Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][S:2]([OH:5])(=[O:4])=[O:3].[Cl-].[Cl-].[Cl-].[Cl-].[Zr+4:10].Cl.N#N>C(Cl)(Cl)(Cl)Cl.O>[CH3:1][S:2]([O-:5])(=[O:4])=[O:3].[Zr+4:10].[CH3:1][S:2]([O-:5])(=[O:4])=[O:3].[CH3:1][S:2]([O-:5])(=[O:4])=[O:3].[CH3:1][S:2]([O-:5])(=[O:4])=[O:3]
Reactant: CS(=O)(=O)O
Agent: [Zr+4]
Agent: Cl
Agent: N#N
Solvent: ClC(Cl)(Cl)Cl
Solvent: O
Product: CS(=O)(=O)[O-]
Temperature: 25 °C
Yield: 70 %

Procedure:
A 1 liter, 3-necked round bottom flask which had been dried was equipped with a condenser, caustic trap, thermometer, and an addition funnel. Under a nitrogen atmosphere, the flask was charged with 250 ml of dry carbon tetrachloride (CCl4), stirring was initiated, and this was followed by 40.0 g (0.42 mole) of anhydrous methanesulfonic acid (MSA) and 4.0 g (0.023 mole) of MSA anhydride (added as a drying agent). Typically, the water content of the reaction solution was found by Karl Fischer analysis to be 16 ppm. Following a satisfactory analysis for water content (i.e., below 25 ppm), 23.3 g (0.1 mole) of zirconium tetrachloride was added dropwise to the solution over 1 hour during which time a white precipitate formed and gaseous HCl evolution was observed. The evolved HCl(g) was swept out of the reaction flask and through a caustic trap with a slow stream of nitrogen. A 50 ml portion of CCl4 was added to lower the viscosity of the mixture, and with N2 (g) flowing, the reaction was stirred for 16 hours at room temperature. Following this, the reaction mixture was heated to 40° C. until no more HCl evolution was observed (normally about three hours). The reaction was cooled to room temperature. The solid product, which precipitated from the reaction solution, was collected by vacuum filtration under nitrogen. The product was washed twice with dry CCl4. The product was split into two portions (portion one was approximately twice the size of portion two). The first portion was washed twice with ether and acetonitrile before removal of the volatiles in-vacuo. After obtaining a constant weight under vacuum, the first portion weighed 21.9 g, while the second portion weighed 11.1 g as is, for a total of 33.0 g, (70% yield). Both lots were analyzed.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[CH2:14][CH:13]([CH2:15][CH:16]3[CH2:21][CH2:20][N:19]([CH2:22][C:23]4[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=4)[CH2:18][CH2:17]3)[C:11](=[O:12])[C:6]2=[CH:7][C:8]=1[O:9][CH3:10].[CH3:29][S:30]([OH:33])(=[O:32])=[O:31]>CC(C)=O.C(O)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[CH2:14][CH:13]([CH2:15][CH:16]3[CH2:17][CH2:18][N:19]([CH2:22][C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=4)[CH2:20][CH2:21]3)[C:11](=[O:12])[C:6]2=[CH:7][C:8]=1[O:9][CH3:10].[S:30]([O-:33])(=[O:32])(=[O:31])[CH3:29]
Reactant: CS(=O)(=O)O
Agent: COc1cc2c(cc1OC)C(=O)C(CC1CCN(Cc3ccccc3)CC1)C2
Solvent: CCO
Solvent: CC(C)=O
Product: CS(=O)(=O)[O-]

