Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]1[C:6]2[C:7]3[C:13](=O)[NH:12][C:11]4[CH:15]=[CH:16][CH:17]=[CH:18][C:10]=4[S:9][C:8]=3[S:19][C:5]=2[CH2:4][CH2:3][CH2:2]1.P(Cl)(Cl)(Cl)=O.CN(C)C1C=CC=CC=1.[CH3:34][N:35]1[CH2:40][CH2:39][NH:38][CH2:37][CH2:36]1>>[CH3:34][N:35]1[CH2:40][CH2:39][N:38]([C:13]2[C:7]3[C:6]4[CH2:1][CH2:2][CH2:3][CH2:4][C:5]=4[S:19][C:8]=3[S:9][C:10]3[CH:18]=[CH:17][CH:16]=[CH:15][C:11]=3[N:12]=2)[CH2:37][CH2:36]1
Reactant: CN1CCNCC1
Reactant: O=C1Nc2ccccc2Sc2sc3c(c21)CCCC3
Solvent: O=P(Cl)(Cl)Cl
Solvent: CN(C)c1ccccc1
Product: CN1CCN(C2=Nc3ccccc3Sc3sc4c(c32)CCCC4)CC1

Procedure:
In the same manner as in Example 80 and using 1,2,3,4-tetrahydro-[1]benzothieno[2,3-b][1,5]benzothiazepin-12(11H)-one, phosphorus oxychloride, N,N-dimethylaniline and 1-methylpiperazine, 1,2,3,4-tetrahydro-12-(4-methylpiperazin-1-yl)-[1]benzothieno[2,3-b][1,5]benzothiazepine is obtained.
Reaction SMILES: [H-].[Na+].[C:3]([NH:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[O:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)(=[O:5])[CH3:4].[Cl:20][C:21]1[CH:28]=[CH:27][CH:26]=[CH:25][C:22]=1[CH2:23]Cl>CN(C)C=O>[C:3]([N:6]([CH2:23][C:22]1[CH:25]=[CH:26][CH:27]=[CH:28][C:21]=1[Cl:20])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[O:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)(=[O:5])[CH3:4]
Reactant: CC(=O)Nc1ccccc1Oc1ccccc1
Reactant: ClCc1ccccc1Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(=O)N(Cc1ccccc1Cl)c1ccccc1Oc1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 94.3 %

Procedure:
To a suspension of 400 mg of sodium hydride (60% in oil) in 30 ml of dimethylformamide was added 2.00 g of N-acetyl-2-phenoxyaniline at room temperature, followed by stirring at room temperature for 30 minutes. To the solution was added dropwise 1.64 g of 2-chlorobenzyl chloride at room temperature with stirring, followed by stirring for 30 minutes. After addition of ice-water, the reaction mixture was extracted with ether. The extract was washed with 0.5 N hydrochloric acid, a saturated aqueous sodium bicarbonate solution and a saturated aqueous sodium chloride solution, successively, and dried over anhydrous sodium sulfate. After removal of the drying agent by filtration, the solvent was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent; ethyl acetate−hexane=1:4) to give 2.92 g of N-acetyl-N-(2-chlorobenzyl)-2-phenoxyaniline as an oil.
Reaction SMILES: [NH2:1][C:2]([CH3:18])([CH3:17])[CH2:3][NH:4][C:5]1[CH:12]=[CH:11][C:8]([C:9]#[N:10])=[C:7]([C:13]([F:16])([F:15])[F:14])[CH:6]=1.[F:19][C:20]1[CH:25]=[CH:24][C:23]([N:26]=[C:27]=[O:28])=[CH:22][CH:21]=1>ClCCl>[C:9]([C:8]1[CH:11]=[CH:12][C:5]([NH:4][CH2:3][C:2]([NH:1][C:27]([NH:26][C:23]2[CH:24]=[CH:25][C:20]([F:19])=[CH:21][CH:22]=2)=[O:28])([CH3:18])[CH3:17])=[CH:6][C:7]=1[C:13]([F:14])([F:15])[F:16])#[N:10]
Reactant: O=C=Nc1ccc(F)cc1
Reactant: CC(C)(N)CNc1ccc(C#N)c(C(F)(F)F)c1
Solvent: ClCCl
Product: CC(C)(CNc1ccc(C#N)c(C(F)(F)F)c1)NC(=O)Nc1ccc(F)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
4-(2-Amino-2-methylpropylamino)-2-trifluoromethylbenzonitrile was dissolved in 60 ml of dichloromethane, 0.49 ml of 4-fluorophenyl isocyanate was added dropwise to the solution and then the mixture was stirred at room temperature for 1 hour. The thus precipitated crystals were collected by filtration, washed with dichloromethane and then dried to obtain 1.30 g of the title compound.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[OH:20][C:21]1[CH:30]=[CH:29][C:24]([C:25]([O:27][CH3:28])=[O:26])=[CH:23][CH:22]=1.O[CH2:32][CH2:33][CH2:34][N:35]1[CH2:39][CH2:38][CH2:37][CH2:36]1.N(C(OCC)=O)=NC(OCC)=O>C(Cl)Cl>[N:35]1([CH2:34][CH2:33][CH2:32][O:20][C:21]2[CH:22]=[CH:23][C:24]([C:25]([O:27][CH3:28])=[O:26])=[CH:29][CH:30]=2)[CH2:39][CH2:38][CH2:37][CH2:36]1
Reactant: COC(=O)c1ccc(O)cc1
Reactant: OCCCN1CCCC1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: COC(=O)c1ccc(OCCCN2CCCC2)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 106.7 %

