Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][S:9]([C:12]1[S:16][C:15]2[CH:17]=[CH:18][CH:19]=[CH:20][C:14]=2[CH:13]=1)(=[O:11])=[O:10].[CH3:21][O:22][C:23]1[CH:28]=[C:27]([N+:29]([O-:31])=[O:30])[CH:26]=[CH:25][C:24]=1[S:32](Cl)(=[O:34])=[O:33]>C(Cl)Cl.N1C=CC=CC=1>[CH3:21][O:22][C:23]1[CH:28]=[C:27]([N+:29]([O-:31])=[O:30])[CH:26]=[CH:25][C:24]=1[S:32]([NH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][S:9]([C:12]1[S:16][C:15]2[CH:17]=[CH:18][CH:19]=[CH:20][C:14]=2[CH:13]=1)(=[O:11])=[O:10])(=[O:34])=[O:33]
Reactant: Nc1ccccc1NS(=O)(=O)c1cc2ccccc2s1
Reactant: COc1cc([N+](=O)[O-])ccc1S(=O)(=O)Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: COc1cc([N+](=O)[O-])ccc1S(=O)(=O)Nc1ccccc1NS(=O)(=O)c1cc2ccccc2s1
Temperature: 25 °C
Reaction time: 8 h
Yield: 67.9 %

Procedure:
To a solution of benzo[b]thiophene-2-sulfonic acid (2-amino-phenyl)-amide (1 mmol, prepared as in Example 1) in DCM (2 mL) and pyridine (2 mL), 2-methoxy-4-nitrobenzenesulfonyl chloride (1.1 mmol) was added at RT and the reaction mixture was then allowed to stir at RT overnight or until the reaction was complete as determined by TLC or LC-MS. The reaction mixture was then diluted with DCM (20 mL). The organic phase was washed with 10% aqueous HCl (20 mL), water (20 mL), and brine (20 mL). The organic phase was dried over anhydrous sodium sulfate and concentrated under vacuum. The residue obtained was purified by flash column chromatography eluting with DCM/EtOAc to yield 353 mg of benzo[b]thiophene-2-sulfonic acid [2-(2-methoxy-4-nitrobenzenesulfonylamino)phenyl]-amide. LC: Tr 1.21 min; MS: 520.7.7 (M+1)+. 1H NMR (CDCl3, 400 MHz): δ 4.24 (s, 3H), 6.72 (bs, 1H), 6.88 (d, 1H), 7.03 (t, 1H), 7.16 (t, 1H), 7.30 (d, 1H), 7.52 (t, 1H), 7.51 (t, 1H), 7.64 (s, 1H), 7.67-7.88 (m, 5H), 7.92 (s, 1H) ppm.
Reaction SMILES: [CH2:1]([O:8][N:9]([C@H:22]1[CH2:27][N:26]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[C@H:25]([CH2:35][O:36][Si](C(C)(C)C)(C)C)[CH:24]=[C:23]1[CH2:44][CH2:45][N+:46]([O-:48])=[O:47])[S:10]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[N+:19]([O-:21])=[O:20])(=[O:12])=[O:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(Cl)(=O)C>CO>[CH2:1]([O:8][N:9]([C@H:22]1[CH2:27][N:26]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[C@H:25]([CH2:35][OH:36])[CH:24]=[C:23]1[CH2:44][CH2:45][N+:46]([O-:48])=[O:47])[S:10]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[N+:19]([O-:21])=[O:20])(=[O:11])=[O:12])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)N1C[C@H](N(OCc2ccccc2)S(=O)(=O)c2ccccc2[N+](=O)[O-])C(CC[N+](=O)[O-])=C[C@H]1CO[Si](C)(C)C(C)(C)C
Solvent: CC(=O)Cl
Solvent: CO
Product: CC(C)(C)OC(=O)N1C[C@H](N(OCc2ccccc2)S(=O)(=O)c2ccccc2[N+](=O)[O-])C(CC[N+](=O)[O-])=C[C@H]1CO
Temperature: 0 °C
Reaction time: 3 h
Yield: 97.9 %

