Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([S:11]([N:14]([CH2:24][C:25]([OH:27])=O)[C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[C:21](=[O:23])[NH2:22])(=[O:13])=[O:12])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH:28]1([NH:31][CH2:32][C:33]2[CH:38]=[CH:37][CH:36]=[C:35]([CH3:39])[CH:34]=2)[CH2:30][CH2:29]1>>[C:1]([C:5]1[CH:6]=[CH:7][C:8]([S:11]([N:14]([CH2:24][C:25](=[O:27])[N:31]([CH:28]2[CH2:30][CH2:29]2)[CH2:32][C:33]2[CH:38]=[CH:37][CH:36]=[C:35]([CH3:39])[CH:34]=2)[C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[C:21]([NH2:22])=[O:23])(=[O:12])=[O:13])=[CH:9][CH:10]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: Cc1cccc(CNC2CC2)c1
Reactant: CC(C)(C)c1ccc(S(=O)(=O)N(CC(=O)O)c2ccccc2C(N)=O)cc1
Product: Cc1cccc(CN(C(=O)CN(c2ccccc2C(N)=O)S(=O)(=O)c2ccc(C(C)(C)C)cc2)C2CC2)c1

Procedure:
prepared by reaction of [(4-tert-butyl-benzenesulfonyl)-(2-carbamoyl-phenyl)-amino]-acetic acid with cyclopropyl-(3-methyl-benzyl)-amine
Reaction SMILES: C([O:4][C:5]1[CH:6]=[CH:7][CH:8]=[C:9]2[C:14]=1[N:13]=[C:12]([CH3:15])[N:11]=[C:10]2[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)(C)C.B(Cl)(Cl)Cl.CO>ClCCl>[OH:4][C:5]1[CH:6]=[CH:7][CH:8]=[C:9]2[C:14]=1[N:13]=[C:12]([CH3:15])[N:11]=[C:10]2[C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: Cc1nc(-c2ccccc2)c2cccc(OC(C)C)c2n1
Agent: ClB(Cl)Cl
Solvent: CO
Solvent: ClCCl
Product: Cc1nc(-c2ccccc2)c2cccc(O)c2n1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a stirred solution of 8-isopropoxy-2-methyl-4-phenyl-quinazoline (36) (0.34 mmol) in dichloromethane (2 mL) at −78° C. was added BCl3 (1.36 mL of a 1 M solution in dichloromethane, 1.36 mmol). The reaction mixture was allowed to warm to RT (over 2 h) and stirred for a further 2 h. MeOH (5 mL) was added and the mixture was concentrated to dryness. The process was repeated four times. Further washing of the remaining residue with diethyl ether (2 mL×3) provided 8-hydroxy-2-methyl-4-phenyl-quinazoline (A24).
Reaction SMILES: [CH:1]1([N:4]([CH:18]2[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]2)[C:5](=[O:17])[C:6]2[CH:11]=[CH:10][C:9]([C:12]3[O:16][CH:15]=[N:14][CH:13]=3)=[CH:8][CH:7]=2)[CH2:3][CH2:2]1.Cl[C:25]1[N:30]=[CH:29][C:28]([C:31]2[CH:36]=[CH:35][C:34]([O:37][CH3:38])=[CH:33][CH:32]=2)=[CH:27][N:26]=1>>[CH:1]1([N:4]([CH:18]2[CH2:23][CH2:22][N:21]([C:25]3[N:26]=[CH:27][C:28]([C:31]4[CH:32]=[CH:33][C:34]([O:37][CH3:38])=[CH:35][CH:36]=4)=[CH:29][N:30]=3)[CH2:20][CH2:19]2)[C:5](=[O:17])[C:6]2[CH:7]=[CH:8][C:9]([C:12]3[O:16][CH:15]=[N:14][CH:13]=3)=[CH:10][CH:11]=2)[CH2:3][CH2:2]1
Reactant: O=C(c1ccc(-c2cnco2)cc1)N(C1CCNCC1)C1CC1
Reactant: COc1ccc(-c2cnc(Cl)nc2)cc1
Product: COc1ccc(-c2cnc(N3CCC(N(C(=O)c4ccc(-c5cnco5)cc4)C4CC4)CC3)nc2)cc1

