Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=O)[CH2:9][C:10](=O)[C:11]([F:14])([F:13])[F:12])=[CH:4][C:3]=1[CH3:17].[NH2:18][C:19]1[C:23]([C:24]#[N:25])=[C:22]([CH2:26][C:27]#[N:28])[NH:21][N:20]=1>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10]([C:11]([F:14])([F:13])[F:12])[N:20]3[N:21]=[C:22]([CH2:26][C:27]#[N:28])[C:23]([C:24]#[N:25])=[C:19]3[N:18]=2)=[CH:4][C:3]=1[CH3:17]
Reactant: Cc1cc(C(=O)CC(=O)C(F)(F)F)ccc1Cl
Reactant: N#CCc1[nH]nc(N)c1C#N
Product: Cc1cc(-c2cc(C(F)(F)F)n3nc(CC#N)c(C#N)c3n2)ccc1Cl
Yield: 52.7 %

Procedure:
Reaction of 1-(4-chloro-3-methyl-phenyl)-4,4,4-trifluoro-butane-1,3-dione (132 mg, 0.5 mmol), prepared from commercially available 4-chloro-3-methyl-acetophenone according to general procedure A, and commercially available 3-amino-4-cyano-5-cyanomethyl-pyrazole (74 mg, 0.5 mmol) according to general procedure B yielded the title compound as a light yellow solid (99 mg, 53%). MS (ISP) 376.1 [(M+H)+]; mp 238° C.
Reaction SMILES: [OH:1][CH2:2][CH2:3][NH:4][S:5]([C:8]1[C:9]2[CH:10]=[CH:11][N:12]=[C:13]([Cl:18])[C:14]=2[CH:15]=[CH:16][CH:17]=1)(=[O:7])=[O:6].[C:19]1([CH3:29])[CH:24]=[CH:23][C:22]([S:25](Cl)(=[O:27])=[O:26])=[CH:21][CH:20]=1>N1C=CC=CC=1>[C:19]1([CH3:29])[CH:24]=[CH:23][C:22]([S:25]([O:1][CH2:2][CH2:3][NH:4][S:5]([C:8]2[C:9]3[CH:10]=[CH:11][N:12]=[C:13]([Cl:18])[C:14]=3[CH:15]=[CH:16][CH:17]=2)(=[O:6])=[O:7])(=[O:27])=[O:26])=[CH:21][CH:20]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: O=S(=O)(NCCO)c1cccc2c(Cl)nccc12
Solvent: c1ccncc1
Product: Cc1ccc(S(=O)(=O)OCCNS(=O)(=O)c2cccc3c(Cl)nccc23)cc1
Temperature: 0 °C
Reaction time: 24 h
Yield: 74.9 %

Procedure:
To 5.74 g of N-(2-hydroxyethyl)-1-chloro-5-isoquinolinesulfonamide was successively added 80 ml of pyridine and 7.62 g of p-toluenesulfonylchloride and the mixture was stirred at 15° to 20 ° C. for 24 hours. After completion of the reaction, the mixture was cooled with 200 g of ice water and the mixture was subjected to extraction with 200 ml of dichloromethane twice. The resultant dichloromethane layer was dried over anhydrous magnesium sulfate and the residue was subjected to purification by means of a chromatography column packed with 200 g of silica gel (Wacogel C-200, manufactured by Wako Pure Chemical Industries, Ltd., Japan) using chloroform as an eluent to obtain 6.61 g of N-(2-paratoluenesulfonyloxyethyl)-1-chloro-5-isoquinolinesulfonamide (yield: 75%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[N:9]1[C:18]2[C:13](=[C:14]([CH:22]=[CH2:23])[C:15]([F:21])=[C:16]([F:20])[C:17]=2[F:19])[C:12](=[O:24])[C:11]([C:25]([O:27]CC)=[O:26])=[CH:10]1.O.S(=O)(=O)(O)O>C(O)(=O)C>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[N:9]1[C:18]2[C:13](=[C:14]([CH:22]=[CH2:23])[C:15]([F:21])=[C:16]([F:20])[C:17]=2[F:19])[C:12](=[O:24])[C:11]([C:25]([OH:27])=[O:26])=[CH:10]1
Reactant: C=Cc1c(F)c(F)c(F)c2c1c(=O)c(C(=O)OCC)cn2-c1ccc(F)cc1F
Agent: O=S(=O)(O)O
Solvent: O
Solvent: CC(=O)O
Product: C=Cc1c(F)c(F)c(F)c2c1c(=O)c(C(=O)O)cn2-c1ccc(F)cc1F
Yield: 69.8 %

