Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: OS(O)(=O)=O.[NH2:6][C:7]1[CH:12]=[C:11]([CH3:13])[C:10]([C:14]#[N:15])=[C:9]([CH3:16])[N:8]=1.[N+:17]([O-])([OH:19])=[O:18]>>[NH2:6][C:7]1[C:12]([N+:17]([O-:19])=[O:18])=[C:11]([CH3:13])[C:10]([C:14]#[N:15])=[C:9]([CH3:16])[N:8]=1
Reactant: O=[N+]([O-])O
Reactant: Cc1cc(N)nc(C)c1C#N
Agent: O=S(=O)(O)O
Product: Cc1nc(N)c([N+](=O)[O-])c(C)c1C#N
Temperature: 55 °C
Reaction time: 0.5 h
Yield: 55.2 %

Procedure:
To 10 mL of H2SO4 (97%) kept in an ice-bath was added portionwise 2.45 g (16.6 mmol) of 2-amino-4,6-dimethyl-5-pyridinecarbonitrile (16) and it was stirred for 30 min. The resulting solution was heated at 55° C. and 1.2 mL (18.8 mmol) of HNO3 (d=1.41, 69-70%) was added dropwise. The solution was heated at 55°-60° C. for 3 h after addition of HNO3. It was cooled to room temperature and poured into 60 mL of ice-water. The yellow precipitate was filtered, washed with water, and dried to leave a yellow solid (1.76 g, 55%). 1H NMR (CDCl3), 2.612 (s, 3), 2.716 (s, 3), 6.51 (mb, 2).
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](O)=[O:7])=[CH:4][C:3]=1[Cl:11].Cl.[CH3:13][N:14](C)[CH2:15]CCN=C=NCC.ON1C2C=CC=CC=2N=N1.C(N(CC)CC)C.Cl.CNC>C(Cl)Cl.C(O)(C)C.C(Cl)(Cl)Cl>[NH2:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([N:14]([CH3:15])[CH3:13])=[O:7])=[CH:4][C:3]=1[Cl:11]
Reactant: Nc1ccc(C(=O)O)cc1Cl
Reactant: CCN=C=NCCCN(C)C
Agent: CNC
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: CC(C)O
Solvent: ClCCl
Product: CN(C)C(=O)c1ccc(N)c(Cl)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 59.6 %

Procedure:
To a solution of 4-amino-3-chlorobenzoic acid (1 equiv) in DCM (0.12 M) was added N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (1.2 equiv), 1-hydroxybenzotriazole (1.2 equiv), triethylamine (4 equiv) and dimethylamine hydrochloride (2 equiv) sequentially. The mixture was stirred at room temperature overnight. After the reaction was complete, as monitored by LCMS, the mixture was diluted with a mixture of isopropanol in chloroform (30%), washed with water and dried over anhydrous sodium sulfate. The organic phase was concentrated and the residue obtained was recrystallized in the mixture of hexane and ethyl acetate (10%) to afford the desired product (Yield: 59.6%) as a light brown solid. MS (ESI) m/z 199.1 [M+1]+.
Reaction SMILES: Cl.[NH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.[C:15]([N:17]1[CH2:22][CH2:21][O:20][CH2:19][CH2:18]1)#[N:16]>C1C(O)=CC=CC=1C>[C:4]1([C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=1[NH:2][C:15]([N:17]1[CH2:22][CH2:21][O:20][CH2:19][CH2:18]1)=[NH:16]
Reactant: N#CN1CCOCC1
Reactant: Nc1ccccc1-c1ccccc1
Agent: Cl
Solvent: Cc1cccc(O)c1
Product: N=C(Nc1ccccc1-c1ccccc1)N1CCOCC1

