Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([CH:7]=[C:8]2[C:13](=O)[C:12](=[CH:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[CH2:11][S:10][CH2:9]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:22]([NH:25][NH2:26])[CH2:23][CH3:24]>CO>[C:1]1([CH:7]2[NH:26][N:25]([CH2:22][CH2:23][CH3:24])[C:13]3[C:12](=[CH:15][C:16]4[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=4)[CH2:11][S:10][CH2:9][C:8]2=3)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CCCNN
Reactant: O=C1C(=Cc2ccccc2)CSCC1=Cc1ccccc1
Solvent: CO
Product: CCCN1NC(c2ccccc2)C2=C1C(=Cc1ccccc1)CSC2
Reaction time: 0.5 h

Procedure:
A mixture of tetrahydro-3,5-bis-(phenylmethylene)-4H-thiopyran-4-one (5.84 g, 20 mmole) and n-propyl hydrazine (1.48 g, 20 mmole, CA 59:8724f) in MeOH (100 ml) is heated at reflux temperature for 3 hours. The initial heterogeneous mixture becomes homogeneous after about 0.5 hour. Upon cooling, crystals form and are collected and washed (MeOH) to give 5.0 g, m.p. 106°-118°. Recrystallization from MeOH gives the major product.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([F:21])=[C:6]([C@:8]2([CH3:20])[C:14]([F:16])([F:15])[C:13]([CH3:18])([CH3:17])[O:12][CH2:11][C:10](=[O:19])[NH:9]2)[CH:7]=1.C(N(CC)CC)C.[Cl:29][C:30]1[CH:35]=[CH:34][CH:33]=[C:32]([C:36]#[CH:37])[CH:31]=1>C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.Cl[Pd]Cl.[Cu]I.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CN(C)C=O>[Cl:29][C:30]1[CH:31]=[C:32]([C:36]#[C:37][C:2]2[CH:3]=[CH:4][C:5]([F:21])=[C:6]([C@:8]3([CH3:20])[C:14]([F:16])([F:15])[C:13]([CH3:18])([CH3:17])[O:12][CH2:11][C:10](=[O:19])[NH:9]3)[CH:7]=2)[CH:33]=[CH:34][CH:35]=1
Reactant: C#Cc1cccc(Cl)c1
Reactant: CC1(C)OCC(=O)N[C@](C)(c2cc(Br)ccc2F)C1(F)F
Agent: Cl[Pd]Cl
Agent: [Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC1(C)OCC(=O)N[C@](C)(c2cc(C#Cc3cccc(Cl)c3)ccc2F)C1(F)F
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 89.6 %

Procedure:
A dried pressure tube was charged with (R)-5-(5-bromo-2-fluorophenyl)-6,6-difluoro-5,7,7-trimethyl-1,4-oxazepan-3-one (intermediate B6.1) (250 mg, 622 μmol) and dimethylformamide (2 ml). The solution was flushed with argon, thereafter, successively bis(triphenylphosphin)palladium(II)chloride (31.2 mg, 43.5 μmol), triphenylphoshine (3.26 mg, 12.4 μmol), triethylamine (126 mg, 1.24 mmol), 1-chloro-3-ethynylbenzene (175 mg, 1.24 mmol), and copper(i) iodide (3.6 mg, 18.7 μmol) were added. The tube was sealed and the reaction mixture stirred at room temperature for 10 minutes, then it was heated at 60° C. for 16 hours. For the workup, the reaction mixture was cooled and evaporated at reduced pressure. The residue was directly purified by chromatography on an amine-silica phase using a gradient of heptane/ethyl acetate=100:0 to 60:10 as the eluent. The (R)-5-[5-(3-chloro-phenylethynyl)-2-fluoro-phenyl]-6,6-difluoro-5,7,7-trimethyl-[1,4]oxazepan-3-one (235 mg, 90% yield) was obtained as a green foam. MS (ISP): m/z=422.1 [M+2+H]+ and 424.2 [M+H]+.
Reaction SMILES: C([N:4]1[CH2:8][CH2:7][N:6]([C:9]2[CH:14]=[C:13](Cl)[CH:12]=[CH:11][C:10]=2[C:16]([N:18]2[CH2:23][CH2:22][N:21]([C:24]3[C:29]([CH3:30])=[CH:28][C:27]([CH3:31])=[CH:26][N:25]=3)[CH2:20][CH2:19]2)=[O:17])[C:5]1=[O:32])(=O)C.[S:33]1(=[O:39])(=[O:38])[CH2:37][CH2:36][CH2:35][NH:34]1>>[CH3:30][C:29]1[C:24]([N:21]2[CH2:20][CH2:19][N:18]([C:16]([C:10]3[CH:11]=[CH:12][C:13]([N:34]4[CH2:35][CH2:36][CH2:37][S:33]4(=[O:39])=[O:38])=[CH:14][C:9]=3[N:6]3[CH2:7][CH2:8][NH:4][C:5]3=[O:32])=[O:17])[CH2:23][CH2:22]2)=[N:25][CH:26]=[C:27]([CH3:31])[CH:28]=1
Reactant: CC(=O)N1CCN(c2cc(Cl)ccc2C(=O)N2CCN(c3ncc(C)cc3C)CC2)C1=O
Reactant: O=S1(=O)CCCN1
Product: Cc1cnc(N2CCN(C(=O)c3ccc(N4CCCS4(=O)=O)cc3N3CCNC3=O)CC2)c(C)c1
Yield: 28.1 %

