Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C1C2C(=CC=CC=2)[C@@H](N)[C@H]1O.B.O1CCCC1.[N:18]([CH2:21][C:22]([C:24]1[C:32]2[S:31][C:30](=[O:33])[NH:29][C:28]=2[C:27]([OH:34])=[CH:26][CH:25]=1)=[O:23])=[N+:19]=[N-:20]>>[N:18]([CH2:21][C@@H:22]([C:24]1[C:32]2[S:31][C:30](=[O:33])[NH:29][C:28]=2[C:27]([OH:34])=[CH:26][CH:25]=1)[OH:23])=[N+:19]=[N-:20]
Reactant: [N-]=[N+]=NCC(=O)c1ccc(O)c2[nH]c(=O)sc12
Agent: B
Agent: N[C@@H]1c2ccccc2C[C@@H]1O
Solvent: C1CCOC1
Product: [N-]=[N+]=NC[C@H](O)c1ccc(O)c2[nH]c(=O)sc12
Temperature: 22.5 °C
Reaction time: 0.5 h

Procedure:
(1R,2S)-(+)-cis-1-Amino-2-indanol (149 g) was added portion wise to borane-tetrahydrofuran complex (1M in tetrahydrofuran, 2997 mL) over 25 minutes maintaining a temperature of 20-25° C. The mixture was stirred at 20° C. for a further 30 minutes, cooled to 0° C. and 7-(2-azido-acetyl)-4-hydroxy-3H-benzothiazol-2-one (example 1, step b) (250 g) added portionwise maintaining the temperature 0-5° C. The reaction mixture was stirred for a further 1 h at 0° C. and then quenched dropwise with methanol (350 g, 442 mL) (caution effervescence!). An exotherm brought the temperature to 17° C. The reaction was evaporated to a brown foam and re-dissolved in ethyl acetate (1.2 L). Aqueous hydrochloric acid (87 mL conc. HCl in 1.2 L water) was added and the mixture stirred vigorously for 30 minutes. The aqueous layer was separated and washed with fresh ethyl acetate (2×600 mL). The combined organic solution was washed with water (1.2 L). The aqueous layer was filtered through Celite and extracted with ethyl acetate (600 mL). The ethyl acetate solutions were combined, dried over Na2SO4, filtered and evaporated. The resulting solid was suspended in 5% ethanol/dichloromethane (2 L), stirred for 3 h, filtered and dried in vacuo to give the subtitled compound. Yield 213 g.
Reaction SMILES: CSC.C([O:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[CH2:18][C:19]1[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][CH:20]=1)C1C=CC=CC=1.O>C(Cl)Cl>[Cl:25][C:22]1[CH:21]=[CH:20][C:19]([CH2:18][C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=2[OH:11])=[CH:24][CH:23]=1
Reactant: Clc1ccc(Cc2ccccc2OCc2ccccc2)cc1
Solvent: CSC
Solvent: O
Solvent: ClCCl
Product: Oc1ccccc1Cc1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 19 h
Yield: 95.5 %

Procedure:
In a nitrogen stream, dimethylsulfide (105.1 μL, 2.43 mmol) and a boron trifluoride-diethyl ether complex (51.3 μL, 0.4 mmol) were added to a solution of 1-benzyloxy-2-(4-chlorobenzyl)benzene (50.0 mg, 0.16 mmol) in methylene chloride (2.0 mL) under cooling with ice, and the reaction mixture was stirred for 19 hours while gradually raising its temperature to room temperature. Thereafter water was added thereto under cooling with ice and the mixture was extracted with methylene chloride. The organic layer was washed with a saturated sodium chloride aqueous solution and dried (anhydrous magnesium sulfate), and then the solvent was distilled under reduced pressure. The obtained residue was purified by silica gel column chromatography [developing solution=ethyl acetate: n-hexane (1:5)] to obtain the title compound (33.4 mg, 94%).
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[S:11]([NH:14][CH:15]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[CH2:16][C:17](O)=[O:18])(=[O:13])=[O:12].[NH2:26][CH:27]1[CH2:36][CH2:35][CH2:34][C:33]2[CH:32]=[C:31]([C:37]#[N:38])[CH:30]=[CH:29][C:28]1=2>>[C:37]([C:31]1[CH:32]=[C:33]2[C:28](=[CH:29][CH:30]=1)[CH:27]([NH:26][C:17](=[O:18])[CH2:16][CH:15]([NH:14][S:11]([C:2]1[CH:3]=[CH:4][C:5]3[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=3)[CH:1]=1)(=[O:13])=[O:12])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[CH2:36][CH2:35][CH2:34]2)#[N:38]
Reactant: N#Cc1ccc2c(c1)CCCC2N
Reactant: O=C(O)CC(NS(=O)(=O)c1ccc2ccccc2c1)c1ccccc1
Product: N#Cc1ccc2c(c1)CCCC2NC(=O)CC(NS(=O)(=O)c1ccc2ccccc2c1)c1ccccc1