Procedure:
3.79 g of Donepezil is dissolved in 80 ml of acetone, and 10 ml of a solution of methanesulfonic acid in absolute ethanol is slowly added. The solid precipitated is filtered to give the title compound, which is dried at 55° C. under vacuum. Melting point: 181.6° C.
Reaction SMILES: [CH3:1][S:2]([OH:5])(=[O:4])=[O:3].COS([O-])(=O)=O.[CH2:12]([N+:30]([CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH3:50])([CH3:32])[CH3:31])[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29].CC(C1SC(C2C=CN=C(N)N=2)=C(C2C=CC=C(NS(C3C(F)=CC=CC=3F)(=O)=O)C=2F)N=1)(C)C.CS(O)(=O)=O>O>[CH3:1][S:2]([O-:5])(=[O:4])=[O:3].[CH2:33]([N+:30]([CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29])([CH3:32])[CH3:31])[CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH3:50]
Reactant: CS(=O)(=O)O
Agent: CC(C)(C)c1nc(-c2cccc(NS(=O)(=O)c3c(F)cccc3F)c2F)c(-c2ccnc(N)n2)s1
Agent: CCCCCCCCCCCCCCCCCC[N+](C)(C)CCCCCCCCCCCCCCCCCC
Agent: COS(=O)(=O)[O-]
Solvent: O
Product: CS(=O)(=O)[O-]
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To 500 milliliters of water was added 54 milliliters (80 grams, 0.83 mol, 3.7 eq.) of methane sulfonic acid, CH3SO3H (available from Aldrich Chemical Compoany or Eastman Kodak Company). This solution, when cooled to room temperature, was added to a suspension of distearyl dimethyl ammonium methyl sulfate (DDAMS) (150.0 grams, 0.227 mol) suspended in 600 milliliters of water. The mixture was heated (70° to 80° C.) on a hot plate with stirring for 4 hours, cooled to room temperature and allowed to stand overnight. The mixture separated into an off-white/tan solid layer atop an aqueous layer. The mixture was filtered under reduced pressure and washed with water and air dried. The crude material was recrystallized from acetone and small amounts of methylene chloride. The methylene chloride appeared to help remove an unidentified waxy/sticky impurity to afford: 110 grams (0.17 mol), m.p. 70° C. (softening), 90° C. (liquid), and a second crop 13.7 grams (0.021 mol), m.p. 70° C. (softening), 87° C. (liquid) of the desired methane sulfonate salt (DDAMES).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]2)=[CH:6][CH:5]=1)([O-:3])=[O:2].CCN(CC)CC.Cl[C:24]([O:26][CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)=[O:25]>C1COCC1.C(Cl)Cl>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]([N:10]2[CH2:15][CH2:14][N:13]([C:24]([O:26][CH2:27][C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)=[O:25])[CH2:12][CH2:11]2)=[CH:8][CH:9]=1)([O-:3])=[O:2]
Reactant: O=C(Cl)OCc1ccccc1
Reactant: O=[N+]([O-])c1ccc(N2CCNCC2)cc1
Solvent: ClCCl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: O=C(OCc1ccccc1)N1CCN(c2ccc([N+](=O)[O-])cc2)CC1
Temperature: 0 °C
Reaction time: 1 h
Yield: 97.9 %

Procedure:
To a mixture of 1-(4-nitrophenyl)piperazine (5 g, 24.13 mmol) and Et3N (5.04 mL, 36.2 mmol) in THF (20 mL) was added benzyl chloroformate (3.79 mL, 26.5 mmol) portion-wise at 0° C. The reaction mixture was stirred at 0° C. for 1 h and then at rt for 2 h. The reaction mixture was diluted with CH2Cl2, washed with satd NaHCO3 and water, and concentrated to give 8.06 g of benzyl 4-(4-nitrophenyl)piperazine-1-carboxylate as yellow solid. LCMS: (M+H)+=342.15.
Reaction SMILES: [CH3:1][N:2]1[CH2:33][CH2:32][C:5]2[N:6]([CH2:14][CH2:15][C:16]([N:18]3[CH2:23][CH2:22][CH:21]([NH:24]C(=O)OC(C)(C)C)[CH2:20][CH2:19]3)=[O:17])[C:7]3[CH:8]=[CH:9][C:10]([CH3:13])=[CH:11][C:12]=3[C:4]=2[CH2:3]1.FC(F)(F)C(O)=O>ClCCl>[NH2:24][CH:21]1[CH2:22][CH2:23][N:18]([C:16](=[O:17])[CH2:15][CH2:14][N:6]2[C:7]3[CH:8]=[CH:9][C:10]([CH3:13])=[CH:11][C:12]=3[C:4]3[CH2:3][N:2]([CH3:1])[CH2:33][CH2:32][C:5]2=3)[CH2:19][CH2:20]1
Reactant: Cc1ccc2c(c1)c1c(n2CCC(=O)N2CCC(NC(=O)OC(C)(C)C)CC2)CCN(C)C1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1ccc2c(c1)c1c(n2CCC(=O)N2CCC(N)CC2)CCN(C)C1
Yield: 25.6 %