Procedure:
The title compound is prepared from N-cyclopropyl-4-oxazol-5-yl-N-piperidin-4-yl-benzamide and 2-chloro-5-(4-methoxy-phenyl)-pyrimidine following a procedure analogous to that described in Example 19. LC (method 9): tR=2.33 min; Mass spectrum (ESI+): m/z=496 [M+H]+.
Reaction SMILES: [C:1]1([N:7]=[N+:8]=[N-:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:10]([O:14][C:15]([N:17]1[CH2:22][CH:21]=[C:20]([C:23]#[CH:24])[CH2:19][CH2:18]1)=[O:16])([CH3:13])([CH3:12])[CH3:11]>C1(C)C=CC=CC=1>[C:10]([O:14][C:15]([N:17]1[CH2:18][CH:19]=[C:20]([C:23]2[N:9]=[N:8][N:7]([C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)[CH:24]=2)[CH2:21][CH2:22]1)=[O:16])([CH3:13])([CH3:12])[CH3:11]
Reactant: C#CC1=CCN(C(=O)OC(C)(C)C)CC1
Reactant: [N-]=[N+]=Nc1ccccc1
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)N1CC=C(c2cn(-c3ccccc3)nn2)CC1

Procedure:
A mixture of the crude phenylazide (1.37 g, 11.5 mmol) from above and 1-tert-butoxycarbonyl-4-ethynyl-1,2,3,6-tetrahydropyridine (2 g, 9.6 mmol) (Example 1) in toluene (20 ml) was refluxed for 24 hours. The reaction was cooled and the solvent evaporated in vacuo. The crude residue was chromatographed on silica eluting with ethyl acetate/petrol (60°-80° C.) (1:2) to give the 1-tert-butoxycarbonyl-4-(1-phenyl-1,2,3-triazol-4-yl)-1,2,3,6-tetrahydropyridine as a tan waxy solid (853 mg, 27%), δH (CDCl3) 1.49 (9H, s, OC(CH3)3), 2.59 (2H, br s, tetrahydropyridinyl CH2), 3.67 (2H, t, J 5.2 Hz, tetrahydropyridinyl CH2), 4.12 (2H, br s, tetrahydropyridinyl CH2), 6.53 (1H, br s, tetrahydropyridinyl 5-H), 7.42-7.46 (1H, m, ArH), 7.51-7.55 (2H, m, ArH), 7.72-7.75 (2H, m, ArH), 7.87 (1H, s, triazolyl 5-H).
Reaction SMILES: [CH3:1][N:2]1[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][C:5](=[O:12])[N:4]([C:13]2[CH:14]=[CH:15][C:16]3[S:20][N:19]=[C:18]([C:21]([CH3:26])([CH3:25])[C:22](O)=[O:23])[C:17]=3[CH:27]=2)[C:3]1=[O:28].[CH2:29](Cl)Cl.C(Cl)(=O)C(Cl)=O.[Cl-].C[Zn+]>CN(C)C=O.O1CCCC1>[CH3:26][C:21]([C:18]1[C:17]2[CH:27]=[C:13]([N:4]3[C:5](=[O:12])[CH:6]=[C:7]([C:8]([F:10])([F:11])[F:9])[N:2]([CH3:1])[C:3]3=[O:28])[CH:14]=[CH:15][C:16]=2[S:20][N:19]=1)([CH3:25])[C:22](=[O:23])[CH3:29]
Reactant: Cn1c(C(F)(F)F)cc(=O)n(-c2ccc3snc(C(C)(C)C(=O)O)c3c2)c1=O
Reactant: ClCCl
Agent: C[Zn+]
Agent: O=C(Cl)C(=O)Cl
Agent: [Cl-]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: CC(=O)C(C)(C)c1nsc2ccc(-n3c(=O)cc(C(F)(F)F)n(C)c3=O)cc12
Yield: 65.7 %