Procedure:
2 g of the product of Example C are refluxed for 2 hours in a mixture of 15 ml of glacial acetic acid, 1.5 ml of water and 0.7 ml of concentrated sulphuric acid. The product is filtered off with suction at room temperature, washed with water and dried. 1.3 g of the title compound are obtained (71% of theory).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][C:16]2[CH:17]=[C:18]([C@@:23]3([OH:50])[C@H:28]([O:29][Si](C)(C)C)[C@@H:27]([O:34][Si](C)(C)C)[C@H:26]([O:39][Si](C)(C)C)[C@@H:25]([CH2:44][O:45][Si](C)(C)C)[O:24]3)[CH:19]=[CH:20][C:21]=2[Cl:22])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:51]S(O)(=O)=O.C(=O)(O)[O-].[Na+]>O1CCCC1.CO>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][C:16]2[CH:17]=[C:18]([C@@:23]3([O:50][CH3:51])[C@H:28]([OH:29])[C@@H:27]([OH:34])[C@H:26]([OH:39])[C@@H:25]([CH2:44][OH:45])[O:24]3)[CH:19]=[CH:20][C:21]=2[Cl:22])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CS(=O)(=O)O
Reactant: C[Si](C)(C)OC[C@H]1O[C@@](O)(c2ccc(Cl)c(Cc3ccc(OCc4ccccc4)cc3)c2)[C@H](O[Si](C)(C)C)[C@@H](O[Si](C)(C)C)[C@@H]1O[Si](C)(C)C
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Product: CO[C@@]1(c2ccc(Cl)c(Cc3ccc(OCc4ccccc4)cc3)c2)O[C@H](CO)[C@@H](O)[C@H](O)[C@H]1O
Temperature: 25 °C
Reaction time: 12 h
Yield: 54.5 %

Procedure:
To a solution of (2S,3R,4S,5R,6R)-2-[3-[(4-benzyloxyphenyl)methyl]-4-chloro-phenyl]-3,4,5-tris(trimethylsilyloxy)-6-(trimethylsilyloxymethyl)tetrahydropyran-2-ol 25d in anhydrous tetrahydrofuran was added a solution of methylsulfonic acid (0.2 mL, 2.82 mmol) in methanol (20 mL) at −78° C. The mixture was warmed up to room temperature and stirred for 12 hours. The reaction mixture was neutralized with saturated aqueous sodium bicarbonate till pH becomes 6-7 and extracted with ethyl acetate (50 mL×4). The combined organic layers were washed with water (60 mL×2) and saturated aqueous sodium chloride (60 mL×2) in turn, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated in vacuo and the residue was purified by re-crystallization from a toluene/n-hexane mixture ((v/v)=1/20, 500 mL) to give the title compound 25e as a white solid (1.28 g, 54.5%). The compound was characterized by the following spectroscopic data: MS (ESI, pos. ion) m/z: 545.3[M+HCOO]−.
Reaction SMILES: [Cl:1][C:2]1[CH:26]=[CH:25][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[C:11]([F:24])[C:12](/[CH:16]=[C:17]4/[C:18](=[O:23])[NH:19][C:20](=[O:22])[S:21]/4)=[CH:13][CH:14]=3)[CH:9]=[N:8]2)=[C:4]([C:27]([F:30])([F:29])[F:28])[CH:3]=1.Br[CH2:32][C:33]([O:35]C(C)(C)C)=[O:34]>>[Cl:1][C:2]1[CH:26]=[CH:25][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[C:11]([F:24])[C:12](/[CH:16]=[C:17]4/[C:18](=[O:23])[N:19]([CH2:32][C:33]([OH:35])=[O:34])[C:20](=[O:22])[S:21]/4)=[CH:13][CH:14]=3)[CH:9]=[N:8]2)=[C:4]([C:27]([F:29])([F:28])[F:30])[CH:3]=1
Reactant: O=C1NC(=O)/C(=C/c2ccc3c(cnn3Cc3ccc(Cl)cc3C(F)(F)F)c2F)S1
Reactant: CC(C)(C)OC(=O)CBr
Product: O=C(O)CN1C(=O)S/C(=C\c2ccc3c(cnn3Cc3ccc(Cl)cc3C(F)(F)F)c2F)C1=O

