Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:24]=[C:23]([F:25])[CH:22]=[CH:21][C:3]=1[O:4][C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][C:13]=1[C:14](O)=[O:15])[N:10]([CH2:17][CH:18]([CH3:20])[CH3:19])[N:9]=[CH:8]2.Cl.Cl.[CH3:28][O:29][C:30](=[O:41])[C@@H:31]([NH2:40])[CH2:32][CH2:33][N:34]([CH2:36][CH2:37][O:38][CH3:39])[CH3:35].CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.C(N(CC)CC)C>ClC(Cl)C>[CH3:28][O:29][C:30](=[O:41])[C@@H:31]([NH:40][C:14]([C:13]1[CH:12]=[C:11]2[C:7]([CH:8]=[N:9][N:10]2[CH2:17][CH:18]([CH3:20])[CH3:19])=[CH:6][C:5]=1[O:4][C:3]1[CH:21]=[CH:22][C:23]([F:25])=[CH:24][C:2]=1[F:1])=[O:15])[CH2:32][CH2:33][N:34]([CH2:36][CH2:37][O:38][CH3:39])[CH3:35]
Reactant: CC(C)Cn1ncc2cc(Oc3ccc(F)cc3F)c(C(=O)O)cc21
Reactant: COCCN(C)CC[C@H](N)C(=O)OC
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: CC(Cl)Cl
Product: COCCN(C)CC[C@H](NC(=O)c1cc2c(cnn2CC(C)C)cc1Oc1ccc(F)cc1F)C(=O)OC
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 69.5 %

Procedure:
To a solution of 5-(2,4-difluorophenoxy)-1-isobutyl-1H-indazole-6-carboxylic acid (prepared as in Example 110, Steps A-G) (0.094 g, 0.27 mmol), (S)-2-amino-4-[(2-methoxy-ethyl)-methyl-amino]-butyric acid methyl ester dihydrochloride (0.079 g, 0.28 mmol), EDCI (0.057 g, 0.30 mmol) and HOBt (0.045 g, 0.30 mmol) in dichloroethane (2 mL) was added dropwise triethylamine (0.23 mL, 1.62 mmol). The reaction mixture was stirred at room temperature for 2.5 hours. The mixture was concentrated under reduced pressure and chromatographed, eluting with ethyl acetate, to afford 0.100 g of product (69% yield).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH2:7][O:8][C:9]2[CH:15]=[C:14]([O:16]CC3C=CC=CC=3)[CH:13]=[CH:12][C:10]=2[CH:11]=1)=[O:5])[CH3:2]>[Pd]>[CH2:1]([O:3][C:4]([CH:6]1[CH2:11][C:10]2[CH:12]=[CH:13][C:14]([OH:16])=[CH:15][C:9]=2[O:8][CH2:7]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)C1=Cc2ccc(OCc3ccccc3)cc2OC1
Agent: [Pd]
Product: CCOC(=O)C1COc2cc(O)ccc2C1
Yield: 89.8 %

Procedure:
The ester from Example 54 (1.4 g) was dissolved in 25 ml of absolute alcohol and hydrogenated at atmospheric pressure in the presence of 0.2 g of 10% palladium on charcoal. The catalyst was removed by filtration on diatomaceous earth and after removal of the solvent, 0.9 g of racemic-3,4-dihydro-7-hydroxy-2H-1-benzopyran-3-carboxylic acid ethyl ester was obtained as a white solid.
Reaction SMILES: OC(C(F)(F)F)=O.[NH:8]1[CH2:11][CH:10]([NH:12][C:13](=[O:31])[CH2:14][NH:15][C:16]2[C:24]3[C:19](=[CH:20][CH:21]=[C:22]([C:25]([F:28])([F:27])[F:26])[CH:23]=3)[N:18]([CH2:29][CH3:30])[N:17]=2)[CH2:9]1.[OH:32][C:33]1([C:40]2[S:44][C:43]([CH3:45])=[N:42][CH:41]=2)[CH2:38][CH2:37][C:36](=O)[CH2:35][CH2:34]1>>[CH2:29]([N:18]1[C:19]2[C:24](=[CH:23][C:22]([C:25]([F:27])([F:26])[F:28])=[CH:21][CH:20]=2)[C:16]([NH:15][CH2:14][C:13]([NH:12][CH:10]2[CH2:9][N:8]([CH:36]3[CH2:35][CH2:34][C:33]([OH:32])([C:40]4[S:44][C:43]([CH3:45])=[N:42][CH:41]=4)[CH2:38][CH2:37]3)[CH2:11]2)=[O:31])=[N:17]1)[CH3:30]
Reactant: Cc1ncc(C2(O)CCC(=O)CC2)s1
Reactant: CCn1nc(NCC(=O)NC2CNC2)c2cc(C(F)(F)F)ccc21
Solvent: O=C(O)C(F)(F)F
Product: CCn1nc(NCC(=O)NC2CN(C3CCC(O)(c4cnc(C)s4)CC3)C2)c2cc(C(F)(F)F)ccc21