Procedure:
Using 1-acetyl-3-{5-chloro-2-[4-(3,5-dimethylpyridin-2-yl)piperazine-1-carbonyl]phenyl}imidazolidin-2-one (117 mg) described in Preparation Example 234 and isothiazolidine 1,1-dioxide (47 mg) and by the reaction and treatment in the same manner as in Example 649, the title compound (36 mg) was obtained.
Reaction SMILES: CN1CCOCC1.[C:8]([O:12][C:13]([NH:15][C@H:16]([C:22]([O:24][CH3:25])=[O:23])[CH2:17][CH2:18][C:19]([OH:21])=O)=[O:14])([CH3:11])([CH3:10])[CH3:9].[C:26]([O:30][C:31]([NH:33][CH2:34][CH2:35][NH:36][CH2:37][CH2:38][NH:39][C:40](=[O:46])[O:41][C:42]([CH3:45])([CH3:44])[CH3:43])=[O:32])([CH3:29])([CH3:28])[CH3:27]>C(Cl)Cl>[C:42]([O:41][C:40]([NH:39][CH2:38][CH2:37][N:36]([CH2:35][CH2:34][NH:33][C:31]([O:30][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:32])[C:19]([CH2:18][CH2:17][C@H:16]([NH:15][C:13]([O:12][C:8]([CH3:9])([CH3:10])[CH3:11])=[O:14])[C:22]([O:24][CH3:25])=[O:23])=[O:21])=[O:46])([CH3:45])([CH3:44])[CH3:43]
Reactant: COC(=O)[C@H](CCC(=O)O)NC(=O)OC(C)(C)C
Reactant: CC(C)(C)OC(=O)NCCNCCNC(=O)OC(C)(C)C
Solvent: CN1CCOCC1
Solvent: ClCCl
Product: COC(=O)[C@H](CCC(=O)N(CCNC(=O)OC(C)(C)C)CCNC(=O)OC(C)(C)C)NC(=O)OC(C)(C)C
Reaction time: 0.17 h
Yield: 72 %

Procedure:
To a solution of CDMT (2.22 g, 12.62 mmol) in DCM (40 mL) and cooled to 0° C. was added N-methylmorpholine (1.38 mL, 12.63 mmol). The mixture was stirred for 10 min before adding (4S)-4-{[(tert-butoxy)carbonyl]amino}-5-methoxy-5-oxopentanoic acid (3.0 g, 11.48 mmol). The solution was stirred for 60 min at 0° C. The tert-butyl N-{2-[(2-{[(tert-butoxy)carbonyl]amino}ethyl)amino]ethyl}carbamate XIV was then added and the mixture stirred at room temperature overnight. The solution was washed with 1 M aq. K2CO3, 1 M aq. HCl, brine and dried over anhydrous MgSO4. The crude product was crystallized from DCM/hexane to give methyl (2S)-4-[bis(2-{[(tert-butoxy)carbonyl]amino}ethyl)carbamoyl]-2-{[(tert-butoxy)carbonyl]amino}butanoate (XV) (4.91 g, 8.98 mmol, 72% yield). 1H NMR (DMSO-d6) δ ppm 1.35-1.47 (m, 27H), 1.80-1.91 (m, 1H), 2.19-2.32 (m, 1H), 2.33-2.42 (m, 1H), 2.46-2.57 (m, 1H), 3.11-3.38 (m, 6H), 3.40-3.53 (m, 1H), 3.54-3.62 (m, 1H), 3.73 (s, 3H), 4.26-4.38 (m, 1H), 4.99-5.09 (brs, 1H), 5.31-5.46 (m, 2H); ESIMS found for C25H46N4O9 m/z 547 (M+H).
Reaction SMILES: [CH3:1][C:2]1([CH3:20])[CH2:7][CH2:6][CH:5]=[C:4]([C:8]2[CH:13]=[CH:12][C:11]([F:14])=[C:10]([CH3:15])[CH:9]=2)[CH:3]1[C:16]([O:18][CH3:19])=[O:17].[BH4-].[Na+].C[OH:24]>CCOCC.O>[F:14][C:11]1[CH:12]=[CH:13][C:8]([C:4]2[CH:3]([C:16]([O:18][CH3:19])=[O:17])[C:2]([CH3:20])([CH3:1])[CH2:7][CH:6]([OH:24])[CH:5]=2)=[CH:9][C:10]=1[CH3:15]
Reactant: CO
Reactant: COC(=O)C1C(c2ccc(F)c(C)c2)=CCCC1(C)C
Agent: [BH4-]
Agent: [Na+]
Solvent: CCOCC
Solvent: O
Product: COC(=O)C1C(c2ccc(F)c(C)c2)=CC(O)CC1(C)C
Reaction time: 1 h