Procedure:
[(5Z)-5-({1-[4-Chloro-2-(trifluoromethyl)benzyl]-4-fluoro-1H-indazol-5-yl}methylidene)-2,4-dioxo-1,3-thiazolidin-3-yl]acetic acid was prepared from [(5Z)-5-({1-[4-chloro-2-(trifluoromethyl)benzyl]-4-fluoro-1H-indazol-5-yl}methylidene)-2,4-dioxo-1,3-thiazolidine and tert-butyl bromoacetate following General Procedure I.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]([NH:19][C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])=[N:10][C:11]1[CH:16]=[CH:15][C:14]([CH2:17][OH:18])=[CH:13][CH:12]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]>C(Cl)Cl.O=[Mn]=O>[C:1]([O:5][C:6]([NH:8][C:9]([NH:19][C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])=[N:10][C:11]1[CH:16]=[CH:15][C:14]([CH:17]=[O:18])=[CH:13][CH:12]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)NC(=Nc1ccc(CO)cc1)NC(=O)OC(C)(C)C
Agent: O=[Mn]=O
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NC(=Nc1ccc(C=O)cc1)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 92.8 %

Procedure:
The alcohol (0.282 g, 0.771 mmol) from above was dissolved in CH2Cl2 (7 mL), treated with activated MnO2 (0.696 g, 8.01 mmol) and stirred at room temperature overnight. The mixture was filtered through celite® and the cake was washed with CH2Cl2. The solvent was removed from the filtrate under reduced pressure and provided N, N′-bis-(tert-butoxycarbonyl)-N″-(4-formyl-phenyl)-guanidine (0.260 g, 93%) as a white solid. 1H NMR (CDCl3) δ 1.53 (s, 9H), 1.55 (s, 9H), 7.85 (s, 4H), 9.93 (s, 1H), 10.34 (br s, 1H).
Reaction SMILES: [C:1](=[O:14])([O:3][CH2:4][CH:5]([NH2:13])[CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[NH2:2].[O-:15][C:16]#[N:17].[Na+].CS(O)(=O)=O>ClCCl>[NH2:17][C:16]([NH:2][C:1](=[O:14])[O:3][CH2:4][CH:5]([NH2:13])[CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)=[O:15]
Reactant: NC(=O)OCC(N)Cc1ccccc1
Reactant: N#C[O-]
Agent: CS(=O)(=O)O
Agent: [Na+]
Solvent: ClCCl
Product: NC(=O)NC(=O)OCC(N)Cc1ccccc1

Procedure:
As shown in Scheme II, 2-amino-3-phenylpropyl carbamate (V) is reacted with sodium cyanate and methansulfonic acid in dichloromethane, to give 2-amino-3-phenylpropyl (aminocarbonyl)carbamate (VI).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([CH3:8])[C:5]([N+:9]([O-:11])=[O:10])=[CH:4][CH:3]=1.[F:12][C:13]1([F:17])[CH2:16][NH:15][CH2:14]1>>[F:12][C:13]1([F:17])[CH2:16][N:15]([C:2]2[N:7]=[C:6]([CH3:8])[C:5]([N+:9]([O-:11])=[O:10])=[CH:4][CH:3]=2)[CH2:14]1
Reactant: Cc1nc(Cl)ccc1[N+](=O)[O-]
Reactant: FC1(F)CNC1
Product: Cc1nc(N2CC(F)(F)C2)ccc1[N+](=O)[O-]