Procedure:
The title compound was prepared as a white solid from reaction of N-azetidin-3-yl-2-(1-ethyl-5-trifluoromethyl-1H-indazol-3-ylamino)-acetamide TFA salt (as prepared in Example 67, Step A) and 4-hydroxy-4-(2-methyl-thiazol-5-yl)-cyclohexanone using the procedure described in Step E of Example 1.
Reaction SMILES: [Cl:1][C:2]1[C:3]2[CH:10]=[C:9]([CH3:11])[NH:8][C:4]=2[N:5]=[CH:6][N:7]=1.O[CH2:13][C@@H:14]1[CH2:18][CH2:17][CH2:16][N:15]1[C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CCN(C(C)C)C(C)C>C1COCC1>[Cl:1][C:2]1[C:3]2[CH:10]=[C:9]([CH3:11])[N:8]([CH2:13][C@@H:14]3[CH2:18][CH2:17][CH2:16][N:15]3[C:19]([O:21][C:22]([CH3:23])([CH3:25])[CH3:24])=[O:20])[C:4]=2[N:5]=[CH:6][N:7]=1
Reactant: Cc1cc2c(Cl)ncnc2[nH]1
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1CO
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: Cc1cc2c(Cl)ncnc2n1C[C@@H]1CCCN1C(=O)OC(C)(C)C
Temperature: 25 °C

Procedure:
To the solution of 4-chloro-6-methyl-7H-pyrrolo[2,3-d]pyrimidine (1.0 g, 5.97 mmol, 1.0 eq) and (S)-tert-butyl 2-(hydroxymethyl)pyrrolidine-1-carboxylate (1.32 g, 6.57 mmol, 1.1 eq) and PPh3 (3.03 g, 11.94 mmol, 2.0 eq) in THF (50 mL), DIEA (2.08 g, 11.94 mmol, 2.0 eq) was added at 0° C. The resulted mixture was stirred and warmed to RT for 12 h. Solvent was removed and purified by column chromatography (eluting with 10% EtOAc in PE) to afford (S)-tert-butyl 2-[(4-chloro-6-methyl-7H-pyrrolo[2,3-d]pyrimidin-7-yl]methyl)pyrrolidine-1-carboxylate as a white solid (2.08 g, 100% in yield).
Reaction SMILES: [CH2:1]([O:3][P:4]([CH2:9][NH:10][C:11]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[C:14]([N+:21]([O-:23])=[O:22])=[CH:13][C:12]=1[NH2:24])(=[O:8])[O:5][CH2:6][CH3:7])[CH3:2].CC[C:27]([C:29](Cl)=[O:30])=[O:28].C(N(CC)CC)C>O1CCCC1>[CH2:1]([O:3][P:4]([CH2:9][N:10]1[C:11]2[C:20]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=3[C:14]([N+:21]([O-:23])=[O:22])=[CH:13][C:12]=2[NH:24][C:27](=[O:28])[C:29]1=[O:30])(=[O:8])[O:5][CH2:6][CH3:7])[CH3:2]
Reactant: CCOP(=O)(CNc1c(N)cc([N+](=O)[O-])c2ccccc12)OCC
Reactant: CCC(=O)C(=O)Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCOP(=O)(Cn1c(=O)c(=O)[nH]c2cc([N+](=O)[O-])c3ccccc3c21)OCC
Temperature: 25 °C