Procedure:
A solution of 6.25 g (23.8 mmol) of triphenylphosphine, 3.30 g (21.7 mmol) of methyl 4-hydroxybenzoate, and 2.80 g (21.7 mmol) of 1-(3-hydroxypropyl)pyrrolidine in 100 mL of CH2Cl2 was treated with 3.80 mL (24.1 mmol) of diethyl azodicarboxylate in a dropwise manner. The reaction was stirred at ambient temperature for 16 h and was quenched by the addition of 20 mL of brine. The two layers were separated, and the organic layer was dried over K2CO3 and concentrated to give 6.10 g of an oily solid which was purified by flash chromatography (SiO2; 0-5% MeOH in CH2Cl2) to afford 2.46 g (9.34 mmol; 43%) of the desired product.
Reaction SMILES: [CH:1]1[C:14]2[NH:13][C:12]3[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=3)[O:6][C:5]=2[CH:4]=[CH:3][CH:2]=1.[CH3:15][C:16]1([CH3:22])[NH:20][C:19](=O)[CH2:18][CH2:17]1.P(Cl)(Cl)(Cl)=O>>[CH3:15][C:16]1([CH3:22])[N:20]=[C:19]([N:13]2[C:14]3[CH:1]=[CH:2][CH:3]=[CH:4][C:5]=3[O:6][C:7]3[C:12]2=[CH:11][CH:10]=[CH:9][CH:8]=3)[CH2:18][CH2:17]1
Reactant: CC1(C)CCC(=O)N1
Reactant: c1ccc2c(c1)Nc1ccccc1O2
Solvent: O=P(Cl)(Cl)Cl
Product: CC1(C)CCC(N2c3ccccc3Oc3ccccc32)=N1

Procedure:
Reaction of phenoxazine, 5,5-dimethyl-2-pyrrolidinone and phosphorus oxychloride according to the procedure of Example 1 provides the free base 10-(5,5-DIMETHYL-1-PYRROLIN-2-YL)PHENOXAZINE, m.p. 148°-150° C. Conversion of the free base to the hydrochloride salt affords 10-(5,5-DIMETHYL-1-PYRROLIN-2-YL)PHENOXAZINE HYDROCHLORIDE, m.p. 239°-242.5° C. (corr.), in a 48% overall yield.
Reaction SMILES: [C:1]([N:8]1[CH2:11][CH2:10][C@H:9]1[CH2:12][OH:13])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].O[C:15]1[CH:16]=[N:17][CH:18]=[C:19]([N+:21]([O-:23])=[O:22])[CH:20]=1>>[N+:21]([C:19]1[CH:20]=[C:15]([O:13][CH2:12][C@@H:9]2[CH2:10][CH2:11][N:8]2[C:1]([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2])[CH:16]=[N:17][CH:18]=1)([O-:23])=[O:22]
Reactant: O=[N+]([O-])c1cncc(O)c1
Reactant: CC(C)(C)OC(=O)N1CC[C@H]1CO
Product: CC(C)(C)OC(=O)N1CC[C@H]1COc1cncc([N+](=O)[O-])c1
Yield: 72.4 %