Procedure:
N,N-Dimethylformamide (8 drops) is added to a mixture of 5-[3,6-dihydro-3-methyl-2,6-dioxo-4-(trifluoromethyl)-1(2H)-pyrimidinyl]-α,α-dimethyl-1,2-benzisothiazole-3-acetic acid (0.800 g, 0.00194 mol) and methylene chloride. The mixture is cooled on an ice bath and oxalyl chloride (2.0 M in methylene chloride, 2.42 ml, 0.00484 mol) is added. The resultant mixture is stirred one hour on an ice bath and concentrated in vacuo. The residue is taken up in tetrahydrofuran. The resultant solution is added dropwise to a mixture of methyl zinc chloride (2.0 M, 0.970 ml, 0.00194 mol) in tetrahydrofuran, followed by addition of palladium tetrakistriphenylphosphine (0.220 g, 0.000190 mol). The resultant mixture is stirred overnight at room temperature, quenched with 10% hydrochloric acid, and extracted with ethyl acetate. The organic layer is washed with saturated sodium bicarbonate and brine, dried over anhydrous magnesium sulfate, filtered, and concentrated in vacuo to an orange solid. The solid is chromatographed on silica gel to afford the title compound as an off-white solid (0.270 g, 65.7%, mp 195-196° C.).
Reaction SMILES: Br[C:2]1[CH:22]=[C:21]([CH3:23])[C:5]([O:6][C:7]2[C:12]([CH3:13])=[C:11]([NH:14][CH:15]([CH2:18][CH3:19])[CH2:16][CH3:17])[CH:10]=[C:9]([CH3:20])[N:8]=2)=[C:4]([CH3:24])[CH:3]=1.C([Li])CCC.[CH3:30][C:31]([CH3:33])=[O:32]>C1COCC1>[CH2:16]([CH:15]([NH:14][C:11]1[CH:10]=[C:9]([CH3:20])[N:8]=[C:7]([O:6][C:5]2[C:21]([CH3:23])=[CH:22][C:2]([C:31]([OH:32])([CH3:33])[CH3:30])=[CH:3][C:4]=2[CH3:24])[C:12]=1[CH3:13])[CH2:18][CH3:19])[CH3:17]
Reactant: CCC(CC)Nc1cc(C)nc(Oc2c(C)cc(Br)cc2C)c1C
Reactant: CC(C)=O
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CCC(CC)Nc1cc(C)nc(Oc2c(C)cc(C(C)(C)O)cc2C)c1C
Temperature: -78 °C
Reaction time: 0.17 h

Procedure:
To a solution of [2-(4-bromo-2,6-dimethyl-phenoxy)-3,6-dimethyl-pyridin-4-yl]-(1-ethyl-propyl)-amine in dry THF was added n-butyllithium at −78° C. After stirring at −78° C. for 10 min, acetone was added and the resulting mixture was stirred at −78° C. for 30 min. The dry-ice bath was removed. After stirring for 5 min, the mixture was quenched with brine and extracted with ethyl acetate. The organic layer was separated, dried, and concentrated to dryness. The residue was purified through silica gel chromatography to give the title compound.1H NMR(CDCl3) d 7.17(s,2H), 6.08(s,1H), 3.73(d,1H), 3.33(m,1H), 2.19(s,3H), 2.15(s,3H), 2.12(s,6H), 1.4-1.7(m,4H), 1.26(s,6H), 0.96(t,6H) ppm.
Reaction SMILES: [Br:1][C:2]1[N:3]=[C:4]([CH:26]([NH:38][C:39]2[CH:40]=[C:41]3[C:46](=[CH:47][CH:48]=2)[C:45]([N:49]([C:57]([O:59][C:60]([CH3:63])([CH3:62])[CH3:61])=[O:58])[C:50]([O:52][C:53]([CH3:56])([CH3:55])[CH3:54])=[O:51])=[N:44][CH:43]=[CH:42]3)[C:27]2[CH:32]=[C:31]([CH2:33][CH3:34])[CH:30]=[C:29]([O:35][CH3:36])[C:28]=2[F:37])[N:5]([C:7]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:6]=1.Br[C:65]1N=C(C(C2C=C(CC)C=C(OCC)C=2F)O)N(C(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)C=1.BrC1N=C(C(Cl)C2C=C(CC)C=C(OC)C=2F)N(C(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)C=1.NC1C=C2C(=CC=1)C(N(C(OC(C)(C)C)=O)C(OC(C)(C)C)=O)=NC=C2>>[Br:1][C:2]1[N:3]=[C:4]([CH:26]([NH:38][C:39]2[CH:40]=[C:41]3[C:46](=[CH:47][CH:48]=2)[C:45]([N:49]([C:50]([O:52][C:53]([CH3:55])([CH3:56])[CH3:54])=[O:51])[C:57]([O:59][C:60]([CH3:62])([CH3:61])[CH3:63])=[O:58])=[N:44][CH:43]=[CH:42]3)[C:27]2[CH:32]=[C:31]([CH2:33][CH3:34])[CH:30]=[C:29]([O:35][CH2:36][CH3:65])[C:28]=2[F:37])[N:5]([C:7]([C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH:6]=1
Reactant: CCc1cc(OC)c(F)c(C(Nc2ccc3c(N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)nccc3c2)c2nc(Br)cn2C(c2ccccc2)(c2ccccc2)c2ccccc2)c1
Reactant: CCOc1cc(CC)cc(C(O)c2nc(Br)cn2C(c2ccccc2)(c2ccccc2)c2ccccc2)c1F
Agent: CC(C)(C)OC(=O)N(C(=O)OC(C)(C)C)c1nccc2cc(N)ccc12
Agent: CCc1cc(OC)c(F)c(C(Cl)c2nc(Br)cn2C(c2ccccc2)(c2ccccc2)c2ccccc2)c1
Product: CCOc1cc(CC)cc(C(Nc2ccc3c(N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)nccc3c2)c2nc(Br)cn2C(c2ccccc2)(c2ccccc2)c2ccccc2)c1F