Procedure:
(2S,5R)-tert-butyl 5-(N-(benzyloxy)-2-nitrophenylsulfonamido)-2-((tert-butyldimethylsilyloxy)methyl)-4-(2-nitroethyl)-5,6-dihydropyridine-1(2H)-carboxylate (Intermediate 220, 5 g, 7.07 mmol) was taken up in methanol (150 mL) cooled to 0° C. and acetyl chloride (0.075 mL, 1.06 mmol) added. The reaction mixture was stirred for 3 hours at 0° C. The solvent was removed in vacuo and the residue was taken up in EtOAc, washed with saturated sodium bicarbonate, dried over Na2SO4, filtered and concentrated to afford the title compound as an oil (4.1 g, 98%).
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10]([NH2:12])=[S:11])=[CH:5][CH:4]=1.Br[CH2:16][C:17](=O)[C:18]([OH:20])=[O:19]>CO>[F:14][C:2]([F:1])([F:13])[C:3]1[CH:4]=[CH:5][C:6]([NH:9][C:10]2[S:11][CH:16]=[C:17]([C:18]([OH:20])=[O:19])[N:12]=2)=[CH:7][CH:8]=1
Reactant: O=C(O)C(=O)CBr
Reactant: NC(=S)Nc1ccc(C(F)(F)F)cc1
Solvent: CO
Product: O=C(O)c1csc(Nc2ccc(C(F)(F)F)cc2)n1
Yield: 95.5 %

Procedure:
2-(4-Trifluoromethyl-phenylamino)-thiazole-4-carboxylic acid (275 mg) was prepared according to General Procedure B using (4-trifluoromethyl-phenyl)-thiourea (220 mg) and 3-bromo-2-oxo-propionic acid (200 mg) in methanol (2 mL). The crude product was used in a subsequent step without further purification.
Reaction SMILES: [OH:1][C@H:2]([C:11]1[CH:20]=[CH:19][C:14]2[C:15](=[O:18])[O:16][CH2:17][C:13]=2[C:12]=1[CH3:21])[CH2:3][N:4]1[CH2:9][CH2:8][NH:7][C:6](=[O:10])[CH2:5]1.Br[C:23]1[CH:33]=[CH:32][C:26]2[CH:27]=[C:28]([C:30]#[N:31])[S:29][C:25]=2[CH:24]=1.CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2.C([O-])([O-])=O.[Cs+].[Cs+]>O1CCOCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[OH:1][C@H:2]([C:11]1[CH:20]=[CH:19][C:14]2[C:15](=[O:18])[O:16][CH2:17][C:13]=2[C:12]=1[CH3:21])[CH2:3][N:4]1[CH2:9][CH2:8][N:7]([C:23]2[CH:33]=[CH:32][C:26]3[CH:27]=[C:28]([C:30]#[N:31])[S:29][C:25]=3[CH:24]=2)[C:6](=[O:10])[CH2:5]1
Reactant: N#Cc1cc2ccc(Br)cc2s1
Reactant: Cc1c([C@@H](O)CN2CCNC(=O)C2)ccc2c1COC2=O
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Product: Cc1c([C@@H](O)CN2CCN(c3ccc4cc(C#N)sc4c3)C(=O)C2)ccc2c1COC2=O
Temperature: 120 °C

Procedure:
A mixture of 4-[(2R)-2-hydroxy-2-(4-methyl-1-oxo-1,3-dihydro-2-benzofuran-5-yl)ethyl]piperazin-2-one (50 mg, 0.17 mmol), 6-Bromo-1-benzothiophene-2-carbonitrile [I-11] (41 mg, 0.17 mmol), Pd2(dba)3 (32 mg, 0.034 mmol), Xantphos (40 mg, 0.069 mmol), and Cs2CO3 (84 mg, 0.26 mmol) in dioxane (1 mL) was sealed in a microwave tube and purged three times with nitrogen. It was heated to 120° C. for 20 minutes in a microwave reactor. LC showed formation of the desired product, which was purified by silica gel flash chromatography. LC-MS (IE, m/z): 448 [M+1]+.
Reaction SMILES: [F:1][C:2]([F:30])([F:29])[C@H:3]1[CH2:8][CH2:7][C@H:6]([C:9]([N:11]2[CH2:15][CH2:14][CH:13]([CH2:16][O:17][C:18]3[C:19]([C:24]([O:26]CC)=[O:25])=[N:20][CH:21]=[CH:22][CH:23]=3)[CH2:12]2)=[O:10])[CH2:5][CH2:4]1.COC1C=C(OC[C@H]2CCCN2C([C@H]2CC[C@H](C(F)(F)F)CC2)=O)C(C(OCC)=O)=NC=1>>[F:30][C:2]([F:1])([F:29])[C@H:3]1[CH2:8][CH2:7][C@H:6]([C:9]([N:11]2[CH2:15][CH2:14][CH:13]([CH2:16][O:17][C:18]3[C:19]([C:24]([OH:26])=[O:25])=[N:20][CH:21]=[CH:22][CH:23]=3)[CH2:12]2)=[O:10])[CH2:5][CH2:4]1
Reactant: CCOC(=O)c1ncccc1OCC1CCN(C(=O)[C@H]2CC[C@H](C(F)(F)F)CC2)C1
Agent: CCOC(=O)c1ncc(OC)cc1OC[C@H]1CCCN1C(=O)[C@H]1CC[C@H](C(F)(F)F)CC1
Product: O=C(O)c1ncccc1OCC1CCN(C(=O)[C@H]2CC[C@H](C(F)(F)F)CC2)C1