Procedure:
tert-butyl 1-(3-(1,2,3,4-tetrahydro-2,8-dimethylpyrido[4,3-b]indol-5-yl)propanoyl)piperidin-4-ylcarbamate (50 mg) was stirred with trifluoroacetic acid (2 ml) in dichloromethane (2 ml) for 16 h at 25° C. to obtain 10 mg of 1-(4-aminopiperidin-1-yl)-3-(1,2,3,4-tetrahydro-2,8-dimethylpyrido[4,3-b]indol-5-yl)propan-1-one as di-TFA salt after purification by reverse-phase chromatography (C-18, 500 mm×50 mm, Mobile Phase A=0.05% TFA in water, B=0.05% TFA in acetonitrile, Gradient: 10% B to 80% B in 30 min, injection vol. 5 mL).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[C:5]([Cl:9])=[CH:4][N:3]=1.[NH:10]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH:12]=[CH:11]1>>[Cl:1][C:2]1[N:7]=[C:6]([C:12]2[C:13]3[C:18](=[CH:17][CH:16]=[CH:15][CH:14]=3)[NH:10][CH:11]=2)[C:5]([Cl:9])=[CH:4][N:3]=1
Reactant: c1ccc2[nH]ccc2c1
Reactant: Clc1ncc(Cl)c(Cl)n1
Product: Clc1ncc(Cl)c(-c2c[nH]c3ccccc23)n1

Procedure:
Starting materials: 2,4,5-trichloropyrimidine and 1H-indole. m/z 265.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([Cl:16])=[C:6]([CH:15]=1)[CH2:7][C:8]1[CH:13]=[CH:12][C:11]([OH:14])=[CH:10][CH:9]=1.[Si:17](Cl)([C:20]([CH3:23])([CH3:22])[CH3:21])([CH3:19])[CH3:18].C(N(CC)CC)C.CN(C1C=CC=CN=1)C>ClCCl>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([Cl:16])=[C:6]([CH:15]=1)[CH2:7][C:8]1[CH:13]=[CH:12][C:11]([O:14][Si:17]([C:20]([CH3:23])([CH3:22])[CH3:21])([CH3:19])[CH3:18])=[CH:10][CH:9]=1
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: Oc1ccc(Cc2cc(Br)ccc2Cl)cc1
Agent: CN(C)c1ccccn1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)[Si](C)(C)Oc1ccc(Cc2cc(Br)ccc2Cl)cc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A solution of 13.9 g 4-(5-bromo-2-chloro-benzyl)-phenol in 140 ml dichloromethane is cooled in the ice bath. Then 7.54 g tert-butyldimethylsilyl chloride in 20 ml dichloromethane are added, followed by 9.8 ml triethylamine and 0.5 g dimethylaminopyridine. The solution is stirred for 16 h at ambient temperature and then diluted with 100 ml dichloromethane. The organic phase is washed twice with aqueous 1 M hydrochloric acid and once with aqueous sodium hydrogen carbonate solution and then dried over sodium sulphate. After the solvent has been eliminated the residue is filtered on silica gel (cyclohexane/ethyl acetate 100:1).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[N:10]=[N:11][C:12]1[CH:17]=[C:16]([C:18]([CH3:21])([CH3:20])[CH3:19])[CH:15]=[C:14]([C:22]([CH3:25])([CH3:24])[CH3:23])[C:13]=1[OH:26])([O-])=O.CO.[OH-].[Na+].[H][H]>P(OCCCC)(OCCCC)(OCCCC)=O.[Ni]>[OH:26][C:13]1[C:14]([C:22]([CH3:25])([CH3:24])[CH3:23])=[CH:15][C:16]([C:18]([CH3:21])([CH3:20])[CH3:19])=[CH:17][C:12]=1[N:11]1[N:10]=[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]2=[N:1]1
Reactant: CC(C)(C)c1cc(N=Nc2ccccc2[N+](=O)[O-])c(O)c(C(C)(C)C)c1
Reactant: [H][H]
Agent: [Ni]
Agent: CCCCOP(=O)(OCCCC)OCCCC
Agent: [Na+]
Solvent: CO
Product: CC(C)(C)c1cc(-n2nc3ccccc3n2)c(O)c(C(C)(C)C)c1
Yield: 85.8 %