Procedure:
According to the procedure for the preparation of Intermediate 206.4, Intermediate 213.1 (1.02 g, 1.74 mmol) was converted to the chloro intermediate, which was displaced with di-tert-butyl (6-aminoisoquinolin-1-yl)imidodicarbonate (688 mg, 1.91 mmol) to afford after flash chromatography (0 to 60% EtOAc/hexanes gradient) 1.47 g of Intermediate 213.2 as a pale yellow solid.
Reaction SMILES: [CH2:1]1[CH:9]2[N:4]([CH2:5][CH2:6][C:7]([C:10](OCC)=[O:11])=[CH:8]2)[CH2:3][CH2:2]1.[H-].[Al+3].[Li+].[H-].[H-].[H-].O.[OH-].[Na+]>C1COCC1>[CH2:1]1[CH:9]2[N:4]([CH2:5][CH2:6][C:7]([CH2:10][OH:11])=[CH:8]2)[CH2:3][CH2:2]1
Reactant: CCOC(=O)C1=CC2CCCN2CC1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: OCC1=CC2CCCN2CC1
Reaction time: 0.5 h
Yield: 95.1 %

Procedure:
Ethyl 1,2,3,5,6,8a-hexahydroindolizine-7-carboxylate (D1, 0.89 g, 4.6 mmol) was stirred under Ar in dry THF (50 ml) as lithium aluminium hydride (0.35 g, 9.2 mmol) was added portionwise. After 30 min, the reaction was worked up by successive addition of water (0.35 ml), 10% NaOH (0.35 ml) and water (1.05 ml). The solid was filtered off, and the filtrate was evaporated to yield the title compound (0.67 g, 97%) as a brown oil.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[CH:15]=[C:16]([NH:20][C:21](=[O:25])[CH:22]([CH3:24])[CH3:23])[CH:17]=[CH:18][CH:19]=2)[CH2:10][CH2:9]1.[CH:26]1[C:35]2[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=2)[CH:29]=[CH:28][C:27]=1[C:36](Cl)=[O:37]>C1COCC1>[C:21]([NH:20][C:16]1[CH:15]=[C:14]([CH:11]2[CH2:12][CH2:13][N:8]([CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][NH:1][C:36]([C:27]3[CH:28]=[CH:29][C:30]4[C:35](=[CH:34][CH:33]=[CH:32][CH:31]=4)[CH:26]=3)=[O:37])[CH2:9][CH2:10]2)[CH:19]=[CH:18][CH:17]=1)(=[O:25])[CH:22]([CH3:23])[CH3:24]
Reactant: CC(C)C(=O)Nc1cccc(C2CCN(CCCCCCN)CC2)c1
Reactant: O=C(Cl)c1ccc2ccccc2c1
Solvent: C1CCOC1
Product: CC(C)C(=O)Nc1cccc(C2CCN(CCCCCCNC(=O)c3ccc4ccccc4c3)CC2)c1

Procedure:
Prepared by Procedure Q1 (THF) and Scheme AT using N-{3-[1-(6-aminohexyl)-4-piperidinyl]phenyl}-2-methylpropanamide and 2-naphthoyl chloride: ESMS m/e: 500.3 (M+H)+.
Reaction SMILES: [OH:1][CH:2]1[O:10][C@H](CO)[C@@H:7](O)[C@H:5](O)[C@H:3]1[NH2:4].[C:13]([O-:16])([OH:15])=O.[Na+]>[Fe]>[NH2:4][C@H:3]([C:2]([OH:10])=[O:1])[CH2:5][CH2:7][C:13](=[O:16])[OH:15]
Reactant: O=C([O-])O
Reactant: N[C@H]1C(O)O[C@H](CO)[C@@H](O)[C@@H]1O
Agent: [Fe]
Agent: [Na+]
Product: N[C@@H](CCC(=O)O)C(=O)O
Reaction time: 2 h