Procedure:
The title compound was prepared according to the procedure described in Step 4 of EXAMPLE 31 using ethyl 3-((1-(trans-4-(trifluoromethyl)cyclohexanecarbonyl)pyrrolidin-3-yl)methoxy)picolinate (EXAMPLE 92 Step 3) in stead of ethyl 5-methoxy-3-(((R)-1-(trans-4-(trifluoromethyl)cyclohexanecarbonyl)pyrrolidin-2-yl)methoxy)picolinate.
Reaction SMILES: [OH-].[Li+].C[O:4][C:5]([C:7]1[CH:44]=[CH:43][C:10]([CH2:11][CH:12](/[CH:25]=[CH:26]/[C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=2[O:33][CH2:34][CH2:35][CH2:36][N:37]2[CH2:41][CH2:40][CH2:39][C:38]2=[O:42])[CH2:13][CH2:14][C:15]2[CH:24]=[CH:23][C:18]([C:19]([O:21]C)=[O:20])=[CH:17][CH:16]=2)=[CH:9][CH:8]=1)=[O:6]>C1COCC1.O>[C:5]([C:7]1[CH:8]=[CH:9][C:10]([CH2:11][CH:12](/[CH:25]=[CH:26]/[C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=2[O:33][CH2:34][CH2:35][CH2:36][N:37]2[CH2:41][CH2:40][CH2:39][C:38]2=[O:42])[CH2:13][CH2:14][C:15]2[CH:24]=[CH:23][C:18]([C:19]([OH:21])=[O:20])=[CH:17][CH:16]=2)=[CH:43][CH:44]=1)([OH:6])=[O:4]
Reactant: COC(=O)c1ccc(CCC(/C=C/c2ccccc2OCCCN2CCCC2=O)Cc2ccc(C(=O)OC)cc2)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)c1ccc(CCC(/C=C/c2ccccc2OCCCN2CCCC2=O)Cc2ccc(C(=O)O)cc2)cc1
Temperature: 50 °C
Reaction time: 12 h

Procedure:
492 mg (20.5 mmol) of lithium hydroxide are added to a solution of 3.90 g (6.8 mmol) of methyl 4-[(4E)-3-[4-(methoxycarbonyl)benzyl]-5-{2-[3-(2-oxopyrrolidin-1-yl)propoxy]phenyl}pent-4-en-1-yl]benzoate (Example 21A) in 20 ml of THF and 20 ml of water, and the mixture is stirred at 50° C. for 12 h. The mixture is then cooled and extracted three times with ethyl acetate. The aqueous phase is then adjusted to pH 2 using 1 M hydrochloric acid and extracted three times with ethyl acetate. The latter organic phases are combined, washed with water and saturated sodium chloride solution and dried over sodium sulfate. After filtration, the solvent is removed to dryness. This gives 2.75 g (content 98%, 4.98 mmol, 73% of theory) of the title compound as a colorless solid.
Reaction SMILES: [CH2:1]([O:8][C:9]([C:11]1([C:14]([OH:16])=O)[CH2:13][CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CN1CCOCC1.S(Cl)(Cl)=O.[NH2:28][C:29]1[C:44]([F:45])=[CH:43][C:32]([O:33][C:34]2[CH:39]=[CH:38][N:37]=[C:36]([C:40]([NH2:42])=[O:41])[CH:35]=2)=[C:31]([F:46])[CH:30]=1>O1CCCC1>[NH2:42][C:40]([C:36]1[CH:35]=[C:34]([O:33][C:32]2[C:31]([F:46])=[CH:30][C:29]([NH:28][C:14]([C:11]3([C:9]([O:8][CH2:1][C:2]4[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=4)=[O:10])[CH2:12][CH2:13]3)=[O:16])=[C:44]([F:45])[CH:43]=2)[CH:39]=[CH:38][N:37]=1)=[O:41]
Reactant: O=C(O)C1(C(=O)OCc2ccccc2)CC1
Reactant: NC(=O)c1cc(Oc2cc(F)c(N)cc2F)ccn1
Solvent: O=S(Cl)Cl
Solvent: CN1CCOCC1
Solvent: C1CCOC1
Product: NC(=O)c1cc(Oc2cc(F)c(NC(=O)C3(C(=O)OCc4ccccc4)CC3)cc2F)ccn1
Reaction time: 0.25 h
Yield: 93.4 %