Procedure:
Prepared from 6-chloro-2-methyl-3-nitropyridine and 3,3-difluoroazetidine following the method used to prepare Intermediate 49. LCMS (ES+) 230 (M+H)+, RT 2.57 minutes (method 1).
Reaction SMILES: [C:1](N1C=CN=C1)(N1C=CN=C1)=[O:2].[CH:13]1([NH:16][C:17]2[C:18]([NH2:25])=[CH:19][C:20]([F:24])=[C:21]([F:23])[CH:22]=2)[CH2:15][CH2:14]1>C1COCC1.C(OCC)(=O)C>[CH:13]1([N:16]2[C:17]3[CH:22]=[C:21]([F:23])[C:20]([F:24])=[CH:19][C:18]=3[NH:25][C:1]2=[O:2])[CH2:15][CH2:14]1
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: Nc1cc(F)c(F)cc1NC1CC1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: O=c1[nH]c2cc(F)c(F)cc2n1C1CC1
Temperature: 25 °C
Reaction time: 20 h
Yield: 68.5 %

Procedure:
Carbonyldiimidazole (4.3 g) was added to the solution of N1-cyclopropyl-4,5-difluorobenzene-1,2-diamine (3.2 g) in THF (30 ml). The mixture was stirred at rt for 20 hours, then diluted with ethyl acetate (200 ml) and washed with hydrochloric acid (1M, 200 ml). Organic layer dried over sodium sulphate, solvent removed to give expected product as a black solid (2.5 g). 1H NMR (CD3OD)δ: 7.20 (dd, 1H), 6.95 (dd, 1H), 2.86 (m, 1H), 1.11 (m, 2H), 0.94 (m, 2H).
Reaction SMILES: Br[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([CH2:12][C:13]([OH:15])=[O:14])=[CH:4][CH:3]=1.[N:16]1[CH:21]=[CH:20][C:19](B(O)O)=[CH:18][CH:17]=1.C(=O)([O-])O.[Na+].O>COCCOC.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[N:16]1[CH:21]=[CH:20][C:19]([C:2]2[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]([CH2:12][C:13]([OH:15])=[O:14])=[CH:4][CH:3]=2)=[CH:18][CH:17]=1
Reactant: OB(O)c1ccncc1
Reactant: O=C(O)Cc1ccc(Br)c2ccccc12
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Product: O=C(O)Cc1ccc(-c2ccncc2)c2ccccc12

