 4,5-dibromo-o-phenylenediamine was obtained.
Reaction SMILES: [CH3:1][C:2]1[N:6]([C:7]2[CH:12]=[CH:11][C:10]([C:13]([F:16])([F:15])[F:14])=[CH:9][CH:8]=2)[N:5]=[CH:4][C:3]=1[C:17](Cl)=[O:18].[CH3:20][C:21]1[CH:22]=[C:23]([CH:25]=[CH:26][C:27]=1[N:28]1[CH2:33][CH2:32][CH:31]([N:34]2[CH2:39][CH2:38][O:37][CH2:36][CH2:35]2)[CH2:30][CH2:29]1)[NH2:24]>>[CH3:1][C:2]1[N:6]([C:7]2[CH:12]=[CH:11][C:10]([C:13]([F:16])([F:15])[F:14])=[CH:9][CH:8]=2)[N:5]=[CH:4][C:3]=1[C:17]([NH:24][C:23]1[CH:25]=[CH:26][C:27]([N:28]2[CH2:29][CH2:30][CH:31]([N:34]3[CH2:39][CH2:38][O:37][CH2:36][CH2:35]3)[CH2:32][CH2:33]2)=[C:21]([CH3:20])[CH:22]=1)=[O:18]
Reactant: Cc1c(C(=O)Cl)cnn1-c1ccc(C(F)(F)F)cc1
Reactant: Cc1cc(N)ccc1N1CCC(N2CCOCC2)CC1
Product: Cc1cc(NC(=O)c2cnn(-c3ccc(C(F)(F)F)cc3)c2C)ccc1N1CCC(N2CCOCC2)CC1
Yield: 60.4 %

Procedure:
By the reaction and treatment the same manner as in Example 150 using 5-methyl-1-(4-trifluoromethylphenyl) pyrazole-4-carboxylic chloride (1.0 g) and 3-methyl-4-(4-morpholinopiperidin-1-yl)aniline (0.95 g), the title compound (1.1 g) was obtained, melting point: 252–255° C.