Procedure:
To a solution of 4a (13.7 g, 47.2 mmol) in 100 mL of methanol at 0°-5° C. was added NaBH4 (2.68 g, 70.9 mmol). The mixture was stirred for 1 hr, diluted with ether and H2O. The organic layer was washed with H2O and brine and dried (MgSO4). Removal of the volatiles in vacuo provided a quantitive yield of product which was taken forward without further purification.
Reaction SMILES: [CH3:1][C:2]1([CH3:11])[CH2:7][CH:6]([OH:8])[CH2:5][C:4]([CH3:10])([CH3:9])[NH:3]1.[CH2:12]1[O:20][CH:13]1[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.C(O)CCCCC>>[OH:20][CH:13]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[CH2:12][N:3]1[C:4]([CH3:10])([CH3:9])[CH2:5][CH:6]([OH:8])[CH2:7][C:2]1([CH3:11])[CH3:1]
Reactant: CC1(C)CC(O)CC(C)(C)N1
Reactant: c1ccc(C2CO2)cc1
Solvent: CCCCCCO
Product: CC1(C)CC(O)CC(C)(C)N1CC(O)c1ccccc1

Procedure:
A mixture of 3.14 parts of 2,2,6,6-tetramethylpiperidin-4-ol, 30 parts of styrene oxide and 30 parts of n-hexanol was heated at reflux for 18 hours. The n-hexanol solvent and unreacted styrene oxide were removed by distillation under reduced pressure. Crystallisation of the residue from cyclohexane gave 4.2 parts of 1-[2-hydroxy-2-phenylethyl]-2,2,6,6-tetramethylpiperidin-4-ol having a melting point of 123°C and the following elemental analysis by weight.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][NH:4][CH2:3][C:2]1=[O:7].C(N(CC)CC)C.[Cl:15][C:16]1[N:21]=[CH:20][C:19]([S:22](Cl)(=[O:24])=[O:23])=[CH:18][CH:17]=1>C(Cl)Cl>[Cl:15][C:16]1[N:21]=[CH:20][C:19]([S:22]([N:4]2[CH2:5][CH2:6][NH:1][C:2](=[O:7])[CH2:3]2)(=[O:24])=[O:23])=[CH:18][CH:17]=1
Reactant: O=C1CNCCN1
Reactant: O=S(=O)(Cl)c1ccc(Cl)nc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C1CN(S(=O)(=O)c2ccc(Cl)nc2)CCN1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 88.5 %