Procedure:
1-BOC-2-(S)-azetidinylmethanol (868 mg, 4.64 mmol) and 3-hydroxy-5-nitropyridine from Example 132d (500 mg, 3.57 mmol) were coupled according the procedure of Example 17a. Solvent was removed, and the residue was chromatographed (silica gel, hexane/ethyl acetate, 5:1) to afford the title compound (800 mg, 73%). 1H NMR (CHCl3, 300 MHz) δ 1.45 (s, 9H), 2.56 (m, 2H), 4.52 (m, 4H), 4.82 (m, 1H), 8.25 (t, J=3 Hz, 1H), 8.65 (d, J=3 Hz, 1H), 9.05 (d, J=3 Hz, 1H). MS (DCI/NH3) m/z 310 (M+H)+.
Reaction SMILES: OC1C=CC(S[CH2:9][C:10]([NH:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[O:11])=CC=1.OO.CSC>C(O)(=O)C>[C:10]([NH:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)(=[O:11])[CH3:9]
Reactant: O=C(CSc1ccc(O)cc1)Nc1ccccc1
Agent: OO
Solvent: CC(=O)O
Solvent: CSC
Product: CC(=O)Nc1ccccc1
Temperature: 100 °C
Reaction time: 5 h
Yield: 185 %

Procedure:
6.0 g (23.2 mmol) of 2-(4-hydroxyphenylthio)acetoanilide and 50 mL of acetic acid were added under a room temperature into a 100 mL flask with four inlets and attached with a stirrer and a thermometer. To the resultant solution, 5.6 g (49.4 mmol) of 30% aqueous solution of hydrogen peroxide was added, and the solution was stirred for 4 hours at a room temperature and consequently for 5 hours at 100° C. Following to the completion of the reaction, 0.5 g of dimethyl sulfide was added into the solution, and then, the solution was extracted with MIBK. The MIBK layer was washed several times with water, and followed by washing with sodium hydrogencarbonate. The MIBK in the solution was distilled out under reduced pressure, and the resultant residue was subjected to recrystallization with MIBK to obtain 5.8 g of 2-(4-hydroxphenylsulfonyl) acetoanilide. The yield was 86% and the melting point of the compound was in a range of 188 to 189° C.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([F:12])[CH:10]=2)[N:5]=[C:4]([C:13]2[CH:18]=[CH:17][C:16]([CH3:19])=[CH:15][CH:14]=2)[CH:3]=1.[NH:20]1[CH2:28][CH2:27][CH:23]([C:24]([NH2:26])=[O:25])[CH2:22][CH2:21]1>N1C=CC=CC=1>[F:12][C:9]1[CH:10]=[C:11]2[C:6](=[CH:7][CH:8]=1)[N:5]=[C:4]([C:13]1[CH:18]=[CH:17][C:16]([CH3:19])=[CH:15][CH:14]=1)[CH:3]=[C:2]2[N:20]1[CH2:28][CH2:27][CH:23]([C:24]([NH2:26])=[O:25])[CH2:22][CH2:21]1
Reactant: Cc1ccc(-c2cc(Cl)c3cc(F)ccc3n2)cc1
Reactant: NC(=O)C1CCNCC1
Solvent: c1ccncc1
Product: Cc1ccc(-c2cc(N3CCC(C(N)=O)CC3)c3cc(F)ccc3n2)cc1