Procedure:
1-[(Benzyloxy)carbonyl]cyclopropanecarboxylic acid (1.04 g) was dissolved in tetrahydrofuran (15 ml) under a nitrogen atmosphere. N-Methylmorpholine (0.520 ml) was added at 0° C., and the mixture was stirred for 15 minutes. Thionyl chloride (0.345 ml) was added to the mixture at 0° C., and the mixture was stirred at the same temperature for 30 minutes. 4-(4-Amino-2,5-difluorophenoxy)pyridine-2-carboxamide (500 mg) and N-methylmorpholine (0.520 ml) was added, and the mixture was stirred at room temperature for 2 hours and 50 minutes. The reaction mixture was partitioned after the addition of a 1N aqueous solution of sodium hydroxide (15 ml) and ethyl acetate (20 ml). The organic layer was washed with a 1N aqueous solution of sodium hydroxide (15 ml), water (15 ml) and brine (15 ml), and dried over anhydrous magnesium sulfate. The desiccant was removed by filtration, and the filtrate was concentrated under reduced pressure. The resultant residue was purified by silica gel column chromatography (Fuji Silysia NH, eluent; heptane:ethyl acetate=1:1, then 1:2). The fractions containing the target compound was concentrated under reduced pressure to give the title compound (822.7 mg, 93%) as white powder.
Reaction SMILES: Br[C:2]1[CH:9]=[CH:8][C:5]([NH:6][CH3:7])=[C:4]([N+:10]([O-:12])=[O:11])[C:3]=1[F:13].[CH3:14][N:15]1[CH:20]=[C:19](B2OC(C)(C)C(C)(C)O2)[C:18]2[CH:30]=[CH:31][N:32]([CH2:33][O:34][CH2:35][CH2:36][Si:37]([CH3:40])([CH3:39])[CH3:38])[C:17]=2[C:16]1=[O:41]>>[F:13][C:3]1[C:4]([N+:10]([O-:12])=[O:11])=[C:5]([NH:6][CH3:7])[CH:8]=[CH:9][C:2]=1[C:19]1[C:18]2[CH:30]=[CH:31][N:32]([CH2:33][O:34][CH2:35][CH2:36][Si:37]([CH3:38])([CH3:40])[CH3:39])[C:17]=2[C:16](=[O:41])[N:15]([CH3:14])[CH:20]=1
Reactant: Cn1cc(B2OC(C)(C)C(C)(C)O2)c2ccn(COCC[Si](C)(C)C)c2c1=O
Reactant: CNc1ccc(Br)c(F)c1[N+](=O)[O-]
Product: CNc1ccc(-c2cn(C)c(=O)c3c2ccn3COCC[Si](C)(C)C)c(F)c1[N+](=O)[O-]