Procedure:
100 mg of (2-amino-4-nitro-1-naphthylamino)-methanephosphonic acid diethyl ester is dissolved in a few ml of tetrahydrofuran and treated with 95 microliters of distilled ethyloxalyl chloride and 118 microliters of triethylamine at ice-bath temperature. The solution is stirred first to room temperature and then the reaction is allowed to be completed at 55° oil bath temperature. The batch is concentrated by evaporation, taken up in ethyl acetate and washed with brine, dried and spun in. The crude product is chromatographed on silica gel with ethanol as mobile solvent. 76 mg or 67% of theory of product is obtained as polar fraction. NMR (DMSO,Delta in ppm): 1.03 (6H tr), 3.8 (4H dq), 4.93 (2H d), 7.73 (2H dd), 8.2, 8.35, 8.47 each 1H.
Reaction SMILES: [CH2:1]([C:4]1[N:5]([CH2:17][CH2:18][CH2:19][CH:20]=[O:21])[C:6]2[C:15]3[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=3[N:9]=[CH:8][C:7]=2[N:16]=1)[CH2:2][CH3:3].N[C:23]1C2N=C(CCCC)N(CCCC(N(OC)C)=O)C=2C2N=CC=CC=2N=1>>[CH2:1]([C:4]1[N:5]([CH2:17][CH2:18][CH2:19][CH:20]([OH:21])[CH3:23])[C:6]2[C:15]3[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=3[N:9]=[CH:8][C:7]=2[N:16]=1)[CH2:2][CH3:3]
Reactant: CCCCc1nc2c(N)nc3cccnc3c2n1CCCC(=O)N(C)OC
Reactant: CCCc1nc2cnc3ccccc3c2n1CCCC=O
Product: CCCc1nc2cnc3ccccc3c2n1CCCC(C)O

Procedure:
The preparation of 4-(2-propyl-1H-imidazo[4,5-c]quinolin-1-yl)butyraldehyde is described in parts A-C of Example 6. The general procedure of Part G of Example 4 was repeated using 4-(2-propyl-1H-imidazo[4,5-c]quinolin-1-yl)butyraldehyde (6.4 g, 22.74 mmol) in lieu of 4-(4-amino-2-butyl-1H-imidazo[4,5-c][1,5]naphthyridin-1-yl)-N-methoxy-N-methylbutanamide to provide 5.2 g of 5-(2-propyl-1H-imidazo[4,5-c]quinolin-1-yl)pentan-2-ol as a tan oil.
Reaction SMILES: CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O.[F:23][C:24]1[CH:29]=[CH:28][C:27]([S:30]([N:33]2[CH2:38][CH2:37][CH2:36][CH2:35][C@H:34]2[C:39]([NH:41][CH2:42][CH:43]([OH:45])[CH3:44])=[O:40])(=[O:32])=[O:31])=[CH:26][CH:25]=1.C(N(CC)CC)C>ClCCl>[F:23][C:24]1[CH:29]=[CH:28][C:27]([S:30]([N:33]2[CH2:38][CH2:37][CH2:36][CH2:35][C@H:34]2[C:39]([NH:41][CH2:42][C:43](=[O:45])[CH3:44])=[O:40])(=[O:32])=[O:31])=[CH:26][CH:25]=1
Reactant: CC(O)CNC(=O)[C@@H]1CCCCN1S(=O)(=O)c1ccc(F)cc1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)CNC(=O)[C@@H]1CCCCN1S(=O)(=O)c1ccc(F)cc1
Reaction time: 1 h
Yield: 55.1 %

Procedure:
Dess-Martin reagent (814 mg) was added to a stirred solution of (2S)-1-[(4-fluorophenyl)sulfonyl]-N2-(2-hydroxypropyl)-2-piperidinecarboxamide (548 mg) [see Preparation 80) and triethylamine (0.89 ml) in dichloromethane (20 ml). The reaction mixture was stirred for 1 hr after which time the mixture was filtered through a pad of basic alumina and washed through with dichloromethane to afford (2S)-1-[(4-fluorophenyl)sulfonyl]-N2-(2-oxopropyl)-2-piperidinecarboxamide (300 mg).
Reaction SMILES: [N:1]([C@H:4]([C@H:7]([C@H:9]([C@@H:11]([CH2:13][OH:14])[OH:12])[OH:10])[OH:8])[CH:5]=[O:6])=[N+]=[N-].[OH:15][CH:16]1O[C@H](CO)[C@H](O)[C@H](O)[C@H:17]1N>>[C:16]([NH:1][C@@H:4]1[C@@H:7]([OH:8])[C@@H:9]([OH:10])[C@@H:11]([CH2:13][OH:14])[O:12][CH:5]1[OH:6])(=[O:15])[CH3:17]
Reactant: [N-]=[N+]=N[C@@H](C=O)[C@@H](O)[C@@H](O)[C@H](O)CO
Reactant: N[C@H]1C(O)O[C@H](CO)[C@H](O)[C@@H]1O
Product: CC(=O)N[C@H]1C(O)O[C@H](CO)[C@H](O)[C@@H]1O