Procedure:
4-Bromonaphth-1-ylacetic acid (J. Org. Chem., 1951, 16, 1588) (1 g, 3.78 mmole) in 1,2-dimethoxyethane (50 ml) was treated with pyridin-4-ylboronic acid (465 mg, 3.78 mmole), sodium hydrogen carbonate (952 mg, 11.3 mmole) and water (10 ml). A stream of argon was bubbled through the mixture for 15 minutes, then tetrakis(triphenylphosphine)palladium (0) (200 mg 0.17 mmole) was added and the mixture heated under reflux for 18 hours. The mixture was then concentrated in vacuo to a gum, which was partitioned between 2M sodium hydroxide solution and dichloromethane. The aqueous layer was separated, adjusted to pH 0 with 6M hydrochloric acid and washed with dichloromethane; then adjusted to pH 7 by addition of aqueous potassium carbonate solution and extracted with dichloromethane. The dichloromethane extract was dried (Na2SO4) and concentrated in vacuo to give the title compound, which crystallised from ether as needles mp 210-215° C. (465 mg, 46%).
Reaction SMILES: [OH-].[Li+].[F:3][C:4]1[CH:9]=[C:8]([F:10])[CH:7]=[CH:6][C:5]=1[C:11]1[CH:16]=[CH:15][C:14]([C:17]([O:19]CC)=[O:18])=[CH:13][CH:12]=1.Cl>C1COCC1.O>[F:3][C:4]1[CH:9]=[C:8]([F:10])[CH:7]=[CH:6][C:5]=1[C:11]1[CH:16]=[CH:15][C:14]([C:17]([OH:19])=[O:18])=[CH:13][CH:12]=1
Reactant: CCOC(=O)c1ccc(-c2ccc(F)cc2F)cc1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)c1ccc(-c2ccc(F)cc2F)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
0.098 ml of 1 N lithium hydroxide solution was added to a solution of 0.051 g of ethyl 2′,4′-difluorobiphenyl-4-carboxylate in 1ml THF/water (1:1), and the mixture was stirred at room temperature overnight. 5% hydrochloric acid was used to neutralize the solution, which was concentrated in vacuo, and the residue was purified by preparative HPLC.
Reaction SMILES: [CH3:1][N:2](S(C1C=CC=CC=1)(=O)=O)[N:3]=[C:4](Cl)[C:5]1[C:10]([F:11])=[CH:9][CH:8]=[CH:7][C:6]=1[F:12].[Cl:23][C:24]1[CH:25]=[C:26]([CH:29]=[CH:30][C:31]=1[O:32][C:33]1[C:38]([Cl:39])=[CH:37][C:36]([C:40]([F:43])([F:42])[F:41])=[CH:35][N:34]=1)[C:27]#[N:28].ClC1C=CC=CC=1Cl>C(Cl)(Cl)Cl.[Fe](Cl)(Cl)Cl>[Cl:23][C:24]1[CH:25]=[C:26]([C:27]2[N:2]([CH3:1])[N:3]=[C:4]([C:5]3[C:6]([F:12])=[CH:7][CH:8]=[CH:9][C:10]=3[F:11])[N:28]=2)[CH:29]=[CH:30][C:31]=1[O:32][C:33]1[C:38]([Cl:39])=[CH:37][C:36]([C:40]([F:43])([F:41])[F:42])=[CH:35][N:34]=1
Reactant: N#Cc1ccc(Oc2ncc(C(F)(F)F)cc2Cl)c(Cl)c1
Reactant: CN(N=C(Cl)c1c(F)cccc1F)S(=O)(=O)c1ccccc1
Agent: Cl[Fe](Cl)Cl
Solvent: Clc1ccccc1Cl
Solvent: ClC(Cl)Cl
Product: Cn1nc(-c2c(F)cccc2F)nc1-c1ccc(Oc2ncc(C(F)(F)F)cc2Cl)c(Cl)c1
Temperature: 140 °C
Reaction time: 0.5 h
Yield: 53.5 %

Procedure:
A mixture of N-methyl-N-(benzenesulfonyl)-2,6-difluorobenzohydrazonoyl chloride (0.90 g), 3-chloro-4-(3-chloro-5-trifluoromethylpyridine-2-yloxy)benzonitrile (0.90 g), anhydrous iron (III) chloride (0.50 g) and o-dichlorobenzene (5 ml) is stirred at an oil bath temperature of 140° C. for 30 minutes. After cooling, it is dissolved in chloroform (100 ml) and washed with dilute hydrochloric acid, dilute aqueous solution of sodium hydroxide and saline. Then, it is dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The concentrate is purified by silica gel column chromatography using mixed solvent of hexaneethyl acetate as eluent to give 0.70 g of desired compound.
Reaction SMILES: [C:1]1([CH:7]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[C:8]([N:10]2[CH:19]([C:20]([O:22][CH2:23][CH3:24])=[O:21])[CH2:18][C:17]3[C:12](=[CH:13][CH:14]=[C:15]([O:26][CH3:27])[C:16]=3[OH:25])[CH2:11]2)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:34]([C:38]1[CH:45]=[CH:44][C:41]([CH2:42]Br)=[CH:40][CH:39]=1)([O:36][CH3:37])=[O:35].C(=O)([O-])[O-].[Na+].[Na+]>CN(C=O)C>[C:34]([C:38]1[CH:45]=[CH:44][C:41]([CH2:42][O:25][C:16]2[C:15]([O:26][CH3:27])=[CH:14][CH:13]=[C:12]3[C:17]=2[CH2:18][CH:19]([C:20]([O:22][CH2:23][CH3:24])=[O:21])[N:10]([C:8](=[O:9])[CH:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=2)[CH2:11]3)=[CH:40][CH:39]=1)([O:36][CH3:37])=[O:35]
Reactant: COC(=O)c1ccc(CBr)cc1
Reactant: CCOC(=O)C1Cc2c(ccc(OC)c2O)CN1C(=O)C(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)C1Cc2c(ccc(OC)c2OCc2ccc(C(=O)OC)cc2)CN1C(=O)C(c1ccccc1)c1ccccc1
Temperature: 0 °C
Reaction time: 0.08 h