Procedure:
This compound was synthesized according to the procedure of Example 10, Step 5, using 4-bromo-3-fluoro-N-methyl-2-nitroaniline and 6-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-{[2-(trimethylsilyl)ethoxy]methyl}-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one as the starting materials. LCMS calculated for C21H28FN4O4Si (M+H)+: m/z=447.2. found: 447.1.
Reaction SMILES: [N:1]([CH2:4][CH2:5][O:6][C:7]1[C:16]2[O:15][C:14]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)=[C:13]([CH3:23])[C:12](=[O:24])[C:11]=2[CH:10]=[CH:9][CH:8]=1)=[N+]=[N-].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH3:44][O:45][C:46]1[CH:55]=[CH:54][CH:53]=[C:52]([O:56][CH3:57])[C:47]=1[O:48][CH2:49][CH:50]=O.[ClH:58]>C1C=CC=CC=1>[ClH:58].[CH3:44][O:45][C:46]1[CH:55]=[CH:54][CH:53]=[C:52]([O:56][CH3:57])[C:47]=1[O:48][CH2:49][CH2:50][NH:1][CH2:4][CH2:5][O:6][C:7]1[C:16]2[O:15][C:14]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)=[C:13]([CH3:23])[C:12](=[O:24])[C:11]=2[CH:10]=[CH:9][CH:8]=1
Reactant: COc1cccc(OC)c1OCC=O
Reactant: Cc1c(-c2ccccc2)oc2c(OCCN=[N+]=[N-])cccc2c1=O
Agent: Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: c1ccccc1
Product: COc1cccc(OC)c1OCCNCCOc1cccc2c(=O)c(C)c(-c3ccccc3)oc12
Reaction time: 18 h
Yield: 40 %

Procedure:
A mixture of 4.5 g of Intermediate XII, 3.7 g of triphenyl phosphine and 2.85 g of 2,6-dimethoxyphenoxy-acetaldehyde (prepared as per Nelson, W. L. et al., J. Med. Chem. 22: 1125, 1979) in 45 ml of benzene was stirred at 20°-25° C. for 18 hours and at reflux for 5 hours. The solvent was evaporated off in vacuo and the residue was dissolved in 80 ml of anhydrous methanol containing 3Å molecular sieves at 0° C. The mixture was stood for 1 hour at 0° C. and for 1 hour at 20°-25° C., and then poured into iced water and extracted with dichloromethane. The organic extracts were washed with water and dried on anhydrous sodium sulfate. The solvent was removed in vacuo and the residue was purified by flash chromatography on silica gel, eluting with dichloromethane:methanol (49:1). The base obtained was treated with ethanolic hydrogen chloride. After crystallization from ethanol, the title compound was obtained. Yield 40%, m.p. 200-°202° C.
Reaction SMILES: O=[C:2]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][N:7]=1)[CH2:3][C:4]#[N:5].C(N(CC)CC)C.[CH:19]1[CH:24]=[CH:23][C:22]([CH2:25][CH2:26][NH:27][NH2:28])=[CH:21][CH:20]=1.OS(O)(=O)=O.C(Cl)Cl.CO>CCO.CCOC(C)=O>[CH2:26]([N:27]1[C:4]([NH2:5])=[CH:3][C:2]([C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][N:7]=2)=[N:28]1)[CH2:25][C:22]1[CH:23]=[CH:24][CH:19]=[CH:20][CH:21]=1
Reactant: NNCCc1ccccc1
Reactant: N#CCC(=O)c1ccccn1
Agent: O=S(=O)(O)O
Solvent: CCOC(C)=O
Solvent: ClCCl
Solvent: CO
Product: Nc1cc(-c2ccccn2)nn1CCc1ccccc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a stirred solution of 3-oxo-3-pyridin-2-yl-propionitrile (0.46 g, 3.1 mmol; CAS 54123-21-6) at r.t. in EtOH (10 ml) under an argon atmosphere were added triethylamine (2.6 ml, 18.9 mmol) and phenelzine sulfate salt (2.2 g, 9.4 mmol). The mixture was heated to reflux and stirring was continued for 2 hrs. The orange solution was cooled to r.t. The solids were filtered off. The filtrate was concentrated to leave an orange viscous oil which was taken up in EtOAc and washed with water. The aqueous layer was extracted with EtOAc and with CH2Cl2/MeOH 9:1. The combined organics were dried over MgSO4, filtered and concentrated. The product was obtained after silica gel chromatography using CH2Cl2/MeOH as gradient as off-white solid (0.722 g, 87%). MS: M=265.1 (M+H)+
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:25]=[CH:26][C:27]=1[CH2:28][CH3:29])[NH:5][C:6]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:9]([CH2:16][CH2:17][C:18]2[CH:23]=[CH:22][N:21]=[C:20](O)[CH:19]=2)=[CH:8][N:7]=1.P(Cl)(Cl)([Cl:32])=O.Cl.N>C(#N)C.O1CCOCC1>[Br:1][C:2]1[CH:3]=[C:4]([CH:25]=[CH:26][C:27]=1[CH2:28][CH3:29])[NH:5][C:6]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:9]([CH2:16][CH2:17][C:18]2[CH:23]=[CH:22][N:21]=[C:20]([Cl:32])[CH:19]=2)=[CH:8][N:7]=1
Reactant: CCc1ccc(Nc2ncc(CCc3ccnc(O)c3)c3ccccc23)cc1Br
Reactant: O=P(Cl)(Cl)Cl
Agent: Cl
Agent: N
Solvent: C1COCCO1
Solvent: CC#N
Product: CCc1ccc(Nc2ncc(CCc3ccnc(Cl)c3)c3ccccc23)cc1Br
Temperature: 65 °C
Reaction time: 48 h