Procedure:
The process which comprises reacting an anomeric mixture of 3,4,6-tri-O-acetyl-2-azido-2-deoxy-D-galactopyranosyl nitrate with sodium acetate in acetic acid to form the 1,3,4,6-tetra-O-acetyl-2-azido-2-deoxy-D-galactopyranosyl acetates, isolating said product, hydrolyzing said isolated product in an aqueous acid to provide 2-azido-2-deoxy-D-galactose, and reducing the 2-azido-2-deoxy-D-galactose and then N-acetylating the D-galactosamine product to form N-acetyl-D-galactosamine.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([F:11])[C:3]=1[C:4]([OH:6])=O.[NH2:12][CH2:13][CH2:14][CH2:15][C@H:16]1[O:20][C:19](=[O:21])[N:18]([C:22]2[CH:23]=[CH:24][C:25]3[S:30][CH2:29][C:28](=[O:31])[NH:27][C:26]=3[CH:32]=2)[CH2:17]1>>[NH2:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([F:11])[C:3]=1[C:4]([NH:12][CH2:13][CH2:14][CH2:15][C@H:16]1[O:20][C:19](=[O:21])[N:18]([C:22]2[CH:23]=[CH:24][C:25]3[S:30][CH2:29][C:28](=[O:31])[NH:27][C:26]=3[CH:32]=2)[CH2:17]1)=[O:6]
Reactant: NCCC[C@@H]1CN(c2ccc3c(c2)NC(=O)CS3)C(=O)O1
Reactant: Nc1cccc(F)c1C(=O)O
Product: Nc1cccc(F)c1C(=O)NCCC[C@@H]1CN(c2ccc3c(c2)NC(=O)CS3)C(=O)O1
Yield: 83 %

Procedure:
Starting from 2-amino-6-fluorobenzoic acid and 6-[(R)-5-(3-amino-propyl)-2-oxo-oxazolidin-3-yl]-4H-benzo[1,4]thiazin-3-one (described in WO 2010/041219) and using Procedure D, the title compound was obtained as a beige solid (190 mg; 83% yield).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][CH:9]2[CH:14]3[CH2:15][CH2:16][N:11]([CH2:12][CH2:13]3)[CH2:10]2)=[C:4]([CH2:17][CH:18](OC)OC)[CH:3]=1.[ClH:23].CO>>[ClH:23].[Br:1][C:2]1[CH:3]=[C:4]2[C:5](=[CH:6][CH:7]=1)[N:8]([CH:9]1[CH:14]3[CH2:15][CH2:16][N:11]([CH2:12][CH2:13]3)[CH2:10]1)[CH:18]=[CH:17]2
Reactant: COC(Cc1cc(Br)ccc1NC1CN2CCC1CC2)OC
Agent: Cl
Solvent: CO
Product: Brc1ccc2c(ccn2C2CN3CCC2CC3)c1
Yield: 100 %

Procedure:
Compound 68 (137 mg, 0.371 mmol) was dissolved in anhydrous 1M HCl/methanol (10 mL) in a dry argon purged flask, refluxed for 1 hour, concentrated under reduced pressure to yield HCl salt of 69 as an off-white solid (129 mg, 100%). 1H NMR (MeOD) δ 1.89-2.00 (m, 2H), 2.10-2.20 (m, 1H), 2.25-2.34 (m, 1H), 2.39-2.44 (m, 1H), 3.43-3.53 (m, 3H), 3.64-3.77 (m, 1H), 3.86-3.93 (m, 1H), 4.00-4.09 (m, 1H), 5.17-5.22 (m, 1H), 6.58 (d, 1H, J=3.4 Hz), 7.31 (dd, 1H, J=8.5, 1.8 Hz), 7.42 (d, 1H, J=8.8 Hz), 7.70 (d, 1H, J=3.5 Hz), 7.73 (d, 1H, J=1.8 Hz); ESI-MS (m/z, %): 305/307 (MH+, 100%).
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[C:12]([N:14]([CH3:16])[CH3:15])[C:11]([C:17]([F:20])([F:19])[F:18])=[CH:10][C:9]=1[NH:21][C:22](=[O:45])[CH2:23][C:24](=O)[C:25]1[CH:30]=[CH:29][CH:28]=[C:27]([N:31]2[C:35]([CH2:36][O:37]C3CCCCO3)=[CH:34][CH:33]=[N:32]2)[CH:26]=1)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH3:15][N:14]([CH3:16])[C:12]1[C:11]([C:17]([F:18])([F:19])[F:20])=[CH:10][C:9]2[NH:21][C:22](=[O:45])[CH2:23][C:24]([C:25]3[CH:30]=[CH:29][CH:28]=[C:27]([N:31]4[C:35]([CH2:36][OH:37])=[CH:34][CH:33]=[N:32]4)[CH:26]=3)=[N:7][C:8]=2[CH:13]=1
Reactant: CN(C)c1cc(NC(=O)OC(C)(C)C)c(NC(=O)CC(=O)c2cccc(-n3nccc3COC3CCCCO3)c2)cc1C(F)(F)F
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CN(C)c1cc2c(cc1C(F)(F)F)NC(=O)CC(c1cccc(-n3nccc3CO)c1)=N2