Procedure:
The named compound was made in a manner analogous to that of Example 4(c) using 4-Chloro-6-fluoro-2-(4-methylphenyl)quinoline and isonipecotamide as starting materials. It was obtained as white needles, mp 246°-249° dec on recrystallization from pyridine.
Reaction SMILES: C(=O)(OCC1C2(O)ON(CC3C2N3)C2C1=C(O)C=C(C=O)C=2)N.NC1C=CC=CC=1.[C:31](=[O:59])([O:33][CH2:34][CH:35]1[C:47]2([OH:49])[O:48][N:42]([CH2:43][CH:44]3[CH:46]2[NH:45]3)[C:41]2[C:36]1=[C:37]([OH:58])[CH:38]=[C:39]([CH:50]=[N:51][C:52]1[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=1)[CH:40]=2)[NH2:32]>CO.[Pd]>[C:31](=[O:59])([O:33][CH2:34][CH:35]1[C:47]2([OH:49])[O:48][N:42]([CH2:43][CH:44]3[CH:46]2[NH:45]3)[C:41]2[C:36]1=[C:37]([OH:58])[CH:38]=[C:39]([CH2:50][NH:51][C:52]1[CH:53]=[CH:54][CH:55]=[CH:56][CH:57]=1)[CH:40]=2)[NH2:32]
Reactant: NC(=O)OCC1c2c(O)cc(C=Nc3ccccc3)cc2N2CC3NC3C1(O)O2
Agent: [Pd]
Agent: NC(=O)OCC1c2c(O)cc(C=O)cc2N2CC3NC3C1(O)O2
Solvent: CO
Solvent: Nc1ccccc1
Product: NC(=O)OCC1c2c(O)cc(CNc3ccccc3)cc2N2CC3NC3C1(O)O2
Temperature: 25 °C
Reaction time: 3 h

Procedure:
4-Formyl-6,9-dihydroxy-14-oxa-1,11-diazatetracyclo[7.4.1.02,7.010,12 ]tetradeca-2,4,6-trien-8-ylmethyl carbamate (50 mg) was dissolved in methanol (5 ml). Aniline (0.05 ml) was added to this solution and the mixture was allowed to stand at room temperature for 3 hours to give a solution containing 6,9-dihydroxy-4-phenyliminomethyl-14-oxa-1,11-diazatetracyclo[7.4.1.02,7.010,12 ]tetradeca-2,4,6-trien-8-ylmethyl carbamate. 10% Palladium on carbon (100 mg) was added to the solution, and the mixture was stirred for 2 hours at room temperature under hydrogen atmosphere (4.5 atm). The mixture was filtered through cellulose powder and the filter cake was washed with methanol (20 ml). The filtrate and the washings were combined and evaporated in vacuo. The residue was subjected to preparative thin layer chromatography, which was developed with a mixture of chloroform, methanol and water (65:25:4, v/v/v) to afford 4-anilinomethyl-6,9-dihydroxy-14-oxa-1,11-diazatetracyclo[7.4.1.02,7.010,12 ]tetradeca-2,4,6-trien-8-ylmethyl carbamate (25 mg).
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][CH:3]=1.[CH3:11][C@H:12]1[O:17][C@@H:16]([CH3:18])[CH2:15][NH:14][CH2:13]1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[CH3:18][C@H:16]1[CH2:15][N:14]([C:2]2[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][CH:3]=2)[CH2:13][C@@H:12]([CH3:11])[O:17]1
Reactant: O=[N+]([O-])c1ccc(F)cc1
Reactant: C[C@@H]1CNC[C@H](C)O1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: C[C@@H]1CN(c2ccc([N+](=O)[O-])cc2)C[C@H](C)O1

Procedure:
1-Fluoro-4-nitrobenzene (4.9 g, 34.75 mmol) was added to cis-2,6-dimethylmorpholine (44.4 g, 38.26 mmol) and anhydrous potassium carbonate (2.5 g, 18.12 mmol) in acetonitrile (50 ml). The reaction was heated under reflux for 19 hours, cooled, filtered and the solid washed with acetonitrile. Evaporation of the filtrate gave the title compound as a yellow solid. (8.1 g, 99%) NMR (CDCl3) 1.28 (d, 6H), 2.61 (t, 2H), 3.66 (td, 2H), 3.76 (m, 2H), 6.82 (d, 2H), 8.13 (d, 2H); m/z 237.
Reaction SMILES: [C:1]([Si:5]([CH3:17])([CH3:16])[O:6][C:7]1[CH:8]=[C:9]2[C:13](=[CH:14][CH:15]=1)[NH:12][CH:11]=[CH:10]2)([CH3:4])([CH3:3])[CH3:2].Br[CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21].C(=O)([O-])[O-].[Cs+].[Cs+].C(OCC)C>CN(C=O)C>[CH2:23]([O:22][C:20](=[O:21])[CH2:19][N:12]1[C:13]2[C:9](=[CH:8][C:7]([O:6][Si:5]([C:1]([CH3:4])([CH3:3])[CH3:2])([CH3:17])[CH3:16])=[CH:15][CH:14]=2)[CH:10]=[CH:11]1)[CH3:24]
Reactant: CCOC(=O)CBr
Reactant: CC(C)(C)[Si](C)(C)Oc1ccc2[nH]ccc2c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CCOCC
Product: CCOC(=O)Cn1ccc2cc(O[Si](C)(C)C(C)(C)C)ccc21
Temperature: 25 °C
Reaction time: 3 h
Yield: 104 %