Procedure:
The title compound was prepared from 3-(naphthalen-2-yl-sulfonylamino)-3-phenyl-propionic acid and 5-amino-5,6,7,8-tetrahydro-naphthalen-2-carbonitrile (Step E) by a method similar to that described in Example 1, Step F. MS (−APCI m/z): 508 (M−H)−.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C@@H:15]([O:18][Si:19]([C:22]([CH3:25])([CH3:24])[CH3:23])([CH3:21])[CH3:20])[CH2:16]Br)=[CH:11][C:10]=1[NH:26][CH:27]=[O:28])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:29]([NH2:36])[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1>CN1CCCC1=O>[CH2:29]([NH:36][CH2:16][C@@H:15]([C:12]1[CH:13]=[CH:14][C:9]([O:8][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[C:10]([NH:26][CH:27]=[O:28])[CH:11]=1)[O:18][Si:19]([C:22]([CH3:25])([CH3:24])[CH3:23])([CH3:21])[CH3:20])[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1
Reactant: NCc1ccccc1
Reactant: CC(C)(C)[Si](C)(C)O[C@@H](CBr)c1ccc(OCc2ccccc2)c(NC=O)c1
Solvent: CN1CCCC1=O
Product: CC(C)(C)[Si](C)(C)O[C@@H](CNCc1ccccc1)c1ccc(OCc2ccccc2)c(NC=O)c1
Temperature: 90 °C
Reaction time: 8 h
Yield: 94.8 %

Procedure:
To a 500 mL three-necked round-bottomed flask was added N-{2-benzyloxy-5-[(R)-2-bromo-1-(tert-butyldimethylsilanyloxy)ethyl]phenyl}formamide (100 g, 215 mmol) and N-methyl-2-pyrrolidone (300 mL). Benzylamine (69.4 mL, 648 mol) was added and the reaction mixture was flushed with nitrogen. The reaction mixture was then heated to 90° C. and stirred for about 8 hours. The reaction mixture was then cooled to room temperature and water (1.5 L) and ethyl acetate (1.5 L) were added. The layers were separated and the organic layer was washed with water (500 mL), a 1:1 mixture of water and saturated brine (500 mL total), and then again with water (500 mL). The organic layer was then dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure to provide crude N-{5-[(R)-2-benzylamino-1-(tert-butyldimethylsilanyloxy)ethyl]-2-benzyloxyphenyl}formamide (100 g, 90% yield, 75-80% purity) as an orange-brown thick oil.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([NH2:9])[C:5]([Cl:8])=[N:6][CH:7]=1.[C:10](Cl)(=[O:12])[CH3:11]>>[Br:1][C:2]1[CH:3]=[C:4]([NH:9][C:10](=[O:12])[CH3:11])[C:5]([Cl:8])=[N:6][CH:7]=1
Reactant: CC(=O)Cl
Reactant: Nc1cc(Br)cnc1Cl
Product: CC(=O)Nc1cc(Br)cnc1Cl

Procedure:
Prepared according to the methods described in reagent preparation 26 using 5-bromo-2-chloropyridin-3-amine and acetyl chloride in step 1.
Reaction SMILES: C([S:4][CH2:5][CH:6]([CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[C:7]([NH:9][N:10]1[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]1)=[O:8])(=O)C.[OH-].[Na+]>>[N:10]1([NH:9][C:7](=[O:8])[CH:6]([CH2:5][SH:4])[CH2:17][C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]1
Reactant: CC(=O)SCC(Cc1ccccc1)C(=O)NN1CCCCCC1
Agent: [Na+]
Agent: [OH-]
Product: O=C(NN1CCCCCC1)C(CS)Cc1ccccc1
Yield: 97.2 %