Procedure:
A mixture of 2-aminobiphenyl hydrochloride (6.17 g) and 4-cyanomorpholine (5.05 g) in m-cresol (25 ml) was heated at 90°-95° C. for 15 hours to yield N-(2-biphenylyl)-4-morpholine carboxamidine (m.p. 153°-154° C.) which was recrystallised from ethylacetate. N-(2-Biphenylyl)morpholine-4-carboxamidine (3.5 g) was dissolved in methanol (15 ml) and treated with fumaric acid (1.45 g) to give N-(2-biphenylyl)morpholine-4-carboxamidine fumarate (m.p. 222°-223° C.) which was recrystallised from a 1:1 mixture of methanol and ether.
Reaction SMILES: C(S[C:4](S(CC)=O)([CH:19]([F:21])[F:20])[CH2:5][CH2:6][CH2:7][N:8]1[C:12](=[O:13])[C:11]2=[CH:14][CH:15]=[CH:16][CH:17]=[C:10]2[C:9]1=[O:18])C.Cl(O)(=O)(=O)=[O:27].O>C(#N)C>[C:12]1(=[O:13])[N:8]([CH2:7][CH2:6][CH2:5][C:4]([CH:19]([F:21])[F:20])=[O:27])[C:9](=[O:18])[C:10]2=[CH:17][CH:16]=[CH:15][CH:14]=[C:11]12
Reactant: CCSC(CCCN1C(=O)c2ccccc2C1=O)(C(F)F)S(=O)CC
Reactant: [O-][Cl+3]([O-])([O-])O
Solvent: O
Solvent: CC#N
Product: O=C(CCCN1C(=O)c2ccccc2C1=O)C(F)F
Temperature: 0 °C
Reaction time: 2 h

Procedure:
A solution of 10 mmole of [((ethylsulfinyl)methyl)-thio]ethane in 20 ml of tetrahydrofuran is treated with 10 mmole of sodium hydride at 25° C for 2 hours after which 10 mmole of N-(3-bromopropyl)phthalimide in 5 ml of tetrahydrofuran is added. The reaction mixture is stirred overnight at 25° C then quenched with brine and extracted with chloroform. The organic phase is washed with brine, dried over magnesium sulfate and concentrated under reduced pressure. The residue is purified by chromotography on silica gel to give N-(4-ethylthio-4-ethylsulfinylbutyl)phthalimide. To a solution of 22 mmole of N-(4-ethylthio-4-ethylsulfinylbutyl)phthalimide in 20 ml of tetrahydrofuran is added under nitrogen at 0° C a solution of lithium diisopropylamide in 23 mmole of tetrahydrofuran. The reaction mixture is stirred for 30 minutes at 25° C then is saturated with difluorochloromethane. Stirring is continued for 2 hours at 40° C. After quenching with brine, the reaction mixture is extracted with ether. The organic phase is decanted, washed with brine, dried over magnesium sulfate and concentrated under reduced pressure to give N-(4-ethylthio-4-ethylsulfinyl-4-difluoro-methylbutyl)phthalimide. To a solution of 30 mole of N-(4-ethylthio-4-ethylsulfinyl-4-difluoromethylbutyl)-phthalimide in 33 ml of acetonitrile is added at 0° C 1.1 ml of a 70% aqueous solution of perchloric acid. After stirring for 2 hours at 0° C the reaction mixture is poured into 60 ml of water then extracted with chloromethane. The organic phase is washed with brine, dried, filtered and the filtrate concentrated under reduced pressure to afford difluoromethyl 3-phthalimidopropyl ketone.
Reaction SMILES: [C:1]1([O:11][CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.[S:18]1[CH:22]=[CH:21][CH:20]=[C:19]1[C:23](Cl)=[O:24].C(Cl)Cl.[Cl-].[Al+3].[Cl-].[Cl-]>O>[C:19]1([C:23]([C:4]2[C:5]3[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=3)[C:1]([O:11][CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14])=[CH:2][CH:3]=2)=[O:24])[S:18][CH:22]=[CH:21][CH:20]=1
Reactant: CCOC(=O)COc1cccc2ccccc12
Reactant: O=C(Cl)c1cccs1
Agent: [Al+3]
Agent: [Cl-]
Solvent: O
Solvent: ClCCl
Product: CCOC(=O)COc1ccc(C(=O)c2cccs2)c2ccccc12
Temperature: -10 °C
Reaction time: 2 h
Yield: 78.7 %