Procedure:
The title compound was prepared from (RS)-[5-dimethylamino-2-(3-oxo-3-{3-[5-(tetrahydro-pyran-2yloxymethyl)-pyrazol-1-yl]-phenyl}-propionylamino)-4-trifluoromethyl-phenyl]-carbamic acid tert.-butyl ester (Example M73) by treatment with TFA in CH2Cl2 according to the general procedure N. Obtained as a light yellow solid (109 mg).
Reaction SMILES: [Br:1][C:2]1[C:10]2[N:9]=[N:8][N:7]([CH2:11][C:12]([CH3:15])([CH3:14])[CH3:13])[C:6]=2[CH:5]=[CH:4][C:3]=1[O:16]C.B(Br)(Br)Br>C(Cl)Cl>[Br:1][C:2]1[C:10]2[N:9]=[N:8][N:7]([CH2:11][C:12]([CH3:14])([CH3:13])[CH3:15])[C:6]=2[CH:5]=[CH:4][C:3]=1[OH:16]
Reactant: COc1ccc2c(nnn2CC(C)(C)C)c1Br
Agent: BrB(Br)Br
Solvent: ClCCl
Product: CC(C)(C)Cn1nnc2c(Br)c(O)ccc21
Temperature: 25 °C

Procedure:
To a solution of 4-bromo-1-(2,2-dimethylpropyl)-5-methoxy-1H-1,2,3-benzotriazole (Example 1-1) (8.97 g, 30.1 mmol, 1.0 equiv.) in DCM (150 ml) at 0° C., was added slowly 1 M solution of BBr3 (60.2 ml, 60.2 mmol, 2.0 equiv.) in DCM. The reaction mixture was allowed to warm up to room temperature overnight. LCMS showed completion. The reaction mixture was quenched with water, neutralized to pH=7, then extracted with EtOAc. The combined organic layers were dried over Na2SO4, filtered and concentrated to give 4-bromo-1-(2,2-dimethylpropyl)-1H-1,2,3-benzotriazol-5-ol (Example 1-2). 1H NMR (500 MHz, CDCl3) δ 7.36 (d, 1H, J=9.0 Hz), 7.24 (d, 1H, J=9.0 Hz), 4.37 (s, 2H), 1.04 (s, 9H) ppm. LRMS m/z (M+H) 283.9 and 285.9 (intensity ratio ˜1:1) found, 284.0 and 286.0 required.
Reaction SMILES: O[C:2]1([C:8]2[S:12][C:11]3[CH:13]=[CH:14][CH:15]=[CH:16][C:10]=3[C:9]=2[CH2:17][CH3:18])[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.O1C[C@H]1COC1C2C=CSC=2C=CC=1>CO>[CH2:17]([C:9]1[C:10]2[CH:16]=[CH:15][CH:14]=[CH:13][C:11]=2[S:12][C:8]=1[CH:2]1[CH2:3][CH2:4][NH:5][CH2:6][CH2:7]1)[CH3:18]
Reactant: CCc1c(C2(O)CCNCC2)sc2ccccc12
Agent: c1cc(OC[C@@H]2CO2)c2ccsc2c1
Solvent: CO
Product: CCc1c(C2CCNCC2)sc2ccccc12
Yield: 72.5 %

Procedure:
A solution 4-hydroxy-4-(3-ethylbenzo[b]thiophen-2-yl)piperidine (0.069 g, 0.281 mmol) and (S)-(+)-4-(oxiranylmethoxy)-benzo[b]thiophene (0.058 g, 0.281 mmol) in methanol (3 mL) was heated at reflux for 18 hours and then cooled and evaporated. The residue was purified using silica gel chromatography (dichloromethane/1% methanol in dichloromethane) to give the free base of the final title compound as a clear colorless oil (0.050 g, 39%). The oxalate salt was prepared to give the title compound. FDMS m/e=452 (M++1 of free base). C26H29NO2S2.C2H2O4
Reaction SMILES: Cl.C[O:3][C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[CH2:10][CH:9]([CH2:14][CH2:15][N:16]1[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1)[CH2:8][CH2:7]2>Br>[OH:3][C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[CH2:10][CH:9]([CH2:14][CH2:15][N:16]1[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1)[CH2:8][CH2:7]2
Reactant: COc1ccc2c(c1)CCC(CCN1CCCCC1)C2
Agent: Br
Agent: Cl
Product: Oc1ccc2c(c1)CCC(CCN1CCCCC1)C2
Yield: 74.5 %