Procedure:
Using the procedure of Example 6, 2 g of the product of Example 7 and 62.8 ml of 0.1N sodium hydroxide were reacted to obtain after chromatography on silica (eluent:methylene chloride - methanol, 100-2), 1.7 g of the expected product melting at about 82° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[N:9]=[C:10]([CH2:17][N:18]2[N:22]=[N:21][C:20]([C:23]([F:26])([F:25])[F:24])=[N:19]2)[S:11][C:12]=1[C:13]([O:15]C)=[O:14].O.[OH-].[Na+]>O1CCOCC1>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[N:9]=[C:10]([CH2:17][N:18]2[N:22]=[N:21][C:20]([C:23]([F:26])([F:25])[F:24])=[N:19]2)[S:11][C:12]=1[C:13]([OH:15])=[O:14]
Reactant: COC(=O)c1sc(Cn2nnc(C(F)(F)F)n2)nc1-c1ccccc1Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: O=C(O)c1sc(Cn2nnc(C(F)(F)F)n2)nc1-c1ccccc1Cl
Temperature: 25 °C

Procedure:
3.60 g (8.91 mmol) of methyl 4-(2-chlorophenyl)-2-{[5-(trifluoromethyl)-2H-tetrazol-2-yl]methyl}-1,3-thiazole-5-carboxylate were dissolved in 18 ml of dioxane and 6 ml of water and 45% strength aqueous sodium hydroxide solution (10.06 mmol) was added dropwise at 0° C. The reaction was stirred for a further hour and warmed to RT. The ethanol was then removed under reduced pressure, and ice-water (10 ml) was added to the residue. The aqueous phase was extracted with ethyl acetate. The organic phase was discarded. Then the aqueous phase was adjusted to a pH of 3 using hydrochloric acid, and again extracted with ethyl acetate (3×20 ml). The combined organic phases were dried over sodium sulphate. (logP: 2.63; MH+: 390; 1H-NMR (400 MHz, DMSO, ppm): 6.65 (s, 2H), 7.36-7.55 (m, 4H).
Reaction SMILES: Br.Br[CH:3]([C:13]1[CH:18]=[CH:17][N:16]=[C:15]([NH:19][C:20](=[O:27])[C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH:14]=1)[C:4]([C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([CH3:12])[CH:7]=1)=O.[CH3:28][N:29]1[CH2:34][CH2:33][CH:32]([C:35](=[S:37])[NH2:36])[CH2:31][CH2:30]1.C(=O)([O-])O.[Na+]>CN(C)C=O>[CH3:12][C:8]1[CH:7]=[C:6]([C:4]2[N:36]=[C:35]([CH:32]3[CH2:33][CH2:34][N:29]([CH3:28])[CH2:30][CH2:31]3)[S:37][C:3]=2[C:13]2[CH:18]=[CH:17][N:16]=[C:15]([NH:19][C:20](=[O:27])[C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[CH:14]=2)[CH:11]=[CH:10][CH:9]=1
Reactant: CN1CCC(C(N)=S)CC1
Reactant: Cc1cccc(C(=O)C(Br)c2ccnc(NC(=O)c3ccccc3)c2)c1
Agent: Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1cccc(-c2nc(C3CCN(C)CC3)sc2-c2ccnc(NC(=O)c3ccccc3)c2)c1
Yield: 47 %