Procedure:
483 g ethyl 1-naphthyloxyacetate and 308 g thiophene-2-carboxylic acid chloride was dissolved in 3.570 l. methylene chloride. While the mixture is being maintained at about -10° C., 291 g aluminium chloride are introduced slowly; after 2 hours at -10° C., the mixture is brought back to 25° C. and the stirring maintained for 12 hours. The mixture is then poured into 2 Kg iced water, the organic phase decanted off, washed with dilute aqueous sodium hydroxide solution then water and the solvent evaporated. 562 g of the ester are thus obtained. After recrystallisation from isopropyl ether, it melts at 79° C.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([Cl:8])[N:5]=[CH:4][N:3]=1.[SH:9][C:10]1[CH:19]=[C:18]([CH3:20])[C:13]2[NH:14][C:15](=[O:17])[O:16][C:12]=2[CH:11]=1.CCN(C(C)C)C(C)C>C(Cl)Cl>[Cl:8][C:6]1[N:5]=[CH:4][N:3]=[C:2]([S:9][C:10]2[CH:19]=[C:18]([CH3:20])[C:13]3[NH:14][C:15](=[O:17])[O:16][C:12]=3[CH:11]=2)[CH:7]=1
Reactant: Cc1cc(S)cc2oc(=O)[nH]c12
Reactant: Clc1cc(Cl)ncn1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cc(Sc2cc(Cl)ncn2)cc2oc(=O)[nH]c12
Temperature: 40 °C
Reaction time: 8 h

Procedure:
820 mg (5.50 mmol) 4,6-dichloropyrimidine, 1.00 g (5.50 mmol) 6-mercapto-4-methyl-3H-benzoxazol-2-one and 5.00 mL (29.1 mmol) DIPEA were combined in 20 mL DCM and stirred overnight at 40° C. The reaction mixture was evaporated down, the residue was taken up in EtOAc and combined with sodium hydrogen carbonate solution. The precipitate formed was suction filtered, washed with copious amounts of water and dried.
Reaction SMILES: [C:1]([C:3]1([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH2:8][CH2:7][C:6](=O)[CH2:5][CH2:4]1)#[N:2].[NH:16]1[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]1.C1(C)C=CC(S(O)(=O)=O)=CC=1.[BH4-].[Na+]>C1(C)C=CC=CC=1.CCO.CCOC(C)=O.CO.CCOC(C)=O>[C:10]1([C:3]2([C:1]#[N:2])[CH2:8][CH2:7][CH:6]([N:16]3[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]3)[CH2:5][CH2:4]2)[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: N#CC1(c2ccccc2)CCC(=O)CC1
Reactant: C1CNCCN1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Solvent: CO
Product: N#CC1(c2ccccc2)CCC(N2CCNCC2)CC1
Yield: 40.2 %

Procedure:
A mixture of 4-cyano-4-phenyl-cyclohexanone (0.23 g, 1.2 mmol) and piperazine (0.30 g, 3.5 mmol) in 20 ml of toluene was stirred at reflux for 2 h in presence of catalytic amount of p-toluenesulfonic acid. The reaction mixture was concentrated in vacuo to provide a white solid, which was redissolved in 20 ml of EtOH and stirred with NaBH4 (0.30 g, 80 mmol) for 12 h at 25° C. Reaction mixture was diluted with 100 ml of EtOAc and washed with brine several times. Organic layer was dried over MgSO4 and concentrated in vacuo, to provide oily residue, which was subjected to column chromatography (10% MeOH/EtOAc) to yield 0.13 g (40%) of the desired product as an oil.
Reaction SMILES: FC(F)(F)C(O)=O.O1CCCCC1[N:14]1[C:22]2[CH:21]=[CH:20][C:19]([O:23]C3CCCCO3)=[C:18]([C:30]#[N:31])[C:17]=2[CH:16]=[N:15]1.C(=O)([O-])O.[Na+]>ClCCl.C(OCC)(=O)C>[OH:23][C:19]1[CH:20]=[CH:21][C:22]2[NH:14][N:15]=[CH:16][C:17]=2[C:18]=1[C:30]#[N:31]
Reactant: N#Cc1c(OC2CCCCO2)ccc2c1cnn2C1CCCCO1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: N#Cc1c(O)ccc2[nH]ncc12
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 97.9 %

