Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([NH:10][S:11]([CH:14]2[CH2:16][CH2:15]2)(=[O:13])=[O:12])[C:5]([O:8][CH3:9])=[N:6][CH:7]=1.[CH3:17][C:18]1[S:19][CH:20]=[C:21]([C:23]([NH:25][C:26]2[CH:34]=[C:33]([Sn](C)(C)C)[CH:32]=[C:31]3[C:27]=2[CH:28]=[N:29][N:30]3S(C2C=CC=CC=2)(=O)=O)=[O:24])[N:22]=1.CN(C=O)C>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.CO>[CH:14]1([S:11]([NH:10][C:4]2[CH:3]=[C:2]([C:33]3[CH:32]=[C:31]4[C:27]([CH:28]=[N:29][NH:30]4)=[C:26]([NH:25][C:23]([C:21]4[N:22]=[C:18]([CH3:17])[S:19][CH:20]=4)=[O:24])[CH:34]=3)[CH:7]=[N:6][C:5]=2[O:8][CH3:9])(=[O:13])=[O:12])[CH2:16][CH2:15]1
Reactant: COc1ncc(Br)cc1NS(=O)(=O)C1CC1
Reactant: Cc1nc(C(=O)Nc2cc([Sn](C)(C)C)cc3c2cnn3S(=O)(=O)c2ccccc2)cs1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Solvent: CO
Product: COc1ncc(-c2cc(NC(=O)c3csc(C)n3)c3cn[nH]c3c2)cc1NS(=O)(=O)C1CC1
Temperature: 120 °C
Reaction time: 0.5 h
Yield: 15 %

Procedure:
N-[5-Bromo-2-(methyloxy)-3-pyridinyl]cyclopropanesulfonamide (208 mg, 0.371 mmol), 2-methyl-N-[1-(phenylsulfonyl)-6-(trimethylstannanyl)-1H-indazol-4-yl]-1,3-thiazole-4-carboxamide (128 mg, 0.417 mmol) and Pd(PPh3)4 (43 mg, 0.037 mmol) were weighed to a microwave vial. DMF (3 ml) was added and the reaction was heated in the microwave at 120° C. for 30 min. LCMS showed incomplete reaction, therefore the mixture was reheated at 120° C. for a further 30 min. The residue was passed through a 1 g silica cartridge, pre-conditioned with methanol, washing with methanol. The solvent was evaporated in the blow down unit. The residue was purified on a 40 g silica cartridge on the ISCO Companion, using a 0.5-6% methanol in DCM gradient over 14 mins at a flow rate of 40 ml/min. Fractions containing desired material were combined and concentrated in vacuo, then subjected to further purification on the ISCO companion using a reverse phase 13 g column, with 0.1% TFA in MeCN and 0.1% TFA in water as eluents and a gradient of 15-65% MeCN over 14 mins. Fractions containing desired material were combined and concentrated in vacuo. The residue was dissolved in IPA (3 ml) and 2M NaOH (aq., 3 ml) was added and the reaction mixture left overnight. The IPA was evaporated and the aqueous was acidified using 2M HCl (aq). The precipitate was filtered, washing with water, then dissolved in 1 ml DMSO:methanol (1:1, v/v) and purified by MDAP (Method E) to afford the title compound (27 mg).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([CH2:8]Cl)[C:5]([C:10]([O:12]C)=O)=[CH:4][CH:3]=1.[CH3:14][NH2:15].O1CCCC1>O>[Cl:1][C:2]1[N:7]=[C:6]2[CH2:8][N:15]([CH3:14])[C:10](=[O:12])[C:5]2=[CH:4][CH:3]=1
Reactant: CN
Reactant: COC(=O)c1ccc(Cl)nc1CCl
Solvent: C1CCOC1
Solvent: O
Product: CN1Cc2nc(Cl)ccc2C1=O