Procedure:
A solution of N-[4-[1-bromo-2-(3-methylphenyl)-2-oxoethyl]-2-pyridyl]benzamide hydrobromide (0.60 g, 1.2 mmol) and 1-methylpiperidine-4-carbothioamide (0.19 g, 1.18 mmol) in N,N-dimethylformamide (20 mL) was stirred at room temperature for 14 hrs. Into the reaction mixture was poured aqueous sodium hydrogen carbonate solution and the mixture was extracted with ethyl acetate. The extract was washed with saturated aqueous sodium hydrogen carbonate solution, dried and concentrated. The residue was purified by column chromatography (packing: Chromatorex NH DM1020 (product name, manufactured by Fuji Silysia Chemical Ltd.), hexane-ethyl acetate=2:1) and the resulting crystals were recrystallized from ethyl acetate to give the title compound (0.26 g, yield 46%).
Reaction SMILES: [O:1]=[C:2]1[C:6]2[CH:7]=[CH:8][C:9]([CH2:11][CH2:12][N:13]3[CH2:18][CH2:17][NH:16][CH2:15][C:14]3=[O:19])=[CH:10][C:5]=2[CH2:4][O:3]1.[CH3:20][O:21][C:22]1[CH:29]=[CH:28][C:27]([CH2:30][CH:31]=O)=[CH:26][C:23]=1[C:24]#[N:25]>>[CH3:20][O:21][C:22]1[CH:29]=[CH:28][C:27]([CH2:30][CH2:31][N:16]2[CH2:17][CH2:18][N:13]([CH2:12][CH2:11][C:9]3[CH:8]=[CH:7][C:6]4[C:2](=[O:1])[O:3][CH2:4][C:5]=4[CH:10]=3)[C:14](=[O:19])[CH2:15]2)=[CH:26][C:23]=1[C:24]#[N:25]
Reactant: O=C1OCc2cc(CCN3CCNCC3=O)ccc21
Reactant: COc1ccc(CC=O)cc1C#N
Product: COc1ccc(CCN2CCN(CCc3ccc4c(c3)COC4=O)C(=O)C2)cc1C#N

Procedure:
The title compound was prepared from 1-[2-(1-Oxo-1,3-dihydro-2-benzofuran-5-yl)ethyl]piperazin-2-one and 2-Methoxy-5-(2-oxoethyl)benzonitrile following essentially the same procedure as Example 6. The product was purified by mass-directed reverse phase HPLC (AcCN-Water with 0.1% TFA). LC-MS (IE, m/z): 420 [M+1]+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([O:8][CH2:9][CH:10]=[C:11]([Cl:13])[Cl:12])[CH:5]=[C:4]([Cl:14])[C:3]=1[O:15][CH2:16][CH2:17][CH2:18][O:19][C:20]1[CH:25]=[CH:24][C:23](I)=[CH:22][CH:21]=1.[NH:27]1[CH:31]=[CH:30][CH:29]=[CH:28]1.C(N)CN.[O-]P(OP(OP([O-])([O-])=O)([O-])=O)(=O)[O-].[K+].[K+].[K+].[K+].[K+]>O1CCOCC1.C(OCC)(=O)C.[Cu]I>[Cl:1][C:2]1[CH:7]=[C:6]([O:8][CH2:9][CH:10]=[C:11]([Cl:13])[Cl:12])[CH:5]=[C:4]([Cl:14])[C:3]=1[O:15][CH2:16][CH2:17][CH2:18][O:19][C:20]1[CH:25]=[CH:24][C:23]([N:27]2[CH:31]=[CH:30][CH:29]=[CH:28]2)=[CH:22][CH:21]=1
Reactant: c1cc[nH]c1
Reactant: ClC(Cl)=CCOc1cc(Cl)c(OCCCOc2ccc(I)cc2)c(Cl)c1
Agent: [Cu]I
Agent: O=P([O-])([O-])OP(=O)([O-])OP(=O)([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: NCCN
Solvent: CCOC(C)=O
Product: ClC(Cl)=CCOc1cc(Cl)c(OCCCOc2ccc(-n3cccc3)cc2)c(Cl)c1