Procedure:
Under a N2 atmosphere, 150 mg (0.334 mmol) of 1-(3-bromo-4-ethyl-anilino)-4-[2-(2-hydroxy-pyridin-4-yl)-ethyl]-isoquinoline (Ex. 32a) in 5 ml of acetonitrile are mixed with 76 μl (0.83 mmol) of phosphorus oxychloride and 0.17 ml (0.68 mmol) of 4 N HCl in dioxane, and stirred at 65° C. A further 76 μl of phosphorus oxychloride is added after 12 h, and stirring continues for 48 h at 65° C. The mixture is cooled to RT, 4 ml of 10% NH3 solution added, and it is partitioned between 3 portions of EtOAc, 2 portions of water and brine. Drying (Na2SO4), concentrating by evaporation and chromatography on silica gel (acetone/methylene chloride 3:2) yield 1-(3-bromo-4-ethyl-anilino)-4-[2-(2-chloro-pyridin-4-yl)ethyl]-isoquinoline; FAB-MS: (M+H)+=466/468; HPLC(gradient20-100) tRef=13.4.
Reaction SMILES: [CH3:1][C:2]1[S:6][C:5]2[CH:7]([C:10]([O:12]CC)=[O:11])[CH2:8][CH2:9][C:4]=2[C:3]=1[C:15](=[O:25])[C:16]1[CH:21]=[CH:20][C:19]([S:22]([CH3:24])=[O:23])=[CH:18][CH:17]=1.[OH-].[Na+].[H][H].Cl>CO>[CH3:1][C:2]1[S:6][C:5]2[CH:7]([C:10]([OH:12])=[O:11])[CH2:8][CH2:9][C:4]=2[C:3]=1[C:15](=[O:25])[C:16]1[CH:17]=[CH:18][C:19]([S:22]([CH3:24])=[O:23])=[CH:20][CH:21]=1
Reactant: [H][H]
Reactant: CCOC(=O)C1CCc2c1sc(C)c2C(=O)c1ccc(S(C)=O)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: Cc1sc2c(c1C(=O)c1ccc(S(C)=O)cc1)CCC2C(=O)O
Yield: 68.2 %

Procedure:
To a solution of 2.29 g (0.0061 moles) ethyl 5,6-dihydro-2-methyl-3-(4-(methylsulfinyl) benzoyl)-4H-cyclopenta[b]thiophene-6-carboxylate, the product of Example 1a. in 40 ml of methanol at reflux was added 9.1 ml (0.0091 moles) of 1N sodium hydroxide dropwise. After 20 min. of refluxing the mixture was cooled in an ice bath and poured into 3N hydrogen chloridede dropwise. After 20 min. of refluxing the mixture was cooled in an ice bath and poured into 3N hydrogen chloride and ice. Solid 5,6-dihydro-2-methyl-3-[4-(methylsulfinyl) benzoyl]-4H-cyclopenta[b]thiophene-6-carboxylic acid was collected. The filtrate was extracted with chloroform, washed with brine and dried (MgSO4). Evaporation of the solvent gave solid acid which was recrystallized from acetonitrile. The two batches of solid were combined and recrystallized from acetonitrile to give 1.45 g of 5,6-dihydro-2-methyl-3-(4(methylsulfinyl)benzoyl)-4H-cyclopenta[b]thiophene-6-carboxylic acid, mp 209-213° C.
Reaction SMILES: [C:1]([O:4][CH2:5][CH:6]=[CH2:7])(=[O:3])[CH3:2].[C:8]1([SiH:14]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1>CC(O)C.[H+].[H+].Cl[Pt-2](Cl)(Cl)(Cl)(Cl)Cl>[C:1]([O:4][CH2:5][CH2:6][CH2:7][Si:14]([C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1)([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1)(=[O:3])[CH3:2]
Reactant: C=CCOC(C)=O
Reactant: c1ccc([SiH](c2ccccc2)c2ccccc2)cc1
Agent: Cl[Pt-2](Cl)(Cl)(Cl)(Cl)Cl
Agent: [H+]
Solvent: CC(C)O
Product: CC(=O)OCCC[Si](c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 92.2 %