Procedure:
A mixture of 0.89 g (0,002 mole) of the compound from Example 31, 0.69 g (0.003 mole) of 4-carbomethoxybenzyl bromide (Aldrich), 5.0 g of powdered anhydrous sodium carbonate, and 5 mL of DMF is heated at reflux, with stirring, for 5 minutes. The cooled mixture is treated with 50 mL of ice water. The precipitated product is extracted into 150 mL of ether. The solution is dried (magnesium sulfate) and concentrated; wt. of amorphous solid 1.20 g; mass spectrum (CI) 594 (M+).
Reaction SMILES: [CH:1]1[CH:6]=[C:5]2[CH:7]=[CH:8][C:9](O)=[C:10]([S:11]([OH:14])(=[O:13])=[O:12])[C:4]2=[CH:3][CH:2]=1.[NH3:16]>>[NH2:16][C:9]1[CH:8]=[CH:7][C:5]2[C:4](=[CH:3][CH:2]=[CH:1][CH:6]=2)[C:10]=1[S:11]([OH:14])(=[O:13])=[O:12]
Reactant: O=S(=O)(O)c1c(O)ccc2ccccc12
Reactant: N
Product: Nc1ccc2ccccc2c1S(=O)(=O)O

Procedure:
treating the resultant aqueous solution of the ammonium salt of oxy-Tobias acid, without increasing the concentration beforehand, with NH3 and concentrated (NH4)2SO3 or (NH4)HSO3 solution in the temperature range from 120° to 150° C. and at a pressure of 10 to 20 bar for 4 to 12 hours until the pH value is 9 to 12, to give the ammonium salt of 2-amino-1-naphthalenesulfonic acid (Tobias acid), and, after stripping off NH3 and removal of 2-naphthylamine by extraction with an aromatic hydrocarbon,
Reaction SMILES: [C:1]1([NH:7][NH2:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:9]([N:11]1[C:23]2[CH:22]=[CH:21][C:20]([CH:24]=O)=[CH:19][C:18]=2[C:17]2[C:12]1=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH3:10]>C(O)(C)C>[C:1]1([NH:7][N:8]=[CH:24][C:20]2[CH:21]=[CH:22][C:23]3[N:11]([CH2:9][CH3:10])[C:12]4[C:17]([C:18]=3[CH:19]=2)=[CH:16][CH:15]=[CH:14][CH:13]=4)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: NNc1ccccc1
Reactant: CCn1c2ccccc2c2cc(C=O)ccc21
Solvent: CC(C)O
Product: CCn1c2ccccc2c2cc(C=NNc3ccccc3)ccc21
Temperature: 25 °C

Procedure:
Phenylhydrazine (0.1 mole, commercially available from Aldrich, Milwaukee, Wis.) and 9-ethyl-3-carbazolecarboxaldehyde (0.1 mole, available from Aldrich Chemical, Milwaukee, Wis.) were dissolved in 100 ml of isopropanol in 250 ml 3-neck round bottom flask equipped with a reflux condenser and a mechanical stirrer. The solution was refluxed for 2 hours. Thin layer chromatography indicated the disappearance of the starting materials. At the end of the reaction, the mixture was cooled to room temperature. The 9-ethyl-3-carbazolecarbaldehyde phenylhydrazone crystals formed upon standing were filtered off and washed with isopropanol and dried in a vacuum oven at 50° C. for 6 hours.
Reaction SMILES: [C:1]([N:8]1C=CN=C1)([N:3]1[CH:7]=[CH:6][N:5]=[CH:4]1)=[S:2].[NH2:13][C:14]1[CH:19]=[CH:18][C:17]([Br:20])=[CH:16][N:15]=1>C(#N)C>[NH2:13][C:14]1[C:19]([NH:8][C:1]([N:3]2[CH:7]=[CH:6][N:5]=[CH:4]2)=[S:2])=[CH:18][C:17]([Br:20])=[CH:16][N:15]=1
Reactant: S=C(n1ccnc1)n1ccnc1
Reactant: Nc1ccc(Br)cn1
Solvent: CC#N
Product: Nc1ncc(Br)cc1NC(=S)n1ccnc1