Procedure:
Methyl 6-chloro-2-(chloromethyl)pyridine-3-carboxylate (1.5 g, 6.82 mmol) was stirred in a solution of methylamine in tetrahydrofuran (35 mL, 70.0 mmol) at room temperature overnight. Water was added and the products extracted into ethyl acetate (2×). The combined organic extracts were washed with brine, dried over MgSO4 and concentrated in vacuo. The residue was triturated in diethyl ether to give a first batch of product. The mother liquor was concentrated in vacuo and the residue purified by flash chromatography (silica, 40-100% ethyl acetate/hexanes) and combined with the first batch to afford the title compound as a white solid. LRMS (APCI) calcd for C8H8ClN2O [M+H]+ 183.0, found 183.0.
Reaction SMILES: Cl[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[C:6](Cl)[N:5]=[CH:4][N:3]=1.[NH3:12]>>[NH2:12][C:4]1[N:5]=[CH:6][C:7]([N+:8]([O-:10])=[O:9])=[CH:2][N:3]=1
Reactant: O=[N+]([O-])c1c(Cl)ncnc1Cl
Reactant: N
Product: Nc1ncc([N+](=O)[O-])cn1

Procedure:
Reaction of 4,6-dichloro-5-nitropyrimidine XX′ with nucleophile NH3 and R7LYH affords amino-5-nitropyrimidine XXI′. Suitable solvents for this reaction include ethanol, methylene chloride, acetonitrile, and tetrahydrofuran.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[O:15]1[CH:19]=[CH:18][CH:17]=[C:16]1[C:20](Cl)=[O:21]>ClCCl>[C:2]1([NH:1][C:20]([C:16]2[O:15][CH:19]=[CH:18][CH:17]=2)=[O:21])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Nc1ccccc1
Reactant: O=C(Cl)c1ccco1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(Nc1ccccc1)c1ccco1
Temperature: -10 °C

Procedure:
N-phenyl furamide was prepared by adding to a mixture of aniline (23.3 g; 250 mmol) and triethylamine (25.3 g; 250 mmol) in dichloromethane slowly 32.6 g (250 mmol) of 2-furoyl chloride, while maintaining the temperature at -10° C. The product obtained was washed with diluted hydrochloric acid and water, dried with magnesium sulphate and evaporated. The product so obtained was than triturated with hexane and filtered. 39.3 g (84% yield of product was recovered.
Reaction SMILES: Cl.[F:2][C:3]([F:28])([F:27])[C:4]1[CH:17]=[CH:16][C:15]2[S:14][C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[N:7]([CH2:18][CH2:19][CH2:20][N:21]3[CH2:25][CH2:24][CH:23]([OH:26])[CH2:22]3)[C:6]=2[CH:5]=1.[C:29](Cl)(=[O:35])[CH2:30][CH2:31][CH2:32][CH2:33][CH3:34].CO>ClC(Cl)C>[F:28][C:3]([F:27])([F:2])[C:4]1[CH:17]=[CH:16][C:15]2[S:14][C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[N:7]([CH2:18][CH2:19][CH2:20][N:21]3[CH2:25][CH2:24][CH:23]([O:26][C:29](=[O:35])[CH2:30][CH2:31][CH2:32][CH2:33][CH3:34])[CH2:22]3)[C:6]=2[CH:5]=1
Reactant: CCCCCC(=O)Cl
Reactant: OC1CCN(CCCN2c3ccccc3Sc3ccc(C(F)(F)F)cc32)C1
Agent: Cl
Solvent: CC(Cl)Cl
Solvent: CO
Product: CCCCCC(=O)OC1CCN(CCCN2c3ccccc3Sc3ccc(C(F)(F)F)cc32)C1