Procedure:
Using the general procedure 6, 35.5 grams of 2-nitro-2'-hydroxy-3',5'-di-tert-butylazobenzene was suspended in 100 grams of tributyl phosphate, 50 grams of methanol and 4 grams of sodium hydroxide. To the suspension was then added 8 grams of Raney nickel catalyst and hydrogenation was carried out under 1 atmosphere of hydrogen at 45° C. for 7 hours. The catalyst was separated by filtration at 80° C. The above named product was obtained in the usual manner in a yield of 85.8%.
Reaction SMILES: C1(C)C(C)=CC=CC=1.[Cl:9][C:10]1[C:15]([Cl:16])=[CH:14][C:13]([Cl:17])=[C:12](Cl)[N:11]=1.[OH-].[Na+].[OH-].C[N+](C)(C)C>[Zn].O>[Cl:9][C:10]1[C:15]([Cl:16])=[CH:14][C:13]([Cl:17])=[CH:12][N:11]=1
Reactant: Clc1cc(Cl)c(Cl)nc1Cl
Agent: C[N+](C)(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1C
Solvent: O
Product: Clc1cnc(Cl)c(Cl)c1
Temperature: 50 °C

Procedure:
A 3000 mL, four neck round bottom flask was equipped with a mechanical stirrer, thermometer, reflux condenser, and an opening for the addition of zinc dust. The flask was charged with ortho-xylene (630.4 g, 725 mL) followed by the addition of 2,3,5,6-tetrachloropyridine (525 g, 2.42 mole). Agitation was started and water (775.1 g, 775 mL), 50% NaOH (1162.7 g, 765 mL), and 25% tetramethylammonium hydroxide (5.2 g) were added to the flask. The reaction mixture was heated to 50° C. and zinc dust (195.0 g, 2.98 mole) was added, in equal portions, over a 5-hour period while holding the temperature between 55-60° C. The reaction mixture was then heated at 55-60° C. for an additional 5 hours. After the reaction, the layers were allowed to separate and the top layer (organics) was filtered. Hydrochloric acid (32%, 750.2 g) was added to the bottom layer which was then heated under reflux for 5 hours to convert unreacted zinc to zinc hydroxide (the zinc hydroxide can subsequently be isolated by filtration for recycle value). Organics present in the bottom layer were removed by steam distillation during this time using a Dean-Stark trap, and added to the organics layer. Fractional distillation of the organics layer gave an isolated yield of 2,3,5-trichloropyridine of 65%.
Reaction SMILES: C([O:4][C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][C:14]=1[O:15][CH3:16])[N:11]=[CH:10][N:9]=[C:8]2[NH:17][C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([C:24]#[CH:25])[CH:19]=1)(=O)C.[OH-].[Na+].Cl>CO>[C:24]([C:20]1[CH:19]=[C:18]([NH:17][C:8]2[C:7]3[C:12](=[CH:13][C:14]([O:15][CH3:16])=[C:5]([OH:4])[CH:6]=3)[N:11]=[CH:10][N:9]=2)[CH:23]=[CH:22][CH:21]=1)#[CH:25]
Reactant: C#Cc1cccc(Nc2ncnc3cc(OC)c(OC(C)=O)cc23)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: C#Cc1cccc(Nc2ncnc3cc(OC)c(O)cc23)c1
Temperature: 25 °C
Reaction time: 5 h
Yield: 83.2 %