Procedure:
0.5 ml of a 0.1 N solution of chloroplatinic acid as the catalyst in 2-propanol was added to an excess amount [58.1 g (581 mmol)]of allyl acetate (B). 40 g (15.4 mmol) of triphenylsilane (A) was added thereto and the mixture was stirred at room temperature for 3 h. After confirming the completion of the reaction according to the disappearance of an absorption due to SiH at 2100 cm-1 in the I.R. absorption spectrum, excess (B) was distilled off under reduced pressure. The residue was purified according to column chromatography to obtain 51.1 g (14.2 mmol) of 3-acetoxypropyltriphenylsilane (C) (yield: 92.2%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:10][C:11]2[CH:16]=[CH:15][C:14]([CH:17]3[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]3)=[CH:13][N:12]=2)[C:5](=[O:9])[N:6]([CH3:8])[N:7]=1.C=O.[C:25](O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C([O-])(O)=O.[Na+]>O.C1COCC1>[Cl:1][C:2]1[CH:3]=[C:4]([NH:10][C:11]2[N:12]=[CH:13][C:14]([CH:17]3[CH2:22][CH2:21][N:20]([CH3:25])[CH2:19][CH2:18]3)=[CH:15][CH:16]=2)[C:5](=[O:9])[N:6]([CH3:8])[N:7]=1
Reactant: Cn1nc(Cl)cc(Nc2ccc(C3CCNCC3)cn2)c1=O
Reactant: CC(=O)O
Agent: C=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Solvent: C1CCOC1
Solvent: O
Product: CN1CCC(c2ccc(Nc3cc(Cl)nn(C)c3=O)nc2)CC1
Temperature: 0 °C
Reaction time: 2 h
Yield: 89.6 %