Procedure:
8.6 G. of 2-trifluoromethyl-10-[3-(3-hydroxypyrrolidino)-propyl]-phenothiazine.hydrochloride were dissolved in 100 ml of dichloroethane. To the solution were added drop by drop 3.0 g of caproylchloride at a room temperature with stirring. This mixture was heated under reflux for two hours. After cooling, 20 ml of methanol were added to said mixture, and the whole was stirred for about 1 hour. The resulting reaction mixture was washed, in turn, with water, aqueous potasium carbonate solution and water respectively, and dried over sodium sulphate. The solvent was distilled off under a reduced pressure. The resulting pale brown oily material was purified by means of silicagel column chromatography (solvent for elution: the mixed solvent of n-hexan.ethylacetate), thereby obtaining the object as the free base, which was pale yellowish viscous liquid.
Reaction SMILES: C1(NC2CCCCC2)CCCCC1.[CH2:14]([O:18][C:19]1[CH:27]=[CH:26][C:22]([C:23](O)=[O:24])=[CH:21][CH:20]=1)[C:15]#[C:16][CH3:17].S(Cl)([Cl:30])=O>ClCCl>[CH2:14]([O:18][C:19]1[CH:27]=[CH:26][C:22]([C:23]([Cl:30])=[O:24])=[CH:21][CH:20]=1)[C:15]#[C:16][CH3:17]
Reactant: O=S(Cl)Cl
Reactant: CC#CCOc1ccc(C(=O)O)cc1
Agent: C1CCC(NC2CCCCC2)CC1
Solvent: ClCCl
Product: CC#CCOc1ccc(C(=O)Cl)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 97.9 %

Procedure:
2.8 ml (14.2 mmol) of dicyclohexylamine are added to a solution of 2.7 g (14.2 mmol) of 4-but-2-ynyloxybenzoic acid diluted in 30 ml of dichloromethane. After stirring for 30 min at ambient temperature, the reaction medium is cooled to 0° C. and 1.0 ml (14.2 mmol) of thionyl chloride is slowly added. The mixture is then stirred at ambient temperature for 1 h 30 min, then the dicyclohexylamine salts are precipitated by adding 50 ml of diethyl ether. After filtration of the reaction medium, the filtrate is concentrated under vacuum. 2.9 g (100%) of 4-but-2-ynyloxybenzoyl chloride are obtained in the form of a brown solid.
Reaction SMILES: [C:1]([OH:14])(=[O:13])[C:2]1[CH:12]=[C:9]([O:10][CH3:11])[C:7]([OH:8])=[C:4]([O:5][CH3:6])[CH:3]=1.[CH2:15](Br)[C:16]#[CH:17]>>[CH2:17]([O:13][C:1](=[O:14])[C:2]1[CH:3]=[C:4]([O:5][CH3:6])[C:7]([OH:8])=[C:9]([O:10][CH3:11])[CH:12]=1)[C:16]#[CH:15]
Reactant: C#CCBr
Reactant: COc1cc(C(=O)O)cc(OC)c1O
Product: C#CCOC(=O)c1cc(OC)c(O)c(OC)c1

Procedure:
By utilizing the procedure of Example 5, by reacting syringic acid and propargyl bromide, there is obtained syringic acid propargyl ester, F. P. 105°-106°C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:9]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[C:12](=[N:19][CH3:20])[CH2:11][CH2:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8].CO.[H][H]>[Ni].ClC1C=CC=CC=1>[CH3:20][NH:19][C@@H:12]1[C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][C:18]=2[C@H:9]([C:4]2[CH:5]=[CH:6][C:7]([Cl:8])=[C:2]([Cl:1])[CH:3]=2)[CH2:10][CH2:11]1
Reactant: CN=C1CCC(c2ccc(Cl)c(Cl)c2)c2ccccc21
Reactant: [H][H]
Agent: [Ni]
Solvent: CO
Solvent: Clc1ccccc1
Product: CN[C@H]1CC[C@@H](c2ccc(Cl)c(Cl)c2)c2ccccc21
Yield: 0.86 %