Procedure:
MION-47 and amino-CLIO (25-35 nm) were prepared as described elsewhere. D-Glucose, D-(+)-Glucosamine hydrochloride, succinic anhydride, Concanavalin A (ConA) and Sephadex G-25 were from Sigma Aldrich Co. 1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (EDC) and sulfo-N-hydroxysuccinimide (sulfo-NHS) were from Pierce (Rockford, Ill.). To synthesize a glucose-functionalized nanoparticle (Glu-CLIO), NH2-CLIO was first converted to a carboxylic group functionalized nanoparticle, followed by coupling of 2-amino-glucose using a water-soluble carbodiimide. To obtain a carboxylic functionalized CLIO, 2.0 mg succinic anhydride was added into 200 uL NH2-CLIO (10 mg Fe/mL, 42 NH2 per 2064 Fe) with 300 uL (0.1 M) NaHCO3 buffer, pH 8.5. The mixture was incubated at room temperature for two hours and succinic acid removed using a Sephadex G-25 column eluted with MES buffer (0.5 M NaCl, 0.05 M MES), pH 6.0. To conjugate 2-amino-glucose to carboxy functionalized CLIO (CLIO-COOH), 2 mg EDC and 2 mg sulfo-NHS were added into 500 uL CLIO-COOH (mg Fe/mL) in MES buffer, pH 6.0. The mixture was allowed to react for two hours at room temperature and purified by Sephadex G-25 column eluted with PBS buffer at pH 7.4. Subsequently 2 mg Glucosamine was added into above solution and the mixture reacted for one hour at room temperature. Unreacted glucosamine was removed with Sephadex G-25 in PBS.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([OH:9])=[CH:4][C:3]=1[NH:10][C:11](=[O:14])[O:12][CH3:13].[CH:15]1(OS(C2C=CC(C)=CC=2)(=O)=O)[CH2:19][CH2:18][CH2:17][CH2:16]1.C(=O)([O-])[O-].[K+].[K+].Cl>CC(C)=O.[I-].[K+]>[F:1][C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([O:9][CH:15]2[CH2:19][CH2:18][CH2:17][CH2:16]2)=[CH:4][C:3]=1[NH:10][C:11](=[O:14])[O:12][CH3:13]
Reactant: COC(=O)Nc1cc(O)c(Cl)cc1F
Reactant: Cc1ccc(S(=O)(=O)OC2CCCC2)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [I-]
Solvent: CC(C)=O
Product: COC(=O)Nc1cc(OC2CCCC2)c(Cl)cc1F
Yield: 93 %

Procedure:
Methyl N-(2-fluoro-4-chloro-5-hydroxyphenyl)carbamate (1.64 Kg, 7.47 mol), cyclopentyl-p-toluenesulfonate (1.80 Kg, 7.48 mol), potassium carbonate (1.03 Kg, 7.46 mol) and potassium iodide (12.3 g, 1.0 mol %) were placed in a 10L three-necked flask equipped with a stirrer and a Dimroth funnel, and, after adding acetone (7.5 liters) as a solvent thereto, the mixture was refluxed under heating for4 hours. After completion of the reaction, the reaction solution was taken out, and 0.5N hydrochloric acid (20 liters) was added thereto while vigorously stirring. The precipitated methyl N-(2-fluoro-4-chloro-5-cyclopentyloxyphenyl)carbamate as a white solid (2.0 Kg, 6.95 mol, 93.1% yield) was isolated by filtration and thoroughly dired.
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][CH2:3][CH2:2]1.[Cl:6][CH2:7][C:8](Cl)=[O:9]>ClCCl>[Cl:6][CH2:7][C:8]([N:1]1[CH2:5][CH2:4][CH2:3][CH2:2]1)=[O:9]
Reactant: O=C(Cl)CCl
Reactant: C1CCNC1
Solvent: ClCCl
Product: O=C(CCl)N1CCCC1
Temperature: 0 °C
Yield: 85.4 %