Procedure:
To a suspension of 4-((3-ethynylphenyl)amino)-7-methoxyquinazolin-6-yl acetate (4.54 g) and methanol (30 mL) was added 5 mol/L NaOH (10.00 mL) at room temperature. The reaction mixture was stirred at room temperature for 5 h, and was adjusted to pH 7 with 0.1 N HCl (aq). The mixture was filtered to give the title compound as a white solid (3.30 g, 86.00%).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]([CH:6]2[O:8][CH2:7]2)=[CH:4][CH:3]=1.N([O-])=O.[Na+]>>[Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C@@H:6]2[O:8][CH2:7]2)=[CH:4][CH:3]=1
Reactant: Clc1ccc(C2CO2)cc1
Agent: O=N[O-]
Agent: [Na+]
Product: Clc1ccc([C@H]2CO2)cc1

Procedure:
To 20 ml of Tris-SO4 buffer (50 mM, pH=7.3) containing 2 mM of para-chlorostyrene oxide and 1.2 mM of NaNO2, 1.0 mg of purified enzyme, obtained as described in Example 1, was added. At 58% conversion, reaction was stopped and the solution was extracted with diethylether. The organic phase was analysed by chiral GC. The remaining (S)-para-chloro styrene oxide was obtained with an e.e. of higher than 99%.
Reaction SMILES: [O-]S([O-])(=O)=O.[Ca+2].[N:7]1[C:11]2[CH:12]=[CH:13][C:14]([C:16]([OH:18])=[O:17])=[CH:15][C:10]=2[NH:9][CH:8]=1.S(=O)(=O)(O)O.[CH3:24]O>>[N:7]1[C:11]2[CH:12]=[CH:13][C:14]([C:16]([O:18][CH3:24])=[O:17])=[CH:15][C:10]=2[NH:9][CH:8]=1
Reactant: O=C(O)c1ccc2nc[nH]c2c1
Reactant: CO
Agent: O=S(=O)(O)O
Agent: O=S(=O)([O-])[O-]
Agent: [Ca+2]
Product: COC(=O)c1ccc2nc[nH]c2c1
Temperature: 25 °C
Yield: 89 %

Procedure:
A 500 ml round bottom flask equipped with a heating mantle, reflux condenser, and a Drierite® filled drying tube was charged with 16.22 g (0.10 mol) of 5-benzimidazolecarboxylic acid (Aldrich), 400 ml of anhydrous methanol and then (Caution!) 20 ml of concentrated sulfuric acid (Fisher). The reaction mixture was heated to reflux for 18 h and then cooled to ambient temperature. Approximately 75% of the solvents were removed under vacuum and then the remaining liquid residue was slowly poured into 500 ml of saturated sodium bicarbonate solution. The resultant two phase system was then extracted with three 250 ml portions of ethyl acetate. The organic layers were combined and washed with three 250 ml portions of 5% sodium bicarbonate solution followed by one 250 ml portion of brine. The ethyl acetate layer was dried over MgSO4, filtered and the solvents were then removed under reduced pressure to give 15.68 g (0.089 mol, 89% yield) of 5-benzimidazolecarboxylic acid, methyl ester, 10, as a tan solid. 1H NMR (CDCl3, TMS): δ7.3-7.9 (m, 3H), 3.70 (s, 3H).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH:4]([OH:11])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.N([C:16]1[NH:17][CH2:18][CH2:19][N:20]=1)[N+]([O-])=O.C1(C)C(C)=CC=CC=1.O>CC(C)CC(=O)C>[NH:20]1[CH2:19][CH2:18][N:17]=[C:16]1[NH:1][CH2:2][CH2:3][CH:4]([OH:11])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1
Reactant: NCCC(O)c1ccccc1
Reactant: O=[N+]([O-])NC1=NCCN1
Solvent: O
Solvent: Cc1ccccc1C
Solvent: CC(=O)CC(C)C
Product: OC(CCNC1=NCCN1)c1ccccc1