Procedure:
N-[4-(3,4-dichlorophenyl)-3,4-dihydro-1(2H)naphthalenylidene]methanamine (Ketimine) (50 g), methanol (300 ml), Raney Nickel (0.15 g wet basis) and chlorobenzene (25 ml) are charged into a reaction vessel. The mixture is hydrogenated at 5 to 6 kg/cm2 over pressure of hydrogen for 6 to 7 hrs at about 28 to 30° C. The catalyst is removed by filtration and the cake is washed with 50 ml methanol. The cis to trans ratio is 87-89/9-13. The amount of dehalogenated by product is <0.1%. Sertraline racemate free base thus formed is treated with hydrochloric acid (24 ml, 33%) and predominantly isomer of sertraline HCl racemate is filtered [Cis>98%, trans<2%, dehalogenation product<0.1%, yield 0.86 to 0.88%].
Reaction SMILES: [CH3:1][N:2]([CH3:10])[CH:3]1[CH2:8][CH2:7][C:6](=O)[CH2:5][CH2:4]1.Cl.[Br:12][C:13]1[CH:18]=[CH:17][C:16]([NH:19][NH2:20])=[CH:15][CH:14]=1.N1C=CC=CC=1.C(=O)([O-])[O-].[K+].[K+]>C(O)C>[Br:12][C:13]1[CH:18]=[CH:17][C:16]([NH:19][N:20]=[C:6]2[CH2:7][CH2:8][CH:3]([N:2]([CH3:10])[CH3:1])[CH2:4][CH2:5]2)=[CH:15][CH:14]=1
Reactant: NNc1ccc(Br)cc1
Reactant: CN(C)C1CCC(=O)CC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Solvent: c1ccncc1
Product: CN(C)C1CCC(=NNc2ccc(Br)cc2)CC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 86.7 %

Procedure:
To a mixture of 6.0 gm (42.0 mMol) 4-dimethylaminocyclohexanone and 9.5 gm (42.0 mMol) 4-bromophenylhydrazine hydrochloride in 100 mL ethanol were added 3.4 mL (42 mMol) pyridine. The resultant mixture was then heated at reflux for 2 hours and then stirred at ambient temperature for 18 hours. The reaction mixture was then treated with aqueous potassium carbonate and extracted well with dichloromethane. The organic phases were combined, dried over sodium sulfate and concentrated under reduced pressure. The resultant residue was treated with toluene and concentrated again under reduced pressure to give 11.3 gm (87%) of the desired compound.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([O:8][C:9]2[CH:14]=[CH:13][C:12]([CH2:15][OH:16])=[CH:11][C:10]=2[F:17])[CH:5]=[CH:4][N:3]=1.C(OC([N:25]1[C:33]2[N:28]([C:29](=[O:35])[N:30]=[C:31](Cl)[CH:32]=2)[CH2:27][C:26]1([CH3:37])[CH3:36])=O)(C)(C)C>>[Cl:1][C:2]1[CH:7]=[C:6]([O:8][C:9]2[CH:14]=[CH:13][C:12]([CH2:15][O:16][C:31]3[CH:32]=[C:33]4[NH:25][C:26]([CH3:37])([CH3:36])[CH2:27][N:28]4[C:29](=[O:35])[N:30]=3)=[CH:11][C:10]=2[F:17])[CH:5]=[CH:4][N:3]=1
Reactant: CC(C)(C)OC(=O)N1c2cc(Cl)nc(=O)n2CC1(C)C
Reactant: OCc1ccc(Oc2ccnc(Cl)c2)c(F)c1
Product: CC1(C)Cn2c(cc(OCc3ccc(Oc4ccnc(Cl)c4)c(F)c3)nc2=O)N1