Procedure:
3.82 moles of pyrrolidine were added to a solution of 1.92 moles of chloroacetyl chloride in 600 ml of dichloromethane. The temperature was maintained at 0° C. The organic phase was washed with solutions of sodium hydrogen sulphate and sodium carbonate and dried. After evaporation of the solvent, 242 g of N-(2-chloroacetyl)pyrrolidine were obtained. 1.64 moles of this compound were dissolved in 500 ml of toluene and 231 ml of triethylamine were added. This was heated under reflux for 3 hrs and after cooling 311.5 g of product were isolated in the form of a precipitate. 119.07 g of the product obtained were dissolved in
Reaction SMILES: [NH2:1][CH:2]1[CH2:7][CH2:6][CH2:5][CH2:4][CH:3]1[N:8]1[CH:17]([C:18]2[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][C:19]=2[Cl:25])[CH:16]([C:26]([NH:28][O:29][CH2:30][C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)=[O:27])[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:9]1=[O:37].CN(C=O)C.C(=O)([O-])[O-].[Na+].[Na+].Cl.[C:50](SC)(=[NH:52])[CH3:51]>O>[CH2:30]([O:29][NH:28][C:26]([CH:16]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:9](=[O:37])[N:8]([CH:3]2[CH2:4][CH2:5][CH2:6][CH2:7][CH:2]2[NH:1][C:50](=[NH:52])[CH3:51])[CH:17]1[C:18]1[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][C:19]=1[Cl:25])=[O:27])[C:31]1[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=1
Reactant: NC1CCCCC1N1C(=O)c2ccccc2C(C(=O)NOCc2ccccc2)C1c1ccc(Cl)cc1Cl
Reactant: CSC(C)=N
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(=N)NC1CCCCC1N1C(=O)c2ccccc2C(C(=O)NOCc2ccccc2)C1c1ccc(Cl)cc1Cl
Temperature: 60 °C
Reaction time: 1 h
Yield: 39 %

Procedure:
To a mixed liquid of 269 mg of (3RS,4RS)-2-[(1SR,2SR)-2-aminocyclohexyl]-N-(benzyloxy)-3-(2,4-dichlorophenyl)-1-oxo-1,2,3,4-tetrahydroisoquinoline-4-carboxamide and 5 ml of DMF were added 58 mg of sodium carbonate and 119 mg of methyl ethanimidothioate hydrochloride, followed by stirring at 60° C. for 1 hour. Thereafter, while stirring at 60° C., 233 mg of sodium carbonate and 478 mg of methyl ethanimidothioate hydrochloride were further added in four divided portions every 1 hour. After cooling the reaction solution, water was added thereto, followed by extraction with chloroform-isopropyl alcohol (5:1). The organic layer was dried over anhydrous magnesium sulfate and then concentrated. The residue was purified by silica gel column chromatography (eluent: chloroform-methanol-aqueous ammonia) and then crystallized with ethyl acetate to obtain 113 mg of (3RS,4RS)—N-(benzyloxy)-3-(2,4-dichlorophenyl)-2-[(1SR,2SR)-2-(ethanimidoylamino)cyclohexyl]-1-oxo-1,2,3,4-tetrahydroisoquinoline-4-carboxamide as a white crystal.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[N+:11]([O-:13])=[O:12])[C:5]([OH:7])=O.[NH2:14][C@@H:15]([CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[CH2:16][OH:17]>>[CH3:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[N+:11]([O-:13])=[O:12])[C:5]([NH:14][CH:15]([CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[CH2:16][OH:17])=[O:7]
Reactant: N[C@H](CO)Cc1ccccc1
Reactant: Cc1cc(C(=O)O)ccc1[N+](=O)[O-]
Product: Cc1cc(C(=O)NC(CO)Cc2ccccc2)ccc1[N+](=O)[O-]
Yield: 82 %