Procedure:
6-Methoxy-2-(2-piperidinoethyl)tetralin hydrochloride (9.3 g) was added to 48% hydrobromic acid (50 ml), which was refluxed with heating for 4 hours. After the reaction mixture was concentrated under reduced pressure, saturated sodium bicarbonate solution was added to the residue to make the water layer alkaline, and the water layer was extracted using a mixed solution of THF and ethyl acetate. The organic layer was washed with water and saturated aqueous sodium chloride solution, dried, and then concentrated. The resulting crystal was washed with IPE to give the titled compound (5.8 g).
Reaction SMILES: [CH:1]1[C:6]2=[C:7]3[C:15](=[CH:16][CH:17]=[C:5]2[CH:4]=[CH:3][CH:2]=1)[C:14]1[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=1)[NH:8]3.[CH3:18]CCCCC>>[CH3:18][N:8]1[C:7]2[C:15](=[CH:16][CH:17]=[C:5]3[CH:4]=[CH:3][CH:2]=[CH:1][C:6]3=2)[C:14]2[C:9]1=[CH:10][CH:11]=[CH:12][CH:13]=2
Reactant: c1ccc2c(c1)ccc1c3ccccc3[nH]c21
Reactant: CCCCCC
Product: Cn1c2ccccc2c2ccc3ccccc3c21
Yield: 97.3 %

Procedure:
Using the procedure outlined in Example 34A, 11H-benzo[a]carbazole (Cambridge Chemicals, Inc.) gave a 97.3% yield of 11-methyl-11H-benzo[a]carbazole, mp 167°-169°, (hexane), (C,H,N).
Reaction SMILES: [Cl:1][C:2]1[C:10]([N+:11]([O-:13])=[O:12])=[CH:9][CH:8]=[CH:7][C:3]=1C(O)=O.[Br:14]Br.C(=O)(O)[O-].[Na+]>[Hg]=O.C(Cl)(Cl)(Cl)Cl>[Br:14][C:3]1[C:2]([Cl:1])=[C:10]([N+:11]([O-:13])=[O:12])[CH:9]=[CH:8][CH:7]=1
Reactant: BrBr
Reactant: O=C(O)c1cccc([N+](=O)[O-])c1Cl
Agent: O=C([O-])O
Agent: O=[Hg]
Agent: [Na+]
Solvent: ClC(Cl)(Cl)Cl
Product: O=[N+]([O-])c1cccc(Br)c1Cl
Temperature: 25 °C
Yield: 60.3 %

Procedure:
A mixture of 2-chloro-3-nitrobenzoic acid (15 g, 74.4 mmol), red mercury oxide (24.2 g, 112 mmol), and carbon tetrachloride (350 mL) were irradiated with a 100 W light bulb and heated at reflux. Bromine (5.75 mL, 112 mmol) was added dropwise over 30 minutes. This was stirred at reflux for 3.5 hours. After cooling to room temperature, aqueous saturated sodium bicarbonate (250 mL) was added and stirred vigorously for 20 minutes. The mixture was filtered and the solids were washed with excess chloroform. This two-phase solution was separated and the aqueous layer back extracted with chloroform (2×200 mL). The organic layers were collected and washed with brine (150 mL), water (150 mL) and dried (magnesium sulfate) and concentrated to give 3-bromo-2-chloronitrobenzene (10.6 g, 60.4%). 1H NMR (CDCl3, 300 MHz): δ7.86 (dd, 1H, J=8.1, 1.5), 7.73 (dd, 1H, J=8.1, 1.5 Hz), 7.31 (t, 1H, J=8.1 Hz) ppm.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7](=[O:27])[N:8]([CH2:18][C:19]2[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=2)[C:9]2[C:14]([C:15]=1O)=[CH:13][C:12]([Cl:17])=[CH:11][N:10]=2)=[O:5])[CH3:2].C(N(CC)CC)C.O=P(Cl)(Cl)[Cl:37]>>[CH2:1]([O:3][C:4]([C:6]1[C:7](=[O:27])[N:8]([CH2:18][C:19]2[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=2)[C:9]2[C:14]([C:15]=1[Cl:37])=[CH:13][C:12]([Cl:17])=[CH:11][N:10]=2)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1c(O)c2cc(Cl)cnc2n(Cc2ccc(OC)cc2)c1=O
Reactant: O=P(Cl)(Cl)Cl
Solvent: CCN(CC)CC
Product: CCOC(=O)c1c(Cl)c2cc(Cl)cnc2n(Cc2ccc(OC)cc2)c1=O
Yield: 85 %