Procedure:
200 mg of 1,3-dichloro-5-(3,3-dichloro-allyloxy)-2-[3-(4-iodo-phenoxy)-propoxy]-benzene, 29 mg of pyrrole, 6.9 mg of copper(I) iodide, 2.2 mg of ethylenediamine and 155 mg of potassium triphosphate are stirred for 24 hours at 110° C. in 4 ml of dioxane. The reaction mixture is diluted with ethyl acetate and filtered. Concentration and purification over silica gel yield the title compound (compound 1.1).
Reaction SMILES: FC(F)(F)C(O)=O.[NH2:8][CH2:9][CH2:10][N:11]1[CH2:16][CH2:15][CH:14]([C:17]([C:19]2[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][CH:20]=2)=[O:18])[CH2:13][CH2:12]1.C(N(CC)CC)C.[CH3:33][O:34][C:35]1[CH:36]=[C:37]([CH:41]=[CH:42][CH:43]=1)[C:38](Cl)=[O:39].Cl>ClCCl.O>[ClH:25].[Cl:25][C:22]1[CH:23]=[CH:24][C:19]([C:17]([CH:14]2[CH2:15][CH2:16][N:11]([CH2:10][CH2:9][NH:8][C:38](=[O:39])[C:37]3[CH:41]=[CH:42][CH:43]=[C:35]([O:34][CH3:33])[CH:36]=3)[CH2:12][CH2:13]2)=[O:18])=[CH:20][CH:21]=1
Reactant: NCCN1CCC(C(=O)c2ccc(Cl)cc2)CC1
Reactant: COc1cccc(C(=O)Cl)c1
Agent: Cl
Solvent: O
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COc1cccc(C(=O)NCCN2CCC(C(=O)c3ccc(Cl)cc3)CC2)c1
Reaction time: 16 h
Yield: 42.4 %

Procedure:
The product of step (i) (2.5 g) was dissolved in dichloromethane (20 ml), triethylamine (0.75 ml) and 3-methoxybenzoyl chloride (0.276 g) were added. After 16 hours, water was added, the organic phase separated, dried and concentrated to a gum. Purification by chromatography (ethyl acetate) gave a gum, which was treated with 1.0M ethereal hydrogen chloride solution to give the sub-titled product as a solid (0.3 g).
Reaction SMILES: [C:1]([O:5][C:6](=[O:18])[CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][C:10]=1[C:16]#[CH:17])([CH3:4])([CH3:3])[CH3:2].Br[C:20]1[CH:30]=[CH:29][C:23]([C:24]([N:26]([CH3:28])[CH3:27])=[O:25])=[CH:22][CH:21]=1>>[C:1]([O:5][C:6](=[O:18])[CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][C:10]=1[C:16]#[C:17][C:20]1[CH:30]=[CH:29][C:23]([C:24]([N:26]([CH3:28])[CH3:27])=[O:25])=[CH:22][CH:21]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CN(C)C(=O)c1ccc(Br)cc1
Reactant: C#Cc1cc(Cl)ccc1OCC(=O)OC(C)(C)C
Product: CN(C)C(=O)c1ccc(C#Cc2cc(Cl)ccc2OCC(=O)OC(C)(C)C)cc1

Procedure:
Following the general method as outlined in Intermediate 20, starting from (4-chloro-2-ethynyl-phenoxy)-acetic acid tert-butyl ester (Intermediate 3) and 4-bromo-N,N-dimethylbenzamide (Intermediate 176), the title compound was obtained as a brown sticky solid after purification by flash column chromatography (silica), eluting with cyclohexane containing increasing amounts of EtOAc.
Reaction SMILES: [C:1]([C:4]1[C:16]([OH:17])=[CH:15][C:7]([O:8][CH2:9][CH2:10][CH2:11][CH2:12][C:13]#[N:14])=[C:6]([CH2:18][CH:19]=[CH2:20])[CH:5]=1)(=[O:3])[CH3:2].[C:21](=O)([O-])[O-].[K+].[K+].CI>CN(C)C=O>[C:1]([C:4]1[C:16]([O:17][CH3:21])=[CH:15][C:7]([O:8][CH2:9][CH2:10][CH2:11][CH2:12][C:13]#[N:14])=[C:6]([CH2:18][CH:19]=[CH2:20])[CH:5]=1)(=[O:3])[CH3:2]
Reactant: C=CCc1cc(C(C)=O)c(O)cc1OCCCCC#N
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CI
Product: C=CCc1cc(C(C)=O)c(OC)cc1OCCCCC#N
Temperature: 25 °C
Reaction time: 5 h
Yield: 83.6 %