Procedure:
A solution of 1,1'-thiocarbonyldiimidazole (17.8 G, 0.1 m) and 2-amino-5-bromopyridine (17.3 g, 0.1 m) in acetonitrile (150 mL) was stirred at room temperature for 2 hours. To this suspension was added the material described below.
Reaction SMILES: [N:1]([CH2:4][CH2:5][CH2:6][OH:7])=[N+:2]=[N-:3].[H-].[Na+].[CH2:10]([O:13][C:14]1[N:19]=[C:18](OCC=C)[N:17]=[C:16]([O:24][CH2:25][CH:26]=[CH2:27])[N:15]=1)[CH:11]=[CH2:12]>C1COCC1>[N:1]([CH2:4][CH2:5][CH2:6][O:7][C:18]1[N:19]=[C:14]([O:13][CH2:10][CH:11]=[CH2:12])[N:15]=[C:16]([O:24][CH2:25][CH:26]=[CH2:27])[N:17]=1)=[N+:2]=[N-:3]
Reactant: [N-]=[N+]=NCCCO
Reactant: C=CCOc1nc(OCC=C)nc(OCC=C)n1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: C=CCOc1nc(OCC=C)nc(OCCCN=[N+]=[N-])n1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 33.9 %

Procedure:
To 3-azido-1-propanol (8.7 g, 85.7 mmol) in THF (200 mL) was added sodium hydride (5.6 g, 128.6 mmol) at −78° C. The reaction mixture was stirred at −78° C. for about 30 minutes and then allowed to equilibrate at room temperature and stirred for an additional 3 hours. The reaction mixture was recooled to −78° C. and added to a solution of 2,4,6-triallyloxy-1,3,5-triazine (21.4 g, 85.7 mmole) in THF (200 mL). The reaction mixture was stirred at room temperature for about 16 hours. The reaction mixture was evaporated to a brown residue. The residue was purified by flash column chromatography over silica gel using EtOAc/hexane as the eluent. The pure fractions were pooled together and evaporated to dryness to give 8.5 g (36%) of the title compound. TLC (Rf: 0.5; 20% EtOAc/Hexane, I2). 1H NMR (CDCl3) δ 2.1 (m, 2H, CH2), 3.5 (t, 2H, CH2), 4.5 (t, 2H, CH2), 4.9 (m, 4H, CH2), 4.3 (m, 4H, CH2), 6.0 (m, 2H, CH).
Reaction SMILES: [CH2:1]([C:4]1[CH:5]=[C:6]([C:11](=[O:13])[CH3:12])[CH:7]=[CH:8][C:9]=1O)[CH:2]=[CH2:3].C(=O)([O-])[O-].[K+].[K+].[F:20][C:21]1[CH:22]=[CH:23][C:24]([O:30][CH3:31])=[C:25](B(O)O)[CH:26]=1.CN(C)C=O>O1CCCC1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH2:1]([C:4]1[CH:5]=[C:6]([C:11](=[O:13])[CH3:12])[CH:7]=[CH:8][C:9]=1[C:23]1[CH:22]=[C:21]([F:20])[CH:26]=[CH:25][C:24]=1[O:30][CH3:31])[CH:2]=[CH2:3]
Reactant: COc1ccc(F)cc1B(O)O
Reactant: C=CCc1cc(C(C)=O)ccc1O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: C=CCc1cc(C(C)=O)ccc1-c1cc(F)ccc1OC
Temperature: 120 °C