Procedure:
A suspension of 5-(tert-butyl-dimethyl-silanyloxy)-1H-indole (9.2 g, 37.2 mmol), ethyl bromoacetate (4.79 ml, 40.9 mmol) and cesium carbonate (36.4 g, 111.5 mmol) in DMF (140 ml) was stirred for 3 h at RT. Diethyl ether was added and the mixture was washed with 1N HCl and water, and dried over sodium sulfate. The ether phase was concentrated under reduced pressure to give 12.9 g (quant.) of [5-(tert-butyl-dimethyl-silanyloxy)-indol-1-yl]-acetic acid ethyl ester which was used in the next step without further purification.
Reaction SMILES: CS([C:5]1[N:10]=[C:9]([C:11]2[CH:16]=[CH:15][N:14]=[C:13]([CH3:17])[CH:12]=2)[CH:8]=[CH:7][N:6]=1)(=O)=O.[O:18]1CCOCC1>>[CH3:17][C:13]1[CH:12]=[C:11]([C:9]2[CH:8]=[CH:7][NH:6][C:5](=[O:18])[N:10]=2)[CH:16]=[CH:15][N:14]=1
Reactant: C1COCCO1
Reactant: Cc1cc(-c2ccnc(S(C)(=O)=O)n2)ccn1
Product: Cc1cc(-c2cc[nH]c(=O)n2)ccn1
Temperature: 25 °C
Reaction time: 2 h
Yield: 52 %

Procedure:
2-Methanesulfonyl-4-(2-methyl-pyridin-4-yl)-pyrimidine (720 mg, 2.89 mmol) was dissolved in dioxane (25 ml) and then 2N NaOHaq (14.4 ml, 28.9 mmol) was added. After stirring at room temperature for 2 hours, the solution was acidified with 37% HClaq. The mixture was evaporated and the residue was re-dissolved in DCM-MeOH—NH4OH (90-10-1) and evaporated. The crude was purified by flash chromatography with DCM-MeOH (9-1) to give 279 mg of the title compound. (52% yield).
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:12]=[CH:11][C:10](B3OC(C)(C)C(C)(C)O3)=[CH:9][CH:8]=2)=[N:4][C:3]=1[CH2:22][CH2:23][OH:24].I[C:26]1[N:27]=[N:28][C:29]([CH3:32])=[CH:30][CH:31]=1.C(Cl)Cl.C(=O)([O-])[O-].[Na+].[Na+]>O1CCOCC1>[CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:8]=[CH:9][C:10]([C:26]3[N:27]=[N:28][C:29]([CH3:32])=[CH:30][CH:31]=3)=[CH:11][CH:12]=2)=[N:4][C:3]=1[CH2:22][CH2:23][OH:24]
Reactant: Cc1oc(-c2ccc(B3OC(C)(C)C(C)(C)O3)cc2)nc1CCO
Reactant: Cc1ccc(I)nn1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: ClCCl
Product: Cc1ccc(-c2ccc(-c3nc(CCO)c(C)o3)cc2)nn1

Procedure:
To a stirring solution of 2-{5-Methyl-2-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)phenyl]-oxazol-4-yl}-ethanol (0.314 g, 0.952 mmol) (See Intermediate 3), 3-Iodo-6-methyl-pyridazine (0.178 g, 0.810 mmol) [CAS# 1618-47-9] and [1,1 bis(diphenylphosphino)ferrocene]dichloropalladium(II) complex with CH2Cl2 (1:1) (0.02 g, 0.024 mmol) in 10 mL dioxane is added aqueous sodium carbonate (2M, 1.22 mL) and the reaction is carried out substantially in accordance with the procedure of Example 9 to provide after purification by radial chromatography pure titled compound (0.208 g, 87%). MS (m/e): 296.3 (M+1).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[N:6][C:7]2[C:12]([C:13]=1[NH:14][CH2:15][CH2:16][CH2:17]O)=[CH:11][CH:10]=[CH:9][CH:8]=2)([O-:3])=[O:2].S(Cl)([Cl:21])=O.ClCCl.C(=O)([O-])[O-].[Na+].[Na+]>O>[Cl:21][CH2:17][CH2:16][CH2:15][NH:14][C:13]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[N:6]=[CH:5][C:4]=1[N+:1]([O-:3])=[O:2]
Reactant: O=[N+]([O-])c1cnc2ccccc2c1NCCCO
Reactant: O=S(Cl)Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Product: O=[N+]([O-])c1cnc2ccccc2c1NCCCCl
Temperature: 25 °C
Reaction time: 2 h
Yield: 97 %