Procedure:
Trifluoroacetic acid (1.5 ml) was added dropwise to a solution of 1-tetrahydro-2H-pyran-2-yl-5-(tetrahydro-2H-pyran-2-yloxy)-1H-indazole-4-carbonitrile (227 mg, 0.693 mmol) in dichloromethane (6.5 ml) at room temperature, and the resulting mixture was stirred for 1.5 hours while being maintained at room temperature. The reaction solution was diluted with ethyl acetate and adjusted to pH 7 with a saturated aqueous sodium hydrogencarbonate solution, followed by partition and extraction. The organic layer was washed with a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and then filtered, and the filtrate was concentrated under reduced pressure to obtain a crude product. The crude product was purified by a silica gel column chromatography (eluent: hexane/ethyl acetate) to obtain 5-hydroxy-1H-indazole-4-carbonitrile (108 mg, 98%).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([Cl:12])=[CH:9][CH:10]=2)[N:5]=[CH:4][CH:3]=1.[IH:13].[OH-].[Na+]>>[Cl:12][C:8]1[CH:7]=[C:6]2[C:11]([C:2]([I:13])=[CH:3][CH:4]=[N:5]2)=[CH:10][CH:9]=1
Reactant: I
Reactant: Clc1ccc2c(Cl)ccnc2c1
Agent: [Na+]
Agent: [OH-]
Product: Clc1ccc2c(I)ccnc2c1
Temperature: 130 °C

Procedure:
4,7-Dichloroquinoline (50 g) (Aldrich) was added in small portions to HI (425 mL) at r.t. and then heated at 130° C. for 5 h. The mixture was cooled, poured into ice/H2O (600 mL), made basic (pH 10) with 10N NaOH, and extracted with CHCl3. The combined organics were washed with NH4OAc buffer, 10% Na2S2O3, brine, dried (Na2SO4) and concentrated providing the title compound which was used as such.
Reaction SMILES: [C:1]([NH:8][C@@H:9]([CH3:28])[CH2:10][O:11][C:12]1[CH:27]=[CH:26][C:15]([C:16]([O:18]CC2C=CC=CC=2)=[O:17])=[CH:14][CH:13]=1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2]>[Pd].C(O)C>[C:1]([NH:8][C@@H:9]([CH3:28])[CH2:10][O:11][C:12]1[CH:27]=[CH:26][C:15]([C:16]([OH:18])=[O:17])=[CH:14][CH:13]=1)([O:3][C:4]([CH3:6])([CH3:7])[CH3:5])=[O:2]
Reactant: C[C@@H](COc1ccc(C(=O)OCc2ccccc2)cc1)NC(=O)OC(C)(C)C
Agent: [Pd]
Solvent: CCO
Product: C[C@@H](COc1ccc(C(=O)O)cc1)NC(=O)OC(C)(C)C
Reaction time: 20 h

Procedure:
A mixture of 22-3 (1.6 g, 4.3 mmol), 10% Pd/C (0.33 g) and ethanol (25 mL) was stirred under a hydrogen atmosphere (1 arm) for 20 h. Filtration through a celite pad followed by concentration of the filtrate gave 22-4 as a colorless solid.
Reaction SMILES: [CH:1]1([S:4]([O-:6])=[O:5])[CH2:3][CH2:2]1.[Na+].Br[CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([N+:16]([O-:18])=[O:17])[CH:11]=1>C(#N)C.O>[CH:1]1([S:4]([CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([N+:16]([O-:18])=[O:17])[CH:11]=2)(=[O:6])=[O:5])[CH2:3][CH2:2]1
Reactant: O=[N+]([O-])c1cccc(CBr)c1
Reactant: O=S([O-])C1CC1
Agent: [Na+]
Solvent: O
Solvent: CC#N
Product: O=[N+]([O-])c1cccc(CS(=O)(=O)C2CC2)c1
Temperature: 90 °C
Reaction time: 4 h
Yield: 96.3 %