Procedure:
To a mixture of 2-piperazinone (0.46 g, 4.59 mmol, Sigma-Aldrich, St. Louis, Mo.) and triethylamine (1.5 mL, 10.76 mmol) in CH2Cl2 (20 mL) at 0° C. was added 6-chloropyridine-3-sulfonyl chloride (0.974 g, 4.59 mmol, Organic Process Research & Development 2009, 13, 875). The resulting slurry was stirred at room temperature for 30 min and then was concentrated. The residue was mixed with saturated aqueous NaHCO3 (10 mL) and was stirred at room temperature for 1 d. The slurry was filtered, washed with water (3×5 mL), and dried under reduced pressure to give 4-((6-chloro-3-pyridinyl)sulfonyl)-2-piperazinone as a white solid (1.12 g).
Reaction SMILES: Br[C:2]1[O:3][C:4]2[C:24]([O:25]C(=O)C)=[C:23]([O:29][CH3:30])[CH:22]=[CH:21][C:5]=2[C:6]=1[C:7](=[O:20])[C:8]1[CH:13]=[C:12]([O:14][CH3:15])[C:11]([O:16][CH3:17])=[C:10]([O:18][CH3:19])[CH:9]=1.[CH2:31]([NH2:38])[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1>N1C=CC=CC=1>[CH2:31]([NH:38][C:2]1[O:3][C:4]2[C:24]([OH:25])=[C:23]([O:29][CH3:30])[CH:22]=[CH:21][C:5]=2[C:6]=1[C:7]([C:8]1[CH:9]=[C:10]([O:18][CH3:19])[C:11]([O:16][CH3:17])=[C:12]([O:14][CH3:15])[CH:13]=1)=[O:20])[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1
Reactant: NCc1ccccc1
Reactant: COc1cc(C(=O)c2c(Br)oc3c(OC(C)=O)c(OC)ccc23)cc(OC)c1OC
Solvent: c1ccncc1
Product: COc1cc(C(=O)c2c(NCc3ccccc3)oc3c(O)c(OC)ccc23)cc(OC)c1OC
Temperature: 80 °C
Reaction time: 1 h
Yield: 83 %

Procedure:
2-bromo-7-acetoxy-3-(3,4,5-trimethoxybenzoyl)-6-methoxy-benzofuran (140 mg, 0.29 mmol) was dissolved in dry pyridine (2 mL) and benzylamine (500 μL, excess) was added to it and the reaction mixture was stirred at 80° C. for 1 hour. Solvent was distilled and the crude product was purified over silica gel column to afford the title compound as light yellow solid (112 mg, 83%); 1H NMR (300 MHz, CDCl3) δ: 9.27 (b, 1H, NH), 7.39-7.32 (m, 5 Hs, Ar Hs), 6.96 (s, 2H, benzoyl Hs), 6.61 (d, 1H, J=8.47 Hz), 6.50 (d, 1H, J=8.10 Hz), 4.83 (d, 2H, J=4.95 Hz, Benzyl Hs), 3.91 (s, 3H, OMe), 3.85 (s, 3H, OMe), 3.84 (s, 6H, 2×OMe).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[N:8]([CH3:12])[CH:7]=[C:6]2[C:13]1[N:22]([CH2:23][O:24][CH2:25][CH2:26][Si:27]([CH3:30])([CH3:29])[CH3:28])[C:16]2=[N:17][CH:18]=[C:19]([NH2:21])[N:20]=[C:15]2[CH:14]=1.Cl[CH2:32][CH:33]=O>CCO>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[N:8]([CH3:12])[CH:7]=[C:6]2[C:13]1[N:22]([CH2:23][O:24][CH2:25][CH2:26][Si:27]([CH3:29])([CH3:28])[CH3:30])[C:16]2[N:17]=[CH:18][C:19]3[N:20]([CH:32]=[CH:33][N:21]=3)[C:15]=2[CH:14]=1
Reactant: COc1ccc2c(c1)c(-c1cc3nc(N)cnc3n1COCC[Si](C)(C)C)cn2C
Reactant: O=CCCl
Solvent: CCO
Product: COc1ccc2c(c1)c(-c1cc3c(ncc4nccn43)n1COCC[Si](C)(C)C)cn2C
Temperature: 80 °C
Yield: 96.8 %

Procedure:
In a round flask was added 6-(5-methoxy-1-methyl-1H-indol-3-yl)-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[2,3-b]pyrazin-2-amine (0.065 g, 0.15 mmol) and 2-chloroacetaldehyde (˜50 wt % solution in water, 0.030 mL, 0.23 mmol) in EtOH (2 mL) and mixture was heated to about 80° C. for about 45 min. The mixture was concentrated under reduced pressure to give 2-(5-methoxy-1-methyl-1H-indol-3-yl)-3-((2-(trimethylsilyl)ethoxy)methyl)-3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazine (0.065 g, 95%): LC/MS (Table 2, b) Rt=1.79 min; MS m/z 448 (M+H)+.
Reaction SMILES: C([S:4][C@H:5]1[N:8]([CH2:9][C:10]([O:12][CH2:13][C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=2)=[O:11])[C:7](=[O:22])[C@@H:6]1[Br:23])(=O)C.[N+]([O-])([O-])=O.[Ag+:28].C(N(CC)CC)C>CO>[Br:23][C@@H:6]1[C@@H:5]([S-:4])[N:8]([CH2:9][C:10]([O:12][CH2:13][C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=2)=[O:11])[C:7]1=[O:22].[Ag+:28]
Reactant: COc1ccc(COC(=O)CN2C(=O)[C@H](Br)[C@H]2SC(C)=O)cc1
Agent: [Ag+]
Agent: O=[N+]([O-])[O-]
Solvent: CO
Solvent: CCN(CC)CC
Product: COc1ccc(COC(=O)CN2C(=O)[C@H](Br)[C@H]2[S-])cc1
Reaction time: 1 h