Procedure:
A round bottom flask was charged with a magnetic stir bar, 3-[(3-nitroquinolin-4-yl)amino]propan-1-ol (20.75 g, 83.93 mmol), thionyl chloride (15.0 g, 125.89 mmol), and dichloromethane (420 mL). The bright yellow, homogeneous solution was stirred at ambient temperature for 2 hours at which time the starting material was completely consumed. The volatiles were removed under reduced pressure and he resulting solid stirred in water (400 mL) made basic (pH 10) with solid sodium carbonate. A bright yellow solid was collected by filtration to afford N-(3-chloropropyl)-3-nitroquinolin-4-amine (21.63 g, 81.41 mmol) which was used without further purification.
Reaction SMILES: N1C(C)=CC(C)=CC=1C.[NH2:10][C:11]1[C:12](=[O:26])[N:13]([CH2:18][C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[C:14]([CH3:17])=[CH:15][CH:16]=1.[CH2:27]([S:34](Cl)(=[O:36])=[O:35])[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>C(#N)C>[CH2:27]([S:34]([NH:10][C:11]1[C:12](=[O:26])[N:13]([CH2:18][C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[C:14]([CH3:17])=[CH:15][CH:16]=1)(=[O:36])=[O:35])[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: O=S(=O)(Cl)Cc1ccccc1
Reactant: Cc1ccc(N)c(=O)n1CC(=O)OC(C)(C)C
Solvent: Cc1cc(C)nc(C)c1
Solvent: CC#N
Product: Cc1ccc(NS(=O)(=O)Cc2ccccc2)c(=O)n1CC(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 46.1 %

Procedure:
Collidine (0.59 mL, 4.5 mmole) was added in one portion to a stirred solution of the compound of Example 94 (0.89 g, 3.7 mmole) and benzylsulfonyl chloride (0.86 g, 4.5 mmole) in acetonitrile (20 ml) cooled in an ice bath. The solution was stirred for 5 minutes at 0° C., followed by 45 min at room temperature. The reaction mixture was quenched with water, then diluted with ethyl acetate (100 mL), washed with 3% HCl (until aqueous layer is pH 1), and brine, dried over magnesium sulfate, and the solvent was removed. The residue was dissolved in methanol, concentrated to a volume of approximately 3 mL, and the product was precipitated with the addition of diethyl ether. The precipitate was filtered to give 0.67 g of the title compound. The filtrate was concentrated and chromatographed on flash silica gel using 20-67% ethyl acetate hexanes as eluent. An additional 0.20 g of the title compound was recovered. A total of 0.87 g of the title compound (59% yield) was recovered. Rf=0.29 (silica gel, 33% ethyl acetate/hexanes).
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[C:3]1[CH:13]=[CH:12][CH:11]=[CH:10][C:4]=1[CH:5]=[CH:6][C:7]([OH:9])=[O:8].S(=O)(=O)(O)O.[CH2:21](O)[CH3:22]>>[CH2:21]([O:8][C:7](=[O:9])[CH:6]=[CH:5][C:4]1[CH:10]=[CH:11][CH:12]=[CH:13][C:3]=1[C:2]([F:14])([F:15])[F:1])[CH3:22]
Reactant: CCO
Reactant: O=C(O)C=Cc1ccccc1C(F)(F)F
Agent: O=S(=O)(O)O
Product: CCOC(=O)C=Cc1ccccc1C(F)(F)F
Yield: 95 %