Procedure:
A mixture of 8 parts of α-(2-aminoethyl)benzylalcohol, 6.5 parts of 2-(nitramino)-2-imidazoline and 40 parts of xylene is stirred and refluxed for 3 hours with water-separator. The reaction mixture is cooled and the separated oily product is dissolved in 4-methyl-2-pentanone. The solvent is evaporated in vacuo, yielding α-{2-[N-(2imidazolin-2 -yl)amino]ethyl}benzylalcohol as a residue.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([OH:9])[CH:5]=[CH:6][C:7]=1[Cl:8].F[C:11]1[CH:16]=[CH:15][C:14]([N+:17]([O-:19])=[O:18])=[CH:13][C:12]=1[O:20][CH3:21].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O.O>[Cl:8][C:7]1[CH:6]=[CH:5][C:4]([O:9][C:11]2[CH:16]=[CH:15][C:14]([N+:17]([O-:19])=[O:18])=[CH:13][C:12]=2[O:20][CH3:21])=[CH:3][C:2]=1[Cl:1]
Reactant: Oc1ccc(Cl)c(Cl)c1
Reactant: COc1cc([N+](=O)[O-])ccc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1cc([N+](=O)[O-])ccc1Oc1ccc(Cl)c(Cl)c1
Temperature: 60 °C
Reaction time: 8 h
Yield: 81.9 %

Procedure:
A mixture of 3,4-dichlorophenol (38 g, 233.13 mmol, 1.00 equiv), 1-fluoro-2-methoxy-4-nitrobenzene (40 g, 233.75 mmol, 1.00 equiv) and potassium carbonate (64 g, 463.77 mmol, 1.99 equiv) in N,N-dimethylformamide (250 mL) was stirred overnight at 60° C. The resulting solution was diluted with 1000 mL of water, extracted with 3×200 mL of ethyl acetate and the organic layers combined. The resulting mixture was washed with 3×500 mL of brine. The mixture was dried over anhydrous sodium sulfate and concentrated under vacuum to yield 60 g (82%) of 1,2-dichloro-4-(2-methoxy-4-nitrophenoxy)benzene as a brown solid.
Reaction SMILES: C([Sn](CCCC)(CCCC)[C:6]1[O:7][CH:8]=[CH:9][N:10]=1)CCC.[C:19]([N:27]1[C:35]2[CH:34]=[CH:33][C:32](I)=[C:31]3[CH2:37][C@@H:38]([N:40]([CH2:44][CH2:45][CH3:46])[CH2:41][CH2:42][CH3:43])[CH2:39][C@H:29]([C:30]=23)[CH2:28]1)(=[O:26])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>C1(C)C=CC=CC=1>[C:19]([N:27]1[C:35]2[CH:34]=[CH:33][C:32]([C:6]3[O:7][CH:8]=[CH:9][N:10]=3)=[C:31]3[CH2:37][C@@H:38]([N:40]([CH2:44][CH2:45][CH3:46])[CH2:41][CH2:42][CH3:43])[CH2:39][C@H:29]([C:30]=23)[CH2:28]1)(=[O:26])[C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1
Reactant: CCCN(CCC)[C@@H]1Cc2c(I)ccc3c2[C@@H](C1)CN3C(=O)c1ccccc1
Reactant: CCCC[Sn](CCCC)(CCCC)c1ncco1
Solvent: Cc1ccccc1
Product: CCCN(CCC)[C@@H]1Cc2c(-c3ncco3)ccc3c2[C@@H](C1)CN3C(=O)c1ccccc1
Yield: 67.5 %