Procedure:
A solution of p-methoxybenzyl [(3S, 4R)-4-acetylthio-3-bromo-2-oxoazetidin-1-yl]acetate (4.13 g, 0.01 mol) in methanol (90 ml) was added with stirring in subdued light to a solution of silver nitrate (2.27 g, 0.0133 mol) in methanol (90 ml). Triethylamine (1.87 ml, 0.0133 mol) was then added with ice cooling, and stirring continued for 1 hr. at 5-10° C. followed by 30 min. at room temperature. The mixture was re-cooled (ice bath) and the precipitated solid filtered and washed twice with ice cold methanol then hexane to give the title compound, yield, 4.6 g (96%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]([O:17][CH2:18][C:19]([F:22])([F:21])[F:20])=[N:10][CH:11]=[C:12]([CH:16]=2)[C:13]([OH:15])=O)=[CH:4][CH:3]=1.[CH3:23][CH:24]([C:26]1[O:30][N:29]=[C:28]([CH2:31][NH2:32])[CH:27]=1)[CH3:25]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[C:9]([O:17][CH2:18][C:19]([F:20])([F:22])[F:21])=[N:10][CH:11]=[C:12]([CH:16]=2)[C:13]([NH:32][CH2:31][C:28]2[CH:27]=[C:26]([CH:24]([CH3:25])[CH3:23])[O:30][N:29]=2)=[O:15])=[CH:6][CH:7]=1
Reactant: CC(C)c1cc(CN)no1
Reactant: O=C(O)c1cnc(OCC(F)(F)F)c(-c2ccc(Cl)cc2)c1
Product: CC(C)c1cc(CNC(=O)c2cnc(OCC(F)(F)F)c(-c3ccc(Cl)cc3)c2)no1

Procedure:
The title compound was synthesized in analogy to Example 1, using 5-(4-chloro-phenyl)-6-(2,2,2-trifluoro-ethoxy)-nicotinic acid (CAS Registry No. 1018782-82-5) and 5-(1-methylethyl)-3-isoxazolemethanamine (CAS Registry No. 154016-49-6) as starting materials, 454.1 (M+H)+.
Reaction SMILES: [F:1][C:2]1[C:3]([NH:18][S:19]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)(=[O:21])=[O:20])=[N:4][C:5]([O:8]CC2C=CC=CC=2OC)=[N:6][CH:7]=1.FC(F)(F)C(O)=O>ClCCl>[F:1][C:2]1[C:3]([NH:18][S:19]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)(=[O:21])=[O:20])=[N:4][C:5]([OH:8])=[N:6][CH:7]=1
Reactant: COc1ccccc1COc1ncc(F)c(NS(=O)(=O)c2ccccc2)n1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=S(=O)(Nc1nc(O)ncc1F)c1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 50.9 %

Procedure:
The solid N-(5-fluoro-2-(2-methoxybenzyloxy)pyrimidin-4-yl)benzenesulfonamide (714 mg, 1.83 mmol) was dissolved in dichloromethane (10 mL) followed by the addition of trifluoroacetic acid (1.0 mL, 13.5 mmol) and allowed to stir at room temperature for 1 h. The solvent was removed in vacuo and the resulting residue was dissolved in dichloromethane:methanol in a 10:1 ratio. The product was purified by column chromatography (dichloromethane/methanol gradient) to yield N-(5-fluoro-2-hydroxypyrimidin-4-yl)benzenesulfonamide (251 mg, 51% yield) as a white solid: mp 221-223° C.; 1H NMR (300 MHz) δ 11.57 (bs, 1H), 11.11 (bs, 1H), 8.04 (d, J=6.1 Hz, 1H), 7.94-7.84 (m, 2H), 7.71-7.51 (m, 3H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH2:8][OH:9])[CH:5]=[CH:6][CH:7]=1.N1C=CC=CC=1.[C:16](Cl)(=[O:27])[O:17][C:18]1[CH:23]=[CH:22][C:21]([N+:24]([O-:26])=[O:25])=[CH:20][CH:19]=1>C(Cl)Cl>[C:16](=[O:27])([O:17][C:18]1[CH:19]=[CH:20][C:21]([N+:24]([O-:26])=[O:25])=[CH:22][CH:23]=1)[O:9][CH2:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([Br:1])[CH:3]=1
Reactant: OCc1cccc(Br)c1
Reactant: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Solvent: c1ccncc1
Solvent: ClCCl
Product: O=C(OCc1cccc(Br)c1)Oc1ccc([N+](=O)[O-])cc1
Temperature: 0 °C
Reaction time: 2 h
Yield: 103.5 %