Procedure:
A solution of 6-chloro-4-hydroxy-1-(4-methoxy-benzyl)-2-oxo-1,2-dihydro-[1,8]-naphthyridine-3-carboxylic acid ethyl ester (75) (6.0 g, 15.43 mmol) and triethylamine (5.36 mL, 38.57 mmol) was heated in neat POCl3 at 90° C. for 3 h. The solution was cooled and the excess POCl3 was distilled under vacuum. The residue was suspended in saturated NaHCO3 solution, sonicated briefly and filtered. The solids were dissolved in dichloromethane, washed subsequently by saturated NaHCO3 solution, water and brine. The organic phase was dried over MgSO4 and evaporated to yield 6.2 g (85%) of 4,6-dichloro-1-(4-methoxy-benzyl)-2-oxo-1,2-dihydro-[1,8]-naphthyridine-3-carboxylic acid ethyl ester (77) as yellow waxy solids. 1H-NMR (DMSO-d6): δ 1.30 (t, J=7.2 Hz, 3H), 3.69 (s, 3H), 4.38 (q, J=7.2 Hz, 2H), 5.50 (s, 2H), 6.82 (m, 2H), 7.24 (m, 2H), 8.48 (d, J=2.4 Hz, 1H), 8.87 (d, J=2.4 Hz, 1H); EIMS: 407 (M).
Reaction SMILES: [OH-].[K+].C(C1C(O)=C(C(C)(C)C)C=C(C)C=1)(C)(C)C.[SH:19][CH2:20][CH2:21][C:22]([OH:24])=[O:23].[CH:25]([C:27]1[CH:34]=[CH:33][C:30]([CH2:31]Cl)=[CH:29][CH:28]=1)=[CH2:26].Cl>C(O)C>[CH:25]([C:27]1[CH:34]=[CH:33][C:30]([CH2:31][S:19][CH2:20][CH2:21][C:22]([OH:24])=[O:23])=[CH:29][CH:28]=1)=[CH2:26]
Reactant: C=Cc1ccc(CCl)cc1
Reactant: O=C(O)CCS
Agent: Cc1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1
Agent: Cl
Agent: [K+]
Solvent: CCO
Product: C=Cc1ccc(CSCCC(=O)O)cc1
Temperature: 25 °C
Yield: 80 %

Procedure:
To a solution of potassium hydroxide (84 g, 1.3 moles) and 2,6-di-tert-butyl-p-cresol (1 g) in ethanol (1.2 liter) at room temperature was added under a nitrogen atmosphere 3-mercaptopropionic acid (65.0 g, 0.61 mole) over 10 minutes. Following addition the solution was stirred an additional hour at room temperature and then p-vinylbenzyl chloride (93 g. 0.6 mole) was added at room temperature over 30 minutes. After addition, the solution was stirred at ambient temperature overnight. The next day the mixture was poured into ice and concentrated hydrochloric acid (150 ml). The solid was filtered and dried on a funnel under vacuum. The solid was dissolved in dichloromethane (1.4 liter), washed with saturated NaCl (200 ml), dried over anhydrous magnesium sulfate, filtered and the solvent removed on a rotary evaporator. The residue was dissolved in diethyl ether (600 ml), hexane (1 liter) was added to the cloud point, and then the mixture was placed in a freezer. The white solid product was collected by filtration: m.p. of 77°-78° C. Yield of 80%. Analysis calculated for C12H14O2S: C, 64.84, H, 6.35, S, 14.42. Found: C, 64.98, H, 6.29, S, 14.02. 1H NMR (CDCl3) δ 2.6 (m, 4H, CH2CH2), 3.7 (s, 2H, ArCH2S), 5.15+5.65 (AB quartet, 2H, CH2 =), 6.65 (m, 1H, CH=), 7.3 (m, 4H, ArH's).
Reaction SMILES: [NH:1]([C:3](=[O:30])[CH2:4][CH2:5][C:6]1[S:10][C:9]([C:11]2[NH:12][C:13]3[C:18]([CH:19]=2)=[CH:17][CH:16]=[CH:15][C:14]=3[N:20]([CH3:29])[S:21]([C:24]2[S:25][CH:26]=[CH:27][CH:28]=2)(=[O:23])=[O:22])=[N:8][CH:7]=1)[NH2:2].[C:31](N1C=CN=C1)(N1C=CN=C1)=[O:32].CN(C)C(=O)C>O>[CH3:29][N:20]([C:14]1[CH:15]=[CH:16][CH:17]=[C:18]2[C:13]=1[NH:12][C:11]([C:9]1[S:10][C:6]([CH2:5][CH2:4][C:3]3[O:30][C:31](=[O:32])[NH:2][N:1]=3)=[CH:7][N:8]=1)=[CH:19]2)[S:21]([C:24]1[S:25][CH:26]=[CH:27][CH:28]=1)(=[O:23])=[O:22]
Reactant: CN(c1cccc2cc(-c3ncc(CCC(=O)NN)s3)[nH]c12)S(=O)(=O)c1cccs1
Reactant: O=C(n1ccnc1)n1ccnc1
Solvent: CC(=O)N(C)C
Solvent: O
Product: CN(c1cccc2cc(-c3ncc(CCc4n[nH]c(=O)o4)s3)[nH]c12)S(=O)(=O)c1cccs1
Temperature: 25 °C
Reaction time: 2 h
Yield: 65.3 %