Procedure:
A solution of 5.0 g (13.8 mmol) of the crude 2-tributylstannyloxazole prepared above and 6.8 g (13.9 mmol) of (+)(2aR,4S)-1-benzoyl-6-iodo-4-(di-n-propylamino)-1,2,2a,3,4,5-hexahydrobenz[cd]indole in 100 ml of toluene was treated with 0.7 g (0.6 mmol) of tetrakis-(triphenylphosphine)palladium then refluxed under nitrogen for 20 hours. After cooling the reaction mixture was washed with a saturated brine solution and then dried over Na2SO4. Concentration in vacuo provided a viscous oil which was chromatographed over a silica gel column using a solvent gradient progressing from toluene to 1:1 toluene/EtOAc. The product from the column was dissolved in 1M HCl. This solution was then washed with ether, made alkaline with 5M NaOH, and extracted with CH2Cl2. Concentration of the extract in vacuo gave about 4 g of a brown oil. When this oil was dissolved in pentane a small amount of a red/brown resin separated leaving a clear, yellow solution. The resin was separated and the pentane was evaporated to provide a residue. This residue was crystallized by dissolving it in a small amount of CH2Cl2 and slowly adding isoctane. The crystalline (-)(2aR,4S)-1-benzoyl-6-(2-oxazolyl)-4-(di-n-propylamino)-1, 2,2a,3,4,5-hexahydrobenz[cd]indole, obtained in four crops, weighed 2.63 g. m.p. 103°-104° C.
Reaction SMILES: P(Cl)(Cl)([Cl:3])=O.[C:6]([O:10][C:11]([N:13]1[CH2:25][C:24]2[S:23][C:22]3[N:21]=[CH:20][NH:19][C:18](=O)[C:17]=3[C:16]=2[CH2:15][CH2:14]1)=[O:12])([CH3:9])([CH3:8])[CH3:7]>C(N(CC)CC)C>[C:6]([O:10][C:11]([N:13]1[CH2:25][C:24]2[S:23][C:22]3[N:21]=[CH:20][N:19]=[C:18]([Cl:3])[C:17]=3[C:16]=2[CH2:15][CH2:14]1)=[O:12])([CH3:9])([CH3:8])[CH3:7]
Reactant: O=P(Cl)(Cl)Cl
Reactant: CC(C)(C)OC(=O)N1CCc2c(sc3nc[nH]c(=O)c23)C1
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CCc2c(sc3ncnc(Cl)c23)C1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 89 %

Procedure:
To a solution of phosphorous oxychloride (30 mL) was added triethylamine (30 mL) over 15 mins at 0° C. under argon. 4-oxo-3,5,6,8-tetrahydro-4H-9-thia-1,3,7-triaza-fluorene-7-carboxylic acid tert-butyl ester (4.20 g, 14 mmol) was then added to the flask. The reaction mixture was stirred at 0° C. for 30 mins then heated at 65° C. for 2 h. The reaction mixture was cooled to rt before concentrated in vacuo. The residue was coevaporated with toluene (2×200 mL). DCM (50 mL) was added to the solid residue and the reaction mixture was quenched with ice/saturated aqueous NaHCO3. The resulting mixture was extracted with DCM (3×100 mL). The combined organic layers was dried over sodium sulfate, filtered and concentrated in vacuo to yield 4.08 g (12.5 mmol, 89%) of a light yellow solid. 1H-NMR (CD2Cl2-d2) δ 8.74 (s, 1H), 4.74 (s, 2H), 3.78 (t, 2H), 3.19 (t, 2H), 1.49 (s, 9H); LCMS RT=3.53 min, [M+H]+=326.0.
Reaction SMILES: [OH:1][CH2:2][C:3]1[N:8]=[C:7]([C:9]([O:11][CH3:12])=[O:10])[CH:6]=[CH:5][CH:4]=1.[CH3:13][S:14](Cl)(=[O:16])=[O:15]>C(Cl)Cl.C(Cl)(Cl)Cl.C([O-])(O)=O.[Na+]>[CH3:13][S:14]([O:1][CH2:2][C:3]1[N:8]=[C:7]([C:9]([O:11][CH3:12])=[O:10])[CH:6]=[CH:5][CH:4]=1)(=[O:16])=[O:15]
Reactant: COC(=O)c1cccc(CO)n1
Reactant: CS(=O)(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: ClCCl
Product: COC(=O)c1cccc(COS(C)(=O)=O)n1
Temperature: 0 °C
Reaction time: 1 h
Yield: 110.5 %