Procedure:
To a solution of (3-bromophenyl)methanol (10 g, 53.5 mmol) and pyridine (8.65 mL, 107 mmol) in DCM (80 mL) at 0° C. was added a solution of 4-nitrophenyl carbonochloridate (12.93 g, 64.2 mmol) in DCM (20 mL) dropwise. Upon the completion of addition, the reaction mixture was stirred at 0° C. for 2 h. After this time, the reaction was quenched with water. The organic layer was separated and washed with water, brine, dried over anhydrous MgSO4, filtered, and concentrated to afford the title compound (19.5 g, 100%). 1H NMR (400 MHz, CDCl3) δ 8.31-8.29 (m, 1H), 8.28-8.25 (m, 1H), 7.61 (t, J=1.6 Hz, 1H), 7.53 (d, J=8.2 Hz, 1H), 7.42-7.34 (m, 3H), 7.30 (d, J=7.8 Hz, 1H), 5.26 (s, 2H).
Reaction SMILES: [H-].[Na+].[C:3]1([SH:9])[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[C:10]1(=[O:15])[O:14][CH2:13][CH2:12][CH2:11]1.[OH-].[Na+]>C1COCC1.O>[C:3]1([S:9][CH2:13][CH2:12][CH2:11][C:10]([OH:15])=[O:14])[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: O=C1CCCO1
Reactant: Sc1ccccc1
Agent: [H-]
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)CCCSc1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 81.1 %

Procedure:
To a suspension of sodium hydride (60% in mineral oil, 10.4 g, 0.26 mol) in anhydrous THF (400 mL) at ambient temperature is added thiophenol (26 g, 0.23 mol) dropwise via syringe. The resulting white suspension is stirred for 30 minutes under a nitrogen atmosphere then γ-butyrolactone (22.4 g, 0.26 mol) is added. The mixture is warmed to gentle reflux and stirred for 6 hours after which it became a solid mass and is allowed to cool to room temperature and stand overnight. The mixture is dissolved in water (1200 mL) containing 1 N NaOH (100 mL) and is extracted with diethyl ether (2×500 mL). The aqueous layer is acidified with 1N HCl and extracted with diethyl ether (3×500 mL). The organic extracts are washed with brine (300 mL) then dried over MgSO4, filtered and concentrated to afford a white solid which is chromatographed on silica gel (pet-ether/EtOAc, 19:1→9:1) to afford 4-phenylsulfanylbutanoic acid (36.6 g, 79%) as a white solid. TLC analysis [pet-ether/EtOAc, 1:1, Rf (thiophenol)=0.90, Rf (acid)=0.50]. m.p. 73-74° C.; 1H NMR (300 MHz, CDCl3) δ 1.95 (quint, J=7.1 Hz, 2H), 2.52 (t, J=7.2 Hz, 2H), 2.97 (t, J=7.1 Hz, 2H), 7.1-7.3 (m, 5H) ppm. Mass spectrum (EI) m/z 196 (M)+.
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[CH:9][C:8]([CH3:11])=[C:7]2[C:3]=1[CH2:4][CH:5]([C:12]([O:14][CH3:15])=[O:13])[NH:6]2.[OH:16]O>CO>[OH:16][N:6]1[C:7]2[C:3](=[C:2]([CH3:1])[CH:10]=[CH:9][C:8]=2[CH3:11])[CH:4]=[C:5]1[C:12]([O:14][CH3:15])=[O:13]
Reactant: COC(=O)C1Cc2c(C)ccc(C)c2N1
Reactant: OO
Solvent: CO
Product: COC(=O)c1cc2c(C)ccc(C)c2n1O
Temperature: 0 °C
Reaction time: 3 h
Yield: 35.5 %