Procedure:
A mixture of 1.365 g of 5-(4-acetyl-5-hydroxy-2-allylphenoxy)pentanenitrile, 0.966 g of potassium carbonate, and 1.42 g of methyl iodide in 50 ml of dimethylformamide was stirred together at room temperature for 5 hours. The mixture was partitioned between dilute hydrochloric acid and ethyl acetate. The organic layer was separated, dried over sodium sulfate, and concentrated in vacuo to provide 1.2 g of the desired title product, m.p.=40°-42° C. NMR, MS.
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[C:3]([NH2:11])[C:2]=1[NH2:12].[C:13](O)(=[O:17])[C:14](O)=[O:15]>Cl>[NH:12]1[C:2]2[CH:1]=[C:10]3[CH:9]=[CH:8][CH:7]=[CH:6][C:5]3=[CH:4][C:3]=2[NH:11][C:14](=[O:15])[C:13]1=[O:17]
Reactant: Nc1cc2ccccc2cc1N
Reactant: O=C(O)C(=O)O
Agent: Cl
Product: O=c1[nH]c2cc3ccccc3cc2[nH]c1=O
Temperature: 25 °C
Yield: 99.3 %

Procedure:
A mixture of 603 mg (3.81 mmol) of 2,3-naphthalenediamine and 382 mg (4.24 mmol) of oxalic acid in 5 mL of 2N HCl was refluxed for 3 h and cooled to room temperature. The mixture was filtered, washed with water, and dried to leave a brown solid 803 mg (99%); mp>250° C.; 1H NMR (DMSO-d6), 7.382 (dd, 2, J=3.16, 6.17), 7.525 (s, 2), 7.815 (dd, 2, J=3.22, 6.18), 12.088 (s, 2).
Reaction SMILES: Cl.[CH3:2][S:3]([C:6]1[CH:7]=[C:8]([CH:10]=[CH:11][CH:12]=1)[NH2:9])(=[O:5])=[O:4].[N:13]([O-])=O.[Na+].O.O.[Sn](Cl)Cl>>[CH3:2][S:3]([C:6]1[CH:7]=[C:8]([NH:9][NH2:13])[CH:10]=[CH:11][CH:12]=1)(=[O:4])=[O:5]
Reactant: O=N[O-]
Reactant: CS(=O)(=O)c1cccc(N)c1
Agent: Cl
Agent: Cl[Sn]Cl
Agent: [Na+]
Solvent: O
Product: CS(=O)(=O)c1cccc(NN)c1

Procedure:
B-012 is prepared analogously to B-05 starting from 3-methylsulfonylaniline hydrochloride (2.50 g, 11.4 mmol), sodium nitrite (1.18 g, 17.1 mmol) and tin(II)chloride dihydrate (14.9 g, 66.0 mmol). The product is purified by precipitation from ethyl acetate with cyclohexane. Yield: 1.08 g.
Reaction SMILES: [C:1]([O:5][C:6](=[O:22])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14](=[O:20])[CH:15]=[CH:16][N:17](C)C)=[C:10]([Cl:21])[CH:9]=1)([CH3:4])([CH3:3])[CH3:2].Cl.NO>O1CCOCC1.C(OCC)(=O)C>[C:1]([O:5][C:6](=[O:22])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[O:20][N:17]=[CH:16][CH:15]=2)=[C:10]([Cl:21])[CH:9]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CN(C)C=CC(=O)c1ccc(NC(=O)OC(C)(C)C)cc1Cl
Agent: Cl
Agent: NO
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)Nc1ccc(-c2ccno2)c(Cl)c1
Temperature: 25 °C
Reaction time: 240 h