Procedure:
To a solution of methyl 6-(hydroxymethyl)picolinate (2.6 g, 15.5 mmol) in CH2Cl2 (15 mL) were added methanesulfonyl chloride (1.81 mL, 23.3 mmol) and TEA (5.42 mL, 38.9 mmol) dropwise at 0° C. The reaction mixture was stirred at 0° C. for 1 h and diluted with CHCl3 and saturated aqueous NaHCO3 solution. The organic layer was separated, washed with brine, dried over MgSO4, filtered, and the filtrate was concentrated to give the desired compound (4.2 g, 85%) as a brown oil. 1H NMR (CDCl3) δ 8.15 (d, J=8.0 Hz, 1H), 7.96 (t, J=8.0 Hz, 1H), 7.12 (d, J=8.0 Hz, 1H), 5.46 (s, 2H), 4.04 (s, 3H), 3.20 (s, 3H). MS (ESI): 246.1 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[N:6][C:5]([NH2:8])=[C:4]([CH3:9])[CH:3]=1.[C:10](Cl)(Cl)=[S:11].O.C(OCC)(=O)C>C(=O)(O)[O-].[Na+].O1CCCC1>[Cl:1][C:2]1[N:7]=[N:6][C:5]([N:8]=[C:10]=[S:11])=[C:4]([CH3:9])[CH:3]=1
Reactant: S=C(Cl)Cl
Reactant: Cc1cc(Cl)nnc1N
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: C1CCOC1
Product: Cc1cc(Cl)nnc1N=C=S
Reaction time: 1 h
Yield: 8.2 %

Procedure:
To a solution of 6-chloro-4-methylpyridazin-3-amine (2.86 g, 20.0 mmol) in aqueous sodium bicarbonate (10 mL) and tetrahydrofuran (40 mL) was added thiophosgene (1.69 mL, 22.0 mmol) dropwise at 0° C. After stirring for 1 hr. water and ethyl acetate were added to the mixture and the insoluble materials were filtered off. The filtrate was washed with brine, dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was purified by flash chromatography on silica gel eluting with a 10-50% ethyl acetate/n-hexane gradient mixture. The filtrate was concentrated in vacuo to give the title compound (304 mg, 1.64 mmol, 8%) as a pale yellow solid.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[F:7][C:8]1[CH:15]=[CH:14][C:11]([CH:12]=[O:13])=[CH:10][C:9]=1[O:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.O.[OH-].[Na+]>C(OCC)C>[F:7][C:8]1[CH:15]=[CH:14][C:11]([CH2:12][OH:13])=[CH:10][C:9]=1[O:16][C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: O=Cc1ccc(F)c(Oc2ccccc2)c1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Solvent: O
Product: OCc1ccc(F)c(Oc2ccccc2)c1
Temperature: 15 °C

Procedure:
A suspension of 1.4 grams (0.038 mole) of lithium aluminum hydride in 50 ml of anhydrous diethyl ether was stirred, and a solution of 21.6 grams (0.1 mole) of commercially available 4-fluoro-3-phenoxybenzaldehyde in 50 ml of anhydrous diethyl ether was added dropwise during a one hour period. Upon completion of addition, the reaction mixture was heated at reflux for 1.0 hour. The reaction mixture was cooled to 15° C., and 1.4 ml of water was cautiously added dropwise. Upon completion of addition, the reaction mixture was again cooled to 15° C., and 1.4 ml of an aqueous, 15% sodium hydroxide solution was added dropwise. This was followed by the addition of 4.2 ml of water. The mixture was filtered through diatomaceous earth, and the filtrate was concentrated under reduced pressure, yielding 19.5 grams of 4-fluoro-3-phenoxyphenylmethanol as an oil.