Procedure:
A flask was charged with 1.0 g (4.9 mmol) of methyl 4,7-dimethylindoline-2-carboxylate and 64 mg (0.193 mmol) of sodium tungstate-dihydrate, and the air in the reaction system was substituted with nitrogen. Methanol (15 ml) was added and the reaction mixture was cooled to 0° C. Then 1.25 g of 30% aqueous hydrogen peroxide solution was added and the reaction mixture was stirred for 3 hours. Yield: 35.5%
Reaction SMILES: Cl.Cl.[NH2:3][C:4]1[S:20][C:7]2[CH2:8][CH2:9][N:10]([CH2:13][C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[CH2:11][CH2:12][C:6]=2[CH:5]=1.[S-:21][C:22]#[N:23].[K+].BrBr>>[NH2:23][C:22]1[S:21][C:5]2[C:6]3[CH2:12][CH2:11][N:10]([CH2:13][C:14]4[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=4)[CH2:9][CH2:8][C:7]=3[S:20][C:4]=2[N:3]=1
Reactant: Nc1cc2c(s1)CCN(Cc1ccccc1)CC2
Reactant: N#C[S-]
Agent: BrBr
Agent: Cl
Agent: [K+]
Product: Nc1nc2sc3c(c2s1)CCN(Cc1ccccc1)CC3

Procedure:
This compound was prepared from 2-amino-6-benzyl-5,6,7,8-tetrahydro-4H-thieno[2,3-d]azepine dihydrochloride, potassium thiocyanate and bromine analogous to Example 1.
Reaction SMILES: [CH2:1]([NH2:3])[CH3:2].Cl[C:5]1[C:12]([N+:13]([O-:15])=[O:14])=[CH:11][CH:10]=[C:9]([Cl:16])[C:6]=1[C:7]#[N:8]>C1COCC1.CCOC(C)=O>[Cl:16][C:9]1[C:6]([C:7]#[N:8])=[C:5]([NH:3][CH2:1][CH3:2])[C:12]([N+:13]([O-:15])=[O:14])=[CH:11][CH:10]=1
Reactant: N#Cc1c(Cl)ccc([N+](=O)[O-])c1Cl
Reactant: CCN
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCNc1c([N+](=O)[O-])ccc(Cl)c1C#N
Reaction time: 1.5 h
Yield: 82 %

Procedure:
A solution of ethylamine in THF (2 M, 13.8 mL, 27.6 mmol) was added slowly to a solution of 2,6-dichloro-3-nitrobenzonitrile (3.0 g, 13.8 mmol) in THF (30 mL) at −5° C. After 1.5 h, the solution was diluted with EtOAc (150 mL) and washed with 0.5 N HCl and brine. Organics were dried (MgSO4) and concentrated in vacuo. Purification by silica gel chromatography (8:1:1 hexanes/CHCl3/EtOAc) gave 2.57 g (82%) of the title compound as an orange solid. 1H NMR (400 MHz, CDCl3): δ 8.51 (br s, 1H), 8.30 (d, 1H, J=8.8 Hz), 6.78 (d, 1H, J=8.4 Hz), 3.89-3.97 (m, 2H), 1.41 (t, 3H, J=7.2 Hz). MS (ES) [m+H] calc'd for C9H8N3O2Cl, 226, 228; found 226, 228.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[C:10]2[C:5]([NH:6][C:7](=[O:19])[C:8](=[O:18])[N:9]2[CH2:12][CH:13]([CH2:16][CH3:17])[CH2:14][CH3:15])=[CH:4][C:3]=1[N+:20]([O-:22])=[O:21].[CH3:23][O:24][C:25]([C:27]1(OC)[CH2:31][CH2:30][CH:29](OC)O1)=[O:26]>C(O)(=O)C>[CH2:14]([CH:13]([CH2:16][CH3:17])[CH2:12][N:9]1[C:10]2[C:5](=[CH:4][C:3]([N+:20]([O-:22])=[O:21])=[C:2]([N:1]3[CH:29]=[CH:30][CH:31]=[C:27]3[C:25]([O:24][CH3:23])=[O:26])[CH:11]=2)[NH:6][C:7](=[O:19])[C:8]1=[O:18])[CH3:15]
Reactant: COC(=O)C1(OC)CCC(OC)O1
Reactant: CCC(CC)Cn1c(=O)c(=O)[nH]c2cc([N+](=O)[O-])c(N)cc21
Solvent: CC(=O)O
Product: CCC(CC)Cn1c(=O)c(=O)[nH]c2cc([N+](=O)[O-])c(-n3cccc3C(=O)OC)cc21
Temperature: 0 °C
Yield: 27.1 %