Procedure:
In a 25 mL round-bottomed flask, 6-chloro-2-methyl-4-(5-(piperidin-4-yl)pyridin-2-ylamino)pyridazin-3(2H)-one (620 mg, 1.94 mmol, Eq: 1.00) and formaldehyde (1.57 g, 1.44 ml, 19.4 mmol, Eq: 10) were combined with THF to give a light yellow solution. Acetic acid (116 mg, 111 μl, 1.94 mmol, Eq: 1.00) was added. The reaction mixture was cooled to 0° C. Sodium triacetoxyborohydride (616 mg, 2.91 mmol, Eq: 1.5) was added. The reaction mixture was stirred at room temperature 2 hr. LC/MS showed reaction was complete. The reaction mixture was poured into water. Saturated NaHCO3 was added to make it basic and the resultant mixture was extracted with EtOAc. The combined extracts were washed with water, dried over Na2SO4 and concentrated in vacuo. The resultant solid was triturated with ether to afford the desired product as an off-white solid (580 mg). (M+H)+=334 m/e. This was combined with previous batches to give 1.06 g 6-chloro-2-methyl-4-(1′-methyl-1′,2′,3′,4′,5′,6′-hexahydro-[3,4′]bipyridinyl-6-ylamino)-2H-pyridazin-3-one, which was carried on as is into the next reaction.
Reaction SMILES: [H-].[Na+].[C:3]([CH2:5][C:6]1[N:7]=[CH:8][NH:9][CH:10]=1)#[N:4].[CH3:11][CH:12](I)[CH3:13].O>CN(C)C=O.C(Cl)(Cl)Cl>[C:3]([CH2:5][C:6]1[N:7]=[CH:8][N:9]([CH:12]([CH3:13])[CH3:11])[CH:10]=1)#[N:4]
Reactant: N#CCc1c[nH]cn1
Reactant: CC(C)I
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: ClC(Cl)Cl
Solvent: CN(C)C=O
Product: CC(C)n1cnc(CC#N)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
450 mg of sodium hydride (60%) was added to 5 ml of dimethylformamide, and a solution of 1.0 g of 4-cyanomethylimidazole in 10 ml of dimethylformamide was added dropwise to the resulting suspension. After 1 hour of stirring at room temperature, 0.94 ml of 2-propyl iodide was added to the resulting solution and stirred at room temperature for 2 hours. To the reaction solution was added water and chloroform, and the resulting organic layer was collected and dried over anhydrous sodium sulfate, followed by evaporation of the solvent. The residue was subjected to silica gel column chromatography eluted with chloroform-methanol (30:1) to obtain 500 mg of 4-cyanomethyl-1-(2-propyl)imidazole.
Reaction SMILES: [O:1]=[C:2]1[N:10]([CH2:11][CH2:12][CH3:13])[C:9]2[N:8]=[C:7]([C:14]3[CH2:20][CH:19]4[CH:21]([C:22]([OH:24])=[O:23])[CH:16]([CH2:17][CH2:18]4)[CH:15]=3)[NH:6][C:5]=2[C:4](=[O:25])[N:3]1[CH2:26][CH2:27][CH3:28]>C(OCC)(=O)C.[Pd]>[O:1]=[C:2]1[N:10]([CH2:11][CH2:12][CH3:13])[C:9]2[N:8]=[C:7]([CH:14]3[CH2:20][CH:19]4[CH:21]([C:22]([OH:24])=[O:23])[CH:16]([CH2:17][CH2:18]4)[CH2:15]3)[NH:6][C:5]=2[C:4](=[O:25])[N:3]1[CH2:26][CH2:27][CH3:28]
Reactant: CCCn1c(=O)c2[nH]c(C3=CC4CCC(C3)C4C(=O)O)nc2n(CCC)c1=O
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CCCn1c(=O)c2[nH]c(C3CC4CCC(C3)C4C(=O)O)nc2n(CCC)c1=O

Procedure:
3-(2,6-Dioxo-1,3-dipropyl-2,3,6,7-tetrahydro-1H-purin-8-yl)-bicyclo[3.2.1]oct-2-ene-8-carboxylic acid (Example 29) was hydrogenated using Pd/C in ethyl acetate. Mass (ES+ 389).
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]([Cl:12])[CH:9]=[C:8]([Cl:13])[C:3]=1[O:4][CH2:5][CH2:6]O.C(Cl)(Cl)(Cl)[Cl:15].S(Cl)(Cl)=O>[Cl-].C([N+](C)(C)C)C1C=CC=CC=1.O>[Cl:1][C:2]1[CH:11]=[C:10]([Cl:12])[CH:9]=[C:8]([Cl:13])[C:3]=1[O:4][CH2:5][CH2:6][Cl:15]
Reactant: OCCOc1c(Cl)cc(Cl)cc1Cl
Reactant: ClC(Cl)(Cl)Cl
Agent: C[N+](C)(C)Cc1ccccc1
Agent: [Cl-]
Solvent: O=S(Cl)Cl
Solvent: O
Product: ClCCOc1c(Cl)cc(Cl)cc1Cl
Temperature: 55 °C
Yield: 98 %

Procedure:
Into a three-necked, round-bottom flask fitted with a stirrer, thermometer, reflux condenser and dropping funnel was added 250 g of 96% 2-(2,4,6-trichlorophenoxy) ethanol, 250 ml carbon tetrachloride and 4 g of benzyl-trimethyl-ammonium chloride. The mixture was heated to 55° C. and 146 g thionyl chloride was added dropwise over 1.5 hours. After the addition of the thionyl chloride the temperature of the reaction was slowly raised to 80° C. for a total reaction tme of 2.5 to 3 hours. The end of the reaction was determined by GLC. The mixture was cooled to 60° C. and water slowly added to decompose the excess thionyl chloride. The phases were separated and the organic phase was washed with a 10% sodium hydroxide solution until it reached a pH of 7. After an additional separation of the phases the organic phase was washed again with water. After a further separation of phases, the carbon tetrachloride was distilled off to yield an oil which slowly crystallized to form 257 g of 2-(2,4,6-trichlorophenoxy)-ethyl chloride in a purity of 96%-98% and yield of 98%.