Procedure:
5 g (27.6 mmol) of 3-methyl-4-nitrobenzoic acid were reacted with (S)-2-amino-3-phenyl-1-propanol by the method of procedure 3c. 7.1 g (82%) of the product were obtained.
Reaction SMILES: [CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:16])=[C:11](F)[C:12]=3[F:14])[C:7](=[O:17])[C:6]([C:18]([OH:20])=[O:19])=[CH:5]2)[CH2:3][CH2:2]1.[C:21]([O:25][C:26]([NH:28][C@H:29]1[C@H:33]([CH3:34])[CH2:32][NH:31][CH2:30]1)=[O:27])([CH3:24])([CH3:23])[CH3:22].C1CCN2C(=NCCC2)CC1>C(#N)C>[C:21]([O:25][C:26]([NH:28][C@H:29]1[C@H:33]([CH3:34])[CH2:32][N:31]([C:11]2[C:12]([F:14])=[C:13]3[C:8]([C:7](=[O:17])[C:6]([C:18]([OH:20])=[O:19])=[CH:5][N:4]3[CH:1]3[CH2:3][CH2:2]3)=[CH:9][C:10]=2[F:16])[CH2:30]1)=[O:27])([CH3:24])([CH3:22])[CH3:23]
Reactant: O=C(O)c1cn(C2CC2)c2c(F)c(F)c(F)cc2c1=O
Reactant: C[C@@H]1CNC[C@H]1NC(=O)OC(C)(C)C
Solvent: C1CCC2=NCCCN2CC1
Solvent: CC#N
Product: C[C@@H]1CN(c2c(F)cc3c(=O)c(C(=O)O)cn(C4CC4)c3c2F)C[C@H]1NC(=O)OC(C)(C)C
Yield: 51.9 %

Procedure:
A mixture of 1-cyclopropyl-6,7,8-trifluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid (0.4 g), anhydrous acetonitrile (4 ml), trans-3-t-butoxycarbonylamino-4-methylpyrrolidine (0.43 g) and DBU (0.22 g) was refluxed for an hour. After cooling, the resulting precipitate was collected by filtration and washed with acetonitrile and ethanol successively to give 7-(trans-3-t-butoxycarbonylamino-4-methyl-1-pyrrolidinyl)-1-cyclopropyl-6,8-difluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid (0.34 g) as white yellowish powder, mp 237°-240° C. (decompd.).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[OH:10])([O-:3])=[O:2].Cl[CH2:12][C:13](=[O:15])[CH3:14].[Br-].[Na+].C(=O)(O)[O-].[Na+].Cl>[Cl-].C([N+](CCCC)(CCCC)C)CCC.O.C1(C)C=CC=CC=1>[N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[O:10][CH2:12][C:13](=[O:15])[CH3:14])([O-:3])=[O:2]
Reactant: O=[N+]([O-])c1ccccc1O
Reactant: CC(=O)CCl
Agent: CCCC[N+](C)(CCCC)CCCC
Agent: Cl
Agent: O=C([O-])O
Solvent: Cc1ccccc1
Solvent: O
Product: CC(=O)COc1ccccc1[N+](=O)[O-]
Temperature: 65 °C
Yield: 354046.59 %

Procedure:
The following materials are combined in a 1000 gallon vessel and heated at 65° C. for 6–8 hours: 499.0 kg (1.000 mole equiv.) of o-Nitrophenol (o-NP, 99%, 3.551 kg-moles), 359.7 kg (1.05 mole equiv.) of chloroacetone (CA, 96%, 3.733 kg-moles), 45.4 kg (0.124 mole equiv.) of sodium bromide (0.441 kg-moles), 328.9 kg (1.102 mole equiv.) of sodium bicarbonate (3.915 kg-moles), 27.2 kg (0.023 mole equiv.) of aqueous tributylmethylammonium chloride (TBMAC, 70%, 0.081 kg-moles), and 989 kg of toluene. The reaction is checked for completion and a trim charge of chloroacetone is added if necessary. Then 682 kg of water are added at 60° C. and the pH of the reaction mixture is adjusted to pH 6.5 –7.0 at 55 to 60° C. (about 66 kg of 10% HCl). The phases are separated and the heavier aqueous phase is removed. A 5–15% NaCl solution (725 kg) is added to the organic phase, the mixture is agitated at 55 to 60° C. and the phases are separated again by decantation. The remaining organic phase of crude o-NPA is vacuum stripped at 65–75° C. to remove toluene and volatile impurities. Toluene (about 70 kg) is added towards the end of the vacuum strip and stripped off again to improve the removal of volatile impurities. About 691 kg of crude o-NPA (96.9% assay, 3.428 kg-moles, 96.5% yield rel. o-NP) are obtained. Finally 339 kg of a toluene/isopropanol (8:2) mixture is added at 55–65° C. to the crude o-NPA melt to obtain approximately a 65% o-NPA solution. This solution is transferred to a hold vessel where it is held at 65° C. for step b.
Reaction SMILES: [CH3:1][O-:2].[Na+].[CH3:4][NH:5][C:6]1[N:11]=[C:10](C(Cl)(Cl)Cl)[N:9]=[C:8]([C:16]([F:19])([F:18])[F:17])[N:7]=1>CO.O.Cl>[CH3:1][O:2][C:10]1[N:11]=[C:6]([NH:5][CH3:4])[N:7]=[C:8]([C:16]([F:19])([F:18])[F:17])[N:9]=1
Reactant: C[O-]
Reactant: CNc1nc(C(F)(F)F)nc(C(Cl)(Cl)Cl)n1
Agent: Cl
Agent: [Na+]
Solvent: CO
Solvent: O
Product: CNc1nc(OC)nc(C(F)(F)F)n1