Procedure:
Sodium cyclopropanesulfinate (1.04 g; 8.1 mmol) was added to a solution of 1-(bromomethyl)-3-nitrobenzene (1.17 g; 5.4 mmol) in acetonitrile (50 mL) at room temperature. The batch was stirred at 90° C. for 4 hours. After cooling, the batch was diluted with water and extracted with DCM (2×). The combined organic phases were filtered using a Whatman filter and concentrated to give the desired product (1.26 g; 5.2 mmol) that was used without further purifications.
Reaction SMILES: [C:1]1(S(OCC#C)(=O)=O)[CH:6]=CC=C[CH:2]=1.[NH2:14][CH:15]1[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH2:17][CH2:16]1.[OH-].[Na+]>C1(C)C=CC=CC=1>[CH:2]#[C:1][CH2:6][NH:14][C@H:15]1[C:23]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[CH2:17][CH2:16]1
Reactant: NC1CCc2ccccc21
Reactant: C#CCOS(=O)(=O)c1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1
Product: C#CCN[C@@H]1CCc2ccccc21

Procedure:
U.S. Pat. No. 5,532,415 discloses process for preparation of R(+)-Rasagiline mesylate which comprises treating a solution of propargyl benzenesulfonate (3) and racemic aminoindan (2) in toluene with aqueous solution of 15% sodium hydroxide to get racemic Rasagiline base (4). The obtained crude racemic Rasagiline is treated with L-tartaric acid in isopropanol (IPA) to get di(R-(+)-N-propargyl-1-aminoindan)-L-tartrate (5) which is recrystallized from 1:1 methanol/isopropanol. The obtained tartrate salt is reacted with methanesulphonic acid in isopropanol at reflux to obtain R(+)-Rasagiline mesylate. The disadvantage of this process is that the scheme consists of low atom efficiency and involves several steps to obtain the final product.
Reaction SMILES: [OH:1][CH2:2][CH2:3][NH:4][C:5]([NH:7]C1C=CC([N+]([O-])=O)=CC=1)=[O:6].[C:17]([O:25]CC)(=O)[CH2:18][C:19]([O:21]CC)=O.[O-]CC.[Na+]>C(O)C>[OH:1][CH2:2][CH2:3][N:4]1[C:17](=[O:25])[CH2:18][C:19](=[O:21])[NH:7][C:5]1=[O:6]
Reactant: CCOC(=O)CC(=O)OCC
Reactant: O=C(NCCO)Nc1ccc([N+](=O)[O-])cc1
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Product: O=C1CC(=O)N(CCO)C(=O)N1
Yield: 96 %

Procedure:
In a 1 liter round-bottom flask equipped with an overhead stirrer and reflux condenser was placed N-(2-hydroxyethyl)-N'-(4-nitrophenyl)urea (40.0 grams, 0.178 mol), diethyl malonate (71.2 grams, 0.445 mol), and ethanol (560 mL). Sodium ethoxide in ethanol (21 wt %, 69.2 grams, 0.214 mol) was added and the reaction mixture was heated to reflux for 6 hours. The reaction mixture was cooled and the ethanol was removed under vacuum. Methylene chloride (500 mL) and water (500 mL) were added. The layers were separated and the aqueous layer was further washed with a second portion of methylene chloride to extract a by-product, 4-nitroaniline which was discarded. The aqueous layer was acidified with 6N HCl (50 mL) and an oily phase precipitated. The oil layer was separated and stirred with 70 mL of benzene. After several minutes the oil turned into a chunky, aggregated solid. The benzene was decanted off and the chunky solid was broken up and triturated with hot benzene. The solution was cooled and suction filtered to isolate the solid, which was oven-dried yielding N-(2-hydroxyethyl)barbituric acid (29.4 grams). Additional product (6.2 grams) crystallized out of the water layer upon standing overnight. The additional product was collected by suction filtration and dried.
Reaction SMILES: [CH3:1][CH:2]1[CH2:9][C@H:8]2[C@H:4]([CH2:5][NH:6][C@@H:7]2[CH2:10][NH:11][C:12]([C:14]2[N:21]3[C:17]([S:18][CH:19]=[CH:20]3)=[N:16][C:15]=2[CH3:22])=[O:13])[CH2:3]1.[CH2:23]([C:25]1[CH:30]=[CH:29][C:28]([C:31]2[S:35][C:34]([CH3:36])=[N:33][C:32]=2[C:37](O)=[O:38])=[CH:27][CH:26]=1)[CH3:24]>>[CH2:23]([C:25]1[CH:26]=[CH:27][C:28]([C:31]2[S:35][C:34]([CH3:36])=[N:33][C:32]=2[C:37]([N:6]2[CH2:5][C@H:4]3[C@H:8]([CH2:9][CH:2]([CH3:1])[CH2:3]3)[C@H:7]2[CH2:10][NH:11][C:12]([C:14]2[N:21]3[C:17]([S:18][CH:19]=[CH:20]3)=[N:16][C:15]=2[CH3:22])=[O:13])=[O:38])=[CH:29][CH:30]=1)[CH3:24]
Reactant: CCc1ccc(-c2sc(C)nc2C(=O)O)cc1
Reactant: Cc1nc2sccn2c1C(=O)NC[C@H]1NC[C@@H]2CC(C)C[C@@H]21
Product: CCc1ccc(-c2sc(C)nc2C(=O)N2C[C@@H]3CC(C)C[C@@H]3[C@H]2CNC(=O)c2c(C)nc3sccn23)cc1