Procedure:
2-Trifluoromethylcinnamic acid (10.1 g), conc. sulfuric acid (1 ml) and ethanol (100 ml) were subjected to reaction and post-treatment in a similar manner to that described in Reference example 10(a) to obtain the title compound (10.8 g, 95%) as a colorless oil.
Reaction SMILES: Cl[CH2:2]/[CH:3]=[C:4]1/[C:5]2[CH:18]=[C:17]([C:19]([O:21][CH3:22])=[O:20])[CH:16]=[CH:15][C:6]=2[O:7][CH2:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]/1=2.[OH:23][C:24]1[NH:25][C:26]2[CH:32]=[CH:31][CH:30]=[CH:29][C:27]=2[N:28]=1>>[OH:23][C:24]1[N:28]([CH2:2]/[CH:3]=[C:4]2/[C:5]3[CH:18]=[C:17]([C:19]([O:21][CH3:22])=[O:20])[CH:16]=[CH:15][C:6]=3[O:7][CH2:8][C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][C:10]/2=3)[C:27]2[CH:29]=[CH:30][CH:31]=[CH:32][C:26]=2[N:25]=1
Reactant: COC(=O)c1ccc2c(c1)/C(=C/CCl)c1ccccc1CO2
Reactant: Oc1nc2ccccc2[nH]1
Product: COC(=O)c1ccc2c(c1)/C(=C/Cn1c(O)nc3ccccc31)c1ccccc1CO2

Procedure:
Compound h, 2.0 g and 4.3 g of 2-hydroxybenzimidazole were treated in a manner similar to Example 173 to give 0.3 g of the objective compound.
Reaction SMILES: [NH2:1][CH2:2][C@H:3]([NH:8][C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[C:4]([O:6][CH3:7])=[O:5].[C:16]([N:24]=[C:25]=[S:26])(=[O:23])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>ClCCl>[C:16]([NH:24][C:25](=[S:26])[NH:1][CH2:2][C@H:3]([NH:8][C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[C:4]([O:6][CH3:7])=[O:5])(=[O:23])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: O=C(N=C=S)c1ccccc1
Reactant: COC(=O)[C@H](CN)NC(=O)OC(C)(C)C
Solvent: ClCCl
Product: COC(=O)[C@H](CNC(=S)NC(=O)c1ccccc1)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 26.1 %

Procedure:
To an ice cold solution of (S)-methyl 3-amino-2-((tert-butoxycarbonyl)amino)propanoate (see US2007/93414A1, 10.3 g, 47.2 mmol) in anhydrous dichloromethane (170 mL) is slowly added benzoyl isothiocyanate (6.35 mL, 47.2 mmol). The reaction is stirred for 2.5 h while slowly warming to room temp. The solvent is removed in vacuo and the residue is purified by BIOTAGE® Silica gel chromatography on a 300 g Thompson Single Step silica cartridge using a linear gradient from 100% hexanes to 100% EtOAc over 10 column volumes to give 4.7 g (26.1%) of the title compound as a pale yellow solid. LC/MS (Condition A): ret. T=3.48 min, (M+Na) 404.
Reaction SMILES: Cl.[NH2:2][OH:3].C([O-])(=O)C.[Na+].[CH2:9]([C:13]1[CH:14]=[C:15]2[C:19](=[CH:20][CH:21]=1)[C:18](=O)[CH2:17][CH2:16]2)[CH2:10][CH2:11][CH3:12]>C(O)C.O>[CH2:9]([C:13]1[CH:14]=[C:15]2[C:19](=[CH:20][CH:21]=1)[C:18](=[N:2][OH:3])[CH2:17][CH2:16]2)[CH2:10][CH2:11][CH3:12]
Reactant: CCCCc1ccc2c(c1)CCC2=O
Reactant: NO
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: CCCCc1ccc2c(c1)CCC2=NO