Procedure:
A mixture of 3′-allyl-4′-hydroxyacetophenone (0.352 g, 2.0 mmol), N-phenyl-bis(trifluoromethane) sulfonimide) (0.710 g, 2.0 mmol) and potassium carbonate (0.830 g, 6.0 mmol) in tetrahydrofuran (3.0 ml) was heated in a microwave oven at 120° C. for 10 min. The resultant mixture was treated with 5-fluoro-2-methoxyphenyl boronic acid (0.680 g, 0.4 mmol), tetrakis(triphenylphosphine)palladium (0) (0.060 g, 0.05 mmol) and dimethylformamide (1.0 ml) and heated in a microwave oven at 120° C. for 10 min. The mixture was partitioned between ethyl acetate and dilute aqueous sodium carbonate solution. The organic phase was dried over anhydrous sodium sulfate, the solvent evaporated and the residue purified by flash chromatography over silica gel eluting with 9:1 heptane/ethyl acetate. Evaporation of solvent under reduced pressure gave 1-(2-allyl-5′-fluoro-2′-methoxy-biphenyl-4-yl)-ethanone. A solution of 1-(2-allyl-5′-fluoro-2′-methoxy-biphenyl-4-yl)-ethanone (0.319 g, 1.1 mmol), sodium cyanoborohydride (0.140 g, 2.2 mmol) and ammomium acetate (1.7 g, 22 mmol) was stirred under nitrogen at ambient temperature for 72 h, evaporated to dryness under reduced pressure and partitioned between dichloromethane and brine. The organic phase was dried over anhydrous sodium sulfate, the solvent evaporated and the residue purified by flash chromatography over silica gel eluting with 98:2 ethyl acetate/2M ammonia in methanol. Evaporation of solvent under reduced pressure gave 1-(2-allyl-5′-fluoro-2′-methoxy-biphenyl-4-yl)-ethylamine. To a solution of 1-(2-allyl-5′-fluoro-2′-methoxy-biphenyl-4-yl)-ethylamine (19.0 mg, 0.07 mmol) in dichloromethane (1 ml) was added triethylamine (6.7 mg, 0.07 mmol) and 3,4-di-fluorophenyl sulfonyl chloride (14.2 mg, 0.06 mmol). The solution was stirred overnight and the solvent evaporated. The residue was purified by flash chromatography over silica gel eluting with dichloromethane. Evaporation of solvent under reduced pressure gave the title compound. 1H NMR (400 MHz, CDCl3): δ 7.52-7.42 (m, 2H), 7.13 (q, 1H), 7.04-6.90 (m, 4H), 6.88-6.83 (m, 1H), 6.77 (q, 1H), 5.67 (dt, 1H), 4.99-4.82 (m, 3H), 4.57 (dq, 1H), 3.71 (s, 3H), 3.09 (br s, 2H), 1.51 (d, 3H) ppm; MS (ESI) m/z: value [M+H]+.
Reaction SMILES: [CH3:1][C@H:2]1[CH2:7][NH:6][CH2:5][C@@H:4]([CH3:8])[NH:3]1.[CH2:9](Br)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>CN(C=O)C>[CH2:9]([N:6]1[CH2:5][C@H:4]([CH3:8])[NH:3][C@H:2]([CH3:1])[CH2:7]1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: C[C@@H]1CNC[C@H](C)N1
Reactant: BrCc1ccccc1
Solvent: CN(C)C=O
Product: C[C@@H]1CN(Cc2ccccc2)C[C@H](C)N1
Temperature: 25 °C
Reaction time: 48 h
Yield: 68.5 %

Procedure:
To an ice cold (˜0° C.) suspension of cis-2,6-dimethylpiperazine (4.0 g, 35 mmol) in DMF (100 mL) was benzyl bromide (6.0 g, 35.0 mmol) added in portions under a period of 45 min and the reaction mixture was stirred at room temperature for 48 h. The solvent was evaporated from the suspension and the residue was dissolved in aqueous HCl and washed twice with CHCl3. The aqueous phase was made alkaline and extracted twice with CHCl3. The combined organic phases were washed with H2O and brine, dried (MgSO4), and concentrated to give 4.9 g (68%) of the title product as a colorless oil.