Procedure:
prepared by reaction of 6-methyl-imidazo[2,1-b]thiazole-5-carboxylic acid-[(1S,2S,5R)-7-methyl-3-aza-bicyclo[3.3.0]oct-2-ylmethyl]-amide with 5-(4-ethyl-phenyl)-2-methyl-thiazole-4-carboxylic acid.
Reaction SMILES: [CH2:1]([N:3]([CH2:33][CH3:34])[CH2:4][CH2:5][N:6]1[C:14]2[C:9](=[C:10]([C:17]([F:20])([F:19])[F:18])[CH:11]=[C:12]([C:15]#[N:16])[CH:13]=2)[C:8]([OH:31])([C:21]2[CH:30]=[CH:29][C:28]3[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=3)[CH:22]=2)[C:7]1=[O:32])[CH3:2].[OH-:35].[K+]>C(O)(C)(C)C>[CH2:33]([N:3]([CH2:1][CH3:2])[CH2:4][CH2:5][N:6]1[C:14]2[C:9](=[C:10]([C:17]([F:18])([F:20])[F:19])[CH:11]=[C:12]([C:15](=[O:35])[NH2:16])[CH:13]=2)[C:8]([OH:31])([C:21]2[CH:30]=[CH:29][C:28]3[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=3)[CH:22]=2)[C:7]1=[O:32])[CH3:34]
Reactant: [OH-]
Reactant: CCN(CC)CCN1C(=O)C(O)(c2ccc3ccccc3c2)c2c1cc(C#N)cc2C(F)(F)F
Agent: [K+]
Solvent: CC(C)(C)O
Product: CCN(CC)CCN1C(=O)C(O)(c2ccc3ccccc3c2)c2c1cc(C(N)=O)cc2C(F)(F)F
Temperature: 50 °C
Reaction time: 1 h
Yield: 103 %

Procedure:
To a solution of 1-(2-diethylaminoethyl)-4-trifluoromethyl-6-cyano-3-hydroxy-3-(2-naphthyl)oxindole of Example 55 (185 mg, 0.396 mmol) in t-butanol (8 mL) was added powdered KOH (ca. 1 g) at 50° C. The mixture was stirred for 1 h at 50° C. and passed through a celite pad. The celite was washed with THF and the filtrate was concentrated. The residue was dispersed between water and ethyl acetate and the organic layer was separated. The organic layer was dried over MgSO4 and concentrated to give the title compound (198 mg, quant.). The hydrochloride of the title compound was obtained by treating with 4 N HCl in dioxane followed by concentration to dryness.
Reaction SMILES: O[CH2:2][C:3]1[C:8]([CH3:9])=[C:7]([O:10][CH2:11][CH2:12][CH2:13][O:14][CH3:15])[CH:6]=[CH:5][N:4]=1.S(Cl)([Cl:18])=O>C(OCC)(=O)C>[Cl:18][CH2:2][C:3]1[C:8]([CH3:9])=[C:7]([O:10][CH2:11][CH2:12][CH2:13][O:14][CH3:15])[CH:6]=[CH:5][N:4]=1
Reactant: O=S(Cl)Cl
Reactant: COCCCOc1ccnc(CO)c1C
Solvent: CCOC(C)=O
Product: COCCCOc1ccnc(CCl)c1C
Temperature: 25 °C
Yield: 112.8 %