Procedure:
A solution of [3-chloro-4-(3-dimethylamino-acryloyl)-phenyl]-carbamic acid tert-butyl ester (270 mg) in dioxane (3 ml) is treated with hydroxylamine hydrochloride (122 mg) and the mixture is stirred at room temperature for 10 days. The mixture is diluted with ethyl acetate, washed successively with water, 5% aqueous sodium bicarbonate, saturated aqueous sodium chloride, and then dried over anhydrous magnesium sulfate. The solvent is removed by evaporation under reduced pressure and the resulting residue is chromatographed over silica gel (33% ethyl acetate in hexanes is used as the eluant) to provide the desired product as a colorless solid.
Reaction SMILES: [CH:1]([O:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[S:11]([NH2:14])(=[O:13])=[O:12])=[C:2]=[CH2:3].[CH3:15][O:16][C:17]1[N:22]=[C:21]([CH3:23])[N:20]=[C:19]([N:24](C2C=CC=CC=2)[C:25](=O)[O-:26])[N:18]=1.N12CCCN=C1CCCCC2.Cl>O.O1CCOCC1>[CH:1]([O:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[S:11]([NH:14][C:25]([NH:24][C:19]1[N:18]=[C:17]([O:16][CH3:15])[N:22]=[C:21]([CH3:23])[N:20]=1)=[O:26])(=[O:12])=[O:13])=[C:2]=[CH2:3]
Reactant: COc1nc(C)nc(N(C(=O)[O-])c2ccccc2)n1
Reactant: C=C=COc1ccccc1S(N)(=O)=O
Agent: Cl
Solvent: O
Solvent: C1CCC2=NCCCN2CC1
Solvent: C1COCCO1
Product: C=C=COc1ccccc1S(=O)(=O)NC(=O)Nc1nc(C)nc(OC)n1
Reaction time: 4 h
Yield: 59.4 %

Procedure:
A mixture of 1.7 g of 2-allenyloxyphenylsulfonamide, 2.08 g of 4-methoxy-6-methyl-1,3,5-triazin-2-ylphenylcarbamate, 1.22 g of 1,8-diazabicyclo[5.4.0]undec-7-ene (1.5-5) and 150 ml of absolute dioxane is stirred for 4 hours at 20°-25° C. The reaction mixture is poured into water and, after adjusting the pH 6 by the dropwise addition of 10% hydrochloric acid, extracted with ethyl acetate. The organic phase is dried and concentrated by evaporation. The residue is crystallised from ethyl acetate to give 1.8 g of the title compound of m.p. 150°-151° C. (dec.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1/[CH:9]=[CH:10]/[C:11]1[CH:20]=[CH:19][C:14]([C:15]([O:17][CH3:18])=[O:16])=[CH:13][CH:12]=1.[Cl:21][C:22]1[CH:27]=[CH:26][C:25]([S:28](Cl)(=[O:30])=[O:29])=[CH:24][CH:23]=1.Cl>C(Cl)Cl.N1C=CC=CC=1>[Cl:21][C:22]1[CH:27]=[CH:26][C:25]([S:28]([NH:1][C:2]2[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=2/[CH:9]=[CH:10]/[C:11]2[CH:12]=[CH:13][C:14]([C:15]([O:17][CH3:18])=[O:16])=[CH:19][CH:20]=2)(=[O:30])=[O:29])=[CH:24][CH:23]=1
Reactant: O=S(=O)(Cl)c1ccc(Cl)cc1
Reactant: COC(=O)c1ccc(/C=C/c2cc(Cl)ccc2N)cc1
Agent: Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: COC(=O)c1ccc(/C=C/c2cc(Cl)ccc2NS(=O)(=O)c2ccc(Cl)cc2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 98.1 %

Procedure:
To methyl 4-[2-(2-amino-5-chlorophenyl)-(E)-vinyl]benzoate (130 mg; prepared in Reference Example 5.) in methylene chloride (3 ml), pyridine (0.073 μl) and p-chlorobenzenesulfonylchloride (114 mg) were added. The mixture was stirred overnight at room temperature. The reaction mixture was poured into diluted HCl and extracted with ethyl acetate. The organic layer was washed, dried over and concentrated under the reduced pressure. The residue was purified on silica gel column chromatography (AcOEt-hexane) to give the title compound (205 mg) having the following physical data.
Reaction SMILES: [CH2:1]([C@@H:3]1[C:8](=[O:9])[N:7]([CH:10]([CH3:12])[CH3:11])[C:6]2[CH:13]=[CH:14][C:15]([C:17]([O:19]C)=[O:18])=[CH:16][C:5]=2[O:4]1)[CH3:2]>Cl>[CH2:1]([C@@H:3]1[C:8](=[O:9])[N:7]([CH:10]([CH3:12])[CH3:11])[C:6]2[CH:13]=[CH:14][C:15]([C:17]([OH:19])=[O:18])=[CH:16][C:5]=2[O:4]1)[CH3:2]
Reactant: CC[C@H]1Oc2cc(C(=O)OC)ccc2N(C(C)C)C1=O
Agent: Cl
Product: CC[C@H]1Oc2cc(C(=O)O)ccc2N(C(C)C)C1=O
Yield: 99.1 %