Procedure:
Hydroxylamine hydrochloride (0.89 g, 12.8 mmol) and sodium acetate (12.8 mmol) are added to a solution of 5-n-butylindan-1-one (1.0 g, 5.31 mmol) in ethanol (30 ml) and water (3 ml). The reaction is heated to reflux for 20 minutes, then water is added and the mixture is extracted with CH2Cl2. The combined organic extracts are washed with brine, dried (MgSO4) and evaporated to afford the title compound. NMR δH 0.86 (t J 7.3 3H), 1.28 (sextet J 7.3 2H), 1.52 (quintet J 7.3 2H), 2.55 (t J 8.0 2H), 2.85-3.0 (m 4H), 7.0 (d J 8.3 1H), 7.05 (s 1H), 7.45 (d J 8.3 2H)
Reaction SMILES: [Cl:1][C:2]1[S:6][C:5]([C:7]([OH:9])=O)=[CH:4][C:3]=1[C:10]1[N:14]([CH2:15][CH3:16])[N:13]=[CH:12][C:11]=1[Cl:17].C1CN([P+](Br)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[NH2:51][C@@H:52]([CH2:65][C:66]1[CH:71]=[CH:70][CH:69]=[C:68]([F:72])[CH:67]=1)[CH2:53][N:54]1[C:62](=[O:63])[C:61]2[C:56](=[CH:57][CH:58]=[CH:59][CH:60]=2)[C:55]1=[O:64]>C(Cl)Cl>[Cl:1][C:2]1[S:6][C:5]([C:7]([NH:51][C@@H:52]([CH2:65][C:66]2[CH:71]=[CH:70][CH:69]=[C:68]([F:72])[CH:67]=2)[CH2:53][N:54]2[C:62](=[O:63])[C:61]3[C:56](=[CH:57][CH:58]=[CH:59][CH:60]=3)[C:55]2=[O:64])=[O:9])=[CH:4][C:3]=1[C:10]1[N:14]([CH2:15][CH3:16])[N:13]=[CH:12][C:11]=1[Cl:17]
Reactant: CCn1ncc(Cl)c1-c1cc(C(=O)O)sc1Cl
Reactant: N[C@@H](Cc1cccc(F)c1)CN1C(=O)c2ccccc2C1=O
Agent: Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCn1ncc(Cl)c1-c1cc(C(=O)N[C@@H](Cc2cccc(F)c2)CN2C(=O)c3ccccc3C2=O)sc1Cl
Reaction time: 0.17 h
Yield: 80.7 %

Procedure:
To a solution of 5-chloro-4-(4-chloro-1-ethyl-1H-pyrazol-5-yl)-2-thiophenecarboxylic acid (180 mg, 0.618 mmol) [from Example 235(c)] in DCM (5 mL) at 25° C. was added PyBrOP in one portion, followed by addition of DIPEA (0.54 mL, 3.09 mmol). After stirring for 10 min, 2-[(2S)-2-amino-3-(3-fluorophenyl)propyl]-1H-isoindole-1,3(2H)-dione (203 mg, 0.68 mmol) was added to above solution in one portion. After stirring for 2 h, the solution was concentrated and purified via column chromatography (silica, 20-50% EtOAc/Hexane) affording the title compound (285 mg, 77%) as a white solid: LC-MS (ES) m/z=571 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]2[NH:8][CH2:9][C:10]3([CH2:15][CH2:14][N:13]([CH3:16])[CH2:12][CH2:11]3)[C:5]2=[CH:4][CH:3]=1.F[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[N+:24]([O-:26])=[O:25].C(=O)(O)[O-].[Na+]>>[Cl:1][C:2]1[CH:7]=[C:6]2[N:8]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[N+:24]([O-:26])=[O:25])[CH2:9][C:10]3([CH2:15][CH2:14][N:13]([CH3:16])[CH2:12][CH2:11]3)[C:5]2=[CH:4][CH:3]=1
Reactant: O=[N+]([O-])c1ccccc1F
Reactant: CN1CCC2(CC1)CNc1cc(Cl)ccc12
Agent: O=C([O-])O
Agent: [Na+]
Product: CN1CCC2(CC1)CN(c1ccccc1[N+](=O)[O-])c1cc(Cl)ccc12
Reaction time: 16 h

Procedure:
A mixture of 2.4 g of 6-chloro-1'-methylspiro[indoline-3,4'-piperidine], Example 23 b, 5.4 g of 2-fluoronitrobenzene and 1.0 g of sodium bicarbonate is stirred at 160°-165° C. under nitrogen, for 16 hours. Thereafter, the mixture is permitted to cool before sequentially being quenched with water and extracted thrice with ether. The combined ether extracts are shaken with a large excess of 1 N hydrochloric acid. The acidified layer is basified providing a reddish oil which upon drying over magnesium sulfate and then cooling leaves an orange solid. The solid is recrystallized from an etherpentane mixture to provide prisms, mp 130°-131° C. of 6-chloro-1'-methyl-1-(2-nitrophenyl)spiro[indoline-3,4'-piperidine].