Procedure:
A mixture of N-{2-[5-(3-hydrazino-3-oxopropyl)-1,3-thiazol-2-yl]-1H-indol-7-yl}-N-methylthiophene-2-sulfonamide (0.29 g), 1,1′-carbonylbis-1H-imidazole (0.22 g) and N,N-dimethylacetamide (15 mL) was stirred at room temperature for 2 hr. Water was added to the reaction mixture and the resulting crystals were collected by filtration, washed with water and dried. The obtained crystals were subjected to silica gel column chromatography and the title compound (0.20 g, yield 65%) was obtained as yellow crystals from a fraction eluted with tetrahydrofuran-hexane (2:1, volume ratio). The crystals were recrystallized from ethyl acetate. melting point 255-256° C.
Reaction SMILES: CNC1C=CC(C#CCCCO)=CC=1.C([O:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][O:25][CH2:26][CH2:27][CH2:28][CH2:29][C:30]1[CH:35]=[CH:34][C:33]([N:36](C)[C:37](=O)C(F)(F)F)=[CH:32][CH:31]=1)(=O)C>>[CH3:37][NH:36][C:33]1[CH:32]=[CH:31][C:30]([CH2:29][CH2:28][CH2:27][CH2:26][O:25][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][OH:18])=[CH:35][CH:34]=1
Reactant: CC(=O)OCCCCCCOCCCCc1ccc(N(C)C(=O)C(F)(F)F)cc1
Agent: CNc1ccc(C#CCCCO)cc1
Product: CNc1ccc(CCCCOCCCCCCO)cc1

Procedure:
The title compound was synthesized in a manner analogous to that described for Intermediate 49, using Intermediate 55 as a substrate. ES/MS calcd. for C17H30NO2+ 280.2. Found m/z=280.3 (M+H)+.
Reaction SMILES: I[C:2]1[CH:3]=[C:4]([N+:10]([O-:12])=[O:11])[CH:5]=[CH:6][C:7]=1[O:8][CH3:9].[CH3:13][C:14]1[C:18](B(O)O)=[C:17]([CH3:22])[O:16][N:15]=1.C(=O)([O-])[O-].[Cs+].[Cs+].COCCOC>C(OCC)(=O)C.O>[CH3:13][C:14]1[C:18]([C:2]2[CH:3]=[C:4]([N+:10]([O-:12])=[O:11])[CH:5]=[CH:6][C:7]=2[O:8][CH3:9])=[C:17]([CH3:22])[O:16][N:15]=1
Reactant: COc1ccc([N+](=O)[O-])cc1I
Reactant: Cc1noc(C)c1B(O)O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: COCCOC
Solvent: O
Product: COc1ccc([N+](=O)[O-])cc1-c1c(C)noc1C
Temperature: 90 °C
Yield: 83.3 %

Procedure:
3-Iodo-4-(methoxy) nitrobenzene (65 g, 233 mmol, Matrix Scientific), (3,5-dimethyl-4-isoxazolyl)boronic acid (36.1 g, 256 mmol) and cesium carbonate (152 g, 466 mmol) were combined with DME (80 ml) and water (40 ml) and the mixture was degassed with nitrogen for 10 min, then PEPPSI™ catalyst (3.96 g, 5.82 mmol) was added and the mixture heated at 90° C. for 4 h, then cooled and diluted with ethyl acetate (800 ml). The resulting suspension was filtered through Celite and the filtrate washed with water (2×500 ml). The solvent was dried (sodium sulphate), filtered and evaporated to give a brown solid which was triturated with ether (30 ml). The solid product was washed with ether (100 ml) to give 3,5-dimethyl-4-[2-(methyloxy)-5-nitrophenyl]isoxazole as beige solid (48.2 g).