Procedure:
A mixture of (R)-2-ethyl-7-methoxycarbonyl-4-(2-propyl)-3-oxo-3,4-dihydro-2H-1,4-benzoxazine (1.70 g) in concentrated hydrochloric acid (30 ml) was stirred under reflux for a day. The concentrated hydrochloric acid was distilled off under reduced pressure. Water was added to the residue and extraction with ethyl acetate was conducted. The extract was washed with water and then the solvent was distilled off under reduced pressure to give (R)-2-ethyl-4-(2-propyl)-3-oxo-3,4-dihydro-2H-1,4-benzoxazine-7-carboxylic acid (1.60 g).
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]([C:8]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[CH:11]=[C:10]([CH:18]=[O:19])[N:9]=2)[CH:5]=[CH:6][CH:7]=1.CC[OH:22]>C1COCC1.O.[N+]([O-])([O-])=O.[Ag+]>[I:1][C:2]1[CH:3]=[C:4]([C:8]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[CH:11]=[C:10]([C:18]([OH:22])=[O:19])[N:9]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: O=Cc1cc2ccccc2c(-c2cccc(I)c2)n1
Reactant: CCO
Agent: [Ag+]
Agent: O=[N+]([O-])[O-]
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)c1cc2ccccc2c(-c2cccc(I)c2)n1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of 1-(3-iodophenyl)-3-methylisoquinoline (5.733 g, 16.62 mmol), N-bromosuccinimide (NBS) (7.399 g, 41.57 mmol), and benzoyl peroxide (BPO) (0.48 g) in CCl4 (100 mL) was heated to reflux while being illuminated by a flood lamp for 5 h. The reaction mixture was cooled to room temperature and filtered. The filtrate was washed with saturated NaHCO3 aqueous solution (40 mL), dried (Na2SO4), then filtered. The filtrate was concentrated in vacuo, thereby affording crude 1-(3-iodophenyl)-3-dibromomethylisoquinoline (8.327 g) as a yellow oil. It was used directly in next step without any purifications. To a refluxing solution of crude dibromide (8.327 g) in EtOH (110 mL) and THF (60 mL) was added dropwise a solution of AgNO3 (7.994 g) in H2O (10 mL). The mixture was refluxed for 1 h and filtered while hot. The filter cake was washed with hot THF (2×30 mL). The combined filtrate was concentrated in vacuo to give crude 1-(3 -Iodophenyl)-3-isoquinoline-carboxaldehyde as an dark yellow oil (11.62 g, containing H2O). This oil was used without further purification. To a solution of crude aldehyde (11.62 g) in absolute EtOH (80 mL)was slowly added a solution of AgNO3 (7.28 g) in H2O (10 mL). To this stirred solution was added dropwise a solution of NaOH (5.80 g) in H2O (100 mL). The resulting black slurry was stirred at room temperature for 2 h. Then the mixture was filtered through a small Celite column. The filter cake was washed with ether. The ether was evaporated and the aqueous solution was made slightly acidic with concentrated HCl. The precipitate was collected by filtration, then washed with H2O. It was recrystallized from CH3CN, thereby affording 1-(3-iodophenyl)-3-isoquinolinecarboxylic acid as a yellow crystalline (2.22 g, 36%). mp 145-146° C. 1H NMR (DMSO-d6) d 7.37 (t, J=6.0 Hz, 1 H, aromatic), 7.65-7.71(m, 2 H, aromatic), 7.80 (t, J=4.8 Hz, 1 H, aromatic), 7.91 (d, J=6.6 Hz, 1 H, aromatic), 7.95 (d, J=6.3 Hz, 1 H, aromatic), 8.01 (s, 1 H, aromatic), 8.14 (d, J=6.0 Hz, 1 H, aromatic), 8.44 (s, 1 H, aromatic). HRMS Calcd for C16H10INO2 : 374.9756. Found: 374.9741.