Procedure:
21.8 g of a 30% strength solution of sodium methanolate in methanol (0.12 mol of sodium methanolate) were added dropwise to a solution of 119.4 g (0.40 mol) of 2-methylamino-4-trichloromethyl-6-trifluoromethyl-1,3,5-triazine in 400 ml of methanol. The resulting yellow mixture was then refluxed for 1 hour during which it gradually became cloudy. After addition of a further 7.2 g of the 30% strength solution of sodium methanolate in methanol (0.04 mol of sodium methanolate), the mixture was refluxed for a further 30 minutes and, after cooling to 20° to 25° C., diluted with 150 ml of water and neutralized with 1 normal aqueous hydrochloric acid. The solvent was then removed at 40° C. under reduced pressure, after which the resulting solid was separated off and dried at 40° C. under reduced pressure for 15 hours.
Reaction SMILES: Br[C:2]1[C:10]2[C:5](=[N:6][CH:7]=[CH:8][C:9]=2[O:11][C:12]2[CH:17]=[CH:16][C:15]([N+:18]([O-:20])=[O:19])=[CH:14][C:13]=2[F:21])[N:4]([CH2:22][O:23][CH2:24][CH2:25][Si:26]([CH3:29])([CH3:28])[CH3:27])[CH:3]=1.[N:30]1[CH:35]=[CH:34][C:33](B(O)O)=[CH:32][CH:31]=1.C(O)C.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>C1(C)C=CC=CC=1>[F:21][C:13]1[CH:14]=[C:15]([N+:18]([O-:20])=[O:19])[CH:16]=[CH:17][C:12]=1[O:11][C:9]1[CH:8]=[CH:7][N:6]=[C:5]2[N:4]([CH2:22][O:23][CH2:24][CH2:25][Si:26]([CH3:29])([CH3:28])[CH3:27])[CH:3]=[C:2]([C:33]3[CH:34]=[CH:35][N:30]=[CH:31][CH:32]=3)[C:10]=12
Reactant: OB(O)c1ccncc1
Reactant: C[Si](C)(C)CCOCn1cc(Br)c2c(Oc3ccc([N+](=O)[O-])cc3F)ccnc21
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: CCO
Solvent: Cc1ccccc1
Product: C[Si](C)(C)CCOCn1cc(-c2ccncc2)c2c(Oc3ccc([N+](=O)[O-])cc3F)ccnc21
Temperature: 95 °C
Yield: 49.3 %

Procedure:
A sealed tube was charged with a solution of 3-bromo-4-(2-fluoro-4-nitrophenoxy)-1-((2-(trimethylsilyl) ethoxy)methyl)-1H-pyrrolo[2,3-b]pyridine (480 mg, 1.0 mmol) in toluene (5 mL), pyridin-4-ylboronic acid (246 mg, 2.0 mmol, Lancaster), 0.5 mL of ethanol, and potassium phosphate (1.0 mL, 2 M solution, 2.0 mmol). Argon was bubbled through the mixture for 15 minutes, and the reaction mixture was treated with tetrakis(triphenylphosphine)Pd(0)(58) mg, 0.05 mmol, Strem). the tube was sealed and the mixture was heated at 95 ° C. for 18 with vigorous stirring. The reaction mixture was then cooled to room temperature and diluted with EtOAc. The mixture ws washed with sasturated aq. NaHCO3 solution and brine, dried (MgSO4), and concentated in vacuo. The residue was purified by flash chromatography (SiO2, eluting with 2% MeOH in dichloromethane) to give the desired product (237 mg, 49%) as a thick brown oil. MS(ESI+) m/z 481.1 (M+H)+.