Procedure:
2-Hydroxymethyl-4-(3-methoxypropoxy)-3-methylpyridine (5.0 g (23.7 mmol)) was dissolved in ethyl acetate (40 ml), and thionyl chloride (4.23 g (35.6 mmol)) was added dropwise thereto so that the temperature did not exceed 25° C. Following stirring at room temperature, disappearance of the raw materials was confirmed by TLC, and 2-chloromethyl-4-(3-methoxypropoxy)-3-methylpyridine (6.14 g) was obtained by concentrating under a reduced pressure (yield: 97.4%).
Reaction SMILES: [NH2:1][C@@H:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][C@@H:3]1[OH:11].[C:12]([OH:21])(=[O:20])[C@@H:13]([C@H:15]([C:17]([OH:19])=[O:18])[OH:16])[OH:14]>CO>[NH2:1][C@H:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][C@H:3]1[OH:11].[CH3:13][OH:14].[C:17]([C@@H:15]([C@H:13]([C:12]([OH:21])=[O:20])[OH:14])[OH:16])([OH:19])=[O:18]
Reactant: N[C@@H]1c2ccccc2C[C@@H]1O
Agent: O=C(O)[C@H](O)[C@@H](O)C(=O)O
Solvent: CO
Product: N[C@H]1c2ccccc2C[C@H]1O
Temperature: 60 °C
Reaction time: 1.5 h

Procedure:
Racemic cis-1-amino-2-indanol (22.5 g, water wet, content 83.2%) was suspended with (R,R)-tartaric acid (65 g) in 120 ml of methanol of 60° C. After stirring for 1.5 hours at 60° C., 210 ml of methanol were added and the mixture was brought to reflux. At reflux a solution of racemic cis-1-amino-2-indanol (42.4 g, water wet, content 83.2%) in 120 ml of hot methanol was added. Stirring of the mixture was continued for half an hour at reflux and then it was cooled down again to 33° C. Methanol (10 ml) was added and after continued stirring (overnight) the solid was isolated by filtration and washed twice with 120 ml of methanol. After drying, 54.3 g of (1S,2R)-1-amino-2-indanol-(R,R)-tartrate methanol solvate were obtained with an e.e. of 97.5%. D[v, 0.9]=147.1 μm (measured with a Malvern 2600 apparatus).
Reaction SMILES: [N:1]([C:4]1[CH:9]=[CH:8][C:7]([S:10]([NH2:13])(=[O:12])=[O:11])=[CH:6][CH:5]=1)=[C:2]=[S:3].[I:14][C:15]1[CH:21]=[CH:20][C:18]([NH2:19])=[CH:17][CH:16]=1>>[I:14][C:15]1[CH:21]=[CH:20][C:18]([NH:19][C:2](=[S:3])[NH:1][C:4]2[CH:5]=[CH:6][C:7]([S:10]([NH2:13])(=[O:11])=[O:12])=[CH:8][CH:9]=2)=[CH:17][CH:16]=1
Reactant: NS(=O)(=O)c1ccc(N=C=S)cc1
Reactant: Nc1ccc(I)cc1
Product: NS(=O)(=O)c1ccc(NC(=S)Nc2ccc(I)cc2)cc1