Procedure:
3.0 g (9.8 mmol) of 7-amino-1-(2-ethylbutyl)-6-nitro-2,3(1H,4H)-quinoxalinedione (Example 40 h) and 1.8 g (9.8 mmol) of 2-methoxycarbonyl-2,5-dimethoxytetrahydrofuran were refluxed in 150 ml of concentrated acetic acid for 1 h. The mixture was then poured into ice-water, and the precipitate was filtered off with suction to yield 1.1 g (28%) of the product. Melting point 240°-241° C.
Reaction SMILES: [CH3:1][C:2]([CH3:13])([CH3:12])[CH2:3][CH:4]=[CH:5][N:6]1[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]1.[C:14]([O:18][CH2:19][CH3:20])(=[O:17])[CH:15]=[CH2:16].C1(C=CC(O)=CC=1)O>C(#N)C>[CH3:1][C:2]([CH3:13])([CH3:12])[CH2:3][CH:4]1[CH2:16][CH:15]([C:14]([O:18][CH2:19][CH3:20])=[O:17])[CH:5]1[N:6]1[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]1
Reactant: CC(C)(C)CC=CN1CCCCC1
Reactant: C=CC(=O)OCC
Agent: Oc1ccc(O)cc1
Solvent: CC#N
Product: CCOC(=O)C1CC(CC(C)(C)C)C1N1CCCCC1
Temperature: 90 °C
Reaction time: 8 h

Procedure:
1-(4,4-Dimethyl-1-pentenyl)piperidine (1146 g) and acetonitrile (910 mL) were mixed. After an addition of ethyl acrylate (549 mL) and hydroquinone (553 mg) to the mixture, the mixture was stirred at 90° C. overnight. The reaction mixture was concentrated in vacuo to give the title compound (1470 g) as a crude product.
Reaction SMILES: Cl[C:2]1[C:14]2[N:13]3[C:8]([CH:9]=[CH:10][CH:11]=[CH:12]3)=[C:7]([C:15]3[C:20]([CH3:21])=[CH:19][C:18]([CH3:22])=[CH:17][C:16]=3[CH3:23])[C:6]=2[N:5]=[C:4]([CH3:24])[CH:3]=1.[CH2:25]([NH:28][CH2:29][CH2:30][CH3:31])[CH2:26][CH3:27]>CS(C)=O.O>[CH2:25]([N:28]([C:2]1[C:14]2[N:13]3[C:8]([CH:9]=[CH:10][CH:11]=[CH:12]3)=[C:7]([C:15]3[C:20]([CH3:21])=[CH:19][C:18]([CH3:22])=[CH:17][C:16]=3[CH3:23])[C:6]=2[N:5]=[C:4]([CH3:24])[CH:3]=1)[CH2:29][CH2:30][CH3:31])[CH2:26][CH3:27]
Reactant: CCCNCCC
Reactant: Cc1cc(C)c(-c2c3nc(C)cc(Cl)c3n3ccccc23)c(C)c1
Solvent: CS(C)=O
Solvent: O
Product: CCCN(CCC)c1cc(C)nc2c(-c3c(C)cc(C)cc3C)c3ccccn3c12
Temperature: 130 °C
Yield: 86.8 %

Procedure:
A mixture of 4-chloro-2-methyl-10-(2,4,6-trimethylphenyl)pyrido[2,3-b]indolizine (10.0 g; 30 mmol) and dipropylamine (15 mL; 1 mol) in DMSO (30 mL) is heated at 130° C. under nitrogen atmosphere for two days. The mixture is cooled to room temperature, diluted with water (ca. 300 mL), and extracted with ether (100 mL×2). The combined organics are washed successively with saturated ammonium chloride and saturated brine, dried (Na2SO4), filtered, and concentrated. The concentrate is chromatographed (first with 5% ethyl acetate in hexane and then with 10% triethylamine in hexane) to give 10.4 g of the title compound (compound 1, Table 1) as a fluorescent yellow foam (87%): 1H nmr (400 MHz, CDCl3) d 0.90 (t, 6 H), 1.6 (br, 4 H), 2.02 (s, 6 H), 2.37 (s, 3 H), 2.62 (s, 3 H), 3.2 (br, 4 H), 6.52 (t, 1 H), 6.73 (s, 1 H), 6.89 (t, 1 H), 7.00 (s, 2 H), 7.06 (d, 1 H), 8.98 (d, 1 H).