Procedure:
The subject compound was prepared utilizing the procedure described above from 4-isothiocyanatobenzenesulfonamide and 4-iodoaniline. 1H NMR (400 MHz, DMSO-d6) δ 10.13 (s, 1H), 10.08 (s, 1H), 7.76-7.65 (m, 6H), 7.32 (d, J=8.8 Hz, 2H), 7.29 (bs, 2H); (M+H)+ (434).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5](B(O)O)=[C:4]([F:11])[CH:3]=1.[NH2:12][C:13]1[CH:18]=[N:17][C:16](Br)=[CH:15][N:14]=1.C1(C)C=CC=CC=1.C([O-])([O-])=O.[Na+].[Na+]>FC(F)(F)C([O-])=O.[Pd+2].FC(F)(F)C([O-])=O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O.C(O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:16]2[N:17]=[CH:18][C:13]([NH2:12])=[N:14][CH:15]=2)=[C:4]([F:11])[CH:3]=1
Reactant: Nc1cnc(Br)cn1
Reactant: OB(O)c1ccc(Cl)cc1F
Agent: [Pd+2]
Agent: O=C([O-])C(F)(F)F
Agent: O=C([O-])[O-]
Solvent: Cc1ccccc1
Solvent: CCO
Solvent: O
Product: Nc1cnc(-c2ccc(Cl)cc2F)cn1
Temperature: 50 °C
Yield: 78.1 %

Procedure:
To a nitrogen flushed flask containing 4-chloro-2-fluorobenzene boronic acid (40.0 g, 229 mmol), 2-amino-5-bromopyrazine (39.9 g, 229 mmol), palladium(II) trifluoroacetate (1.5 g, 4.6 mmol), and triphenylphosphine (2.4 g, 9.2 mmol) were added sparged toluene (750 mL), ethanol (750 mL), and 2 M Na2CO3(aq) (418 mL, 836 mmol). The mixture was stirred and heated at 50° Celsius for 15 hours and then cooled to rt. Water (750 mL) was added and the layers were separated. The aqueous layer was washed with ethyl acetate (750 mL). The combined organic layers were washed with brine (500 mL), dried over Na2SO4, filtered, and concentrated to dryness to give 55.4 g of crude product. The crude solid was crystallized from toluene (450 mL) to provide the title compound (40.0 g, 78%). MS (ESI): mass calcd. for C10H7ClFN3, 223.03; m/z found, 224.1 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ 8.34 (dd, J=2.6, 1.5, 1H), 8.03 (d, J=1.6, 1H), 7.89 (m, 1H), 7.52 (dd, J=11.3, 2.1, 1H), 7.38 (dd, J=8.5, 2.1, 1H), 6.79 (s, 2H).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[C:15](=[O:19])[N:14]([CH2:20][CH:21]([CH3:23])[CH3:22])[C:13]([CH2:24]O)=[C:12]2[C:26]1[CH:31]=[CH:30][C:29]([F:32])=[CH:28][CH:27]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.S(Cl)([Cl:35])=O.C(=O)([O-])O.[Na+]>C1(C)C=CC=CC=1>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[C:15](=[O:19])[N:14]([CH2:20][CH:21]([CH3:23])[CH3:22])[C:13]([CH2:24][Cl:35])=[C:12]2[C:26]1[CH:31]=[CH:30][C:29]([F:32])=[CH:28][CH:27]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=S(Cl)Cl
Reactant: CC(C)Cn1c(CO)c(-c2ccc(F)cc2)c2cc(OCc3ccccc3)ccc2c1=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: Cc1ccccc1
Product: CC(C)Cn1c(CCl)c(-c2ccc(F)cc2)c2cc(OCc3ccccc3)ccc2c1=O
Yield: 94.2 %

Procedure:
To a suspension of 6-benzyloxy-4-(4-fluorophenyl)-3-hydroxymethyl-2-isobutyl-1(2H)-isoquinolinone (3.24 g, 7.5 mmol) in toluene (50 mL) was added thionyl chloride (1.1 mL, 15 mmol). The obtained mixture was refluxed under heating for 2 h. The reaction mixture was poured into saturated aqueous sodium hydrogencarbonate solution and extracted with ethyl acetate. The extract was washed with brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure to give 6-benzyloxy-3-chloromethyl-4-(4-fluorophenyl)-2-isobutyl-1(2H)-isoquinolinone (3.18 g, 94.4%) as crystals.