Procedure:
The title compound was prepared by a procedure similar to that described for E9 starting from (4-((2-chloropyridin-4-yl)oxy)-3-fluorophenyl)methanol and tert-butyl-7-chloro-2,2-dimethyl-5-oxo-2,3-dihydroimidazo[1,2-c]pyrimidine-1(5H)-carboxylate.
Reaction SMILES: [Cl-].[N:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4][C:3]=1[CH2:12][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C([Li])CCC.[C:37]([O:41][C:42]([N:44]1[CH2:49][CH2:48][C:47](=O)[CH2:46][CH2:45]1)=[O:43])([CH3:40])([CH3:39])[CH3:38].O>C1COCC1>[C:37]([O:41][C:42]([N:44]1[CH2:49][CH2:48][C:47](=[CH:12][C:3]2[CH:4]=[CH:5][C:6]3[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=3)[N:2]=2)[CH2:46][CH2:45]1)=[O:43])([CH3:40])([CH3:38])[CH3:39]
Reactant: c1ccc([P+](Cc2ccc3ccccc3n2)(c2ccccc2)c2ccccc2)cc1
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Agent: [Cl-]
Agent: [Li]CCCC
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(=Cc2ccc3ccccc3n2)CC1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
Under argon, 2-quinolylmethyltriphenylphosphonium chloride (8.72 g) was dissolved in anhydrous THF (60 ml), and a 1.6N solution (15 ml) of butyllithium was added dropwise over 20 minutes under cooling on ice. The mixture was then stirred for 10 minutes at room temperature. To the mixture, an anhydrous THF (24 ml) solution of 1-tert-butoxycarbonyl-4-ketopiperidine (4.29 g) was added dropwise over 15 minutes under cooling on ice. The mixture was stirred for 30 minutes under cooling on ice and further stirred overnight at room temperature. Water (200 ml) was added to the reaction mixture, then the resultant mixture was extracted with ether. The organic phase was back-extracted with 1N hydrochloric acid, and the aqueous phase was neutralized with a saturated solution of sodium hydrogencarbonate. The resultant mixture was extracted with ethyl acetate. The organic phase was washed with saturated brine, dried over sodium sulfate anhydrate, and concentrated under reduced pressure, to thereby obtain the title compound as a solid. This solid was used for subsequent reaction without further purification.
Reaction SMILES: [CH3:1][C:2]1([CH3:23])[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([C:12]([F:15])([F:14])[F:13])[CH:10]=2)[NH:5][CH:4]([C:16]2[CH:17]=[C:18]([NH2:22])[CH:19]=[CH:20][CH:21]=2)[CH2:3]1.N1C=CC=CC=1.[CH3:30][C:31]1[CH:36]=[CH:35][C:34]([S:37](Cl)(=[O:39])=[O:38])=[CH:33][CH:32]=1>ClCCl>[CH3:1][C:2]1([CH3:23])[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([C:12]([F:15])([F:13])[F:14])[CH:10]=2)[NH:5][CH:4]([C:16]2[CH:17]=[C:18]([NH:22][S:37]([C:34]3[CH:35]=[CH:36][C:31]([CH3:30])=[CH:32][CH:33]=3)(=[O:39])=[O:38])[CH:19]=[CH:20][CH:21]=2)[CH2:3]1
Reactant: CC1(C)CC(c2cccc(N)c2)Nc2ccc(C(F)(F)F)cc21
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: c1ccncc1
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)Nc2cccc(C3CC(C)(C)c4cc(C(F)(F)F)ccc4N3)c2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 82.9 %

Procedure:
To a stirred solution of 3-(4,4-dimethyl-6-trifluoromethyl-1,2,3,4-tetrahydro-quinolin-2-yl)-phenylamine (100 mg, 0.31 mmol) in pyridine (49 mg, 0.62 mmol) and dichloromethane (1.5 mL) at 0° C. was added dropwise a solution of 4-Methyl-benzenesulfonyl chloride (71 mg, 0.37 mmol) in dichloromethane (0.5 mL). The mixture was stirred at room temperature overnight. The mixture was quenched with water (5 mL) and extracted with dichloromethane (5 mL×2). The combined organic layers were dried over anhydrous sodium sulfate and evaporated. The residue was purified by column chromatography on silica gel to afford N-[3-(4,4-dimethyl-6-trifluoromethyl-1,2,3,4-tetrahydro-quinolin-2-yl)-phenyl]-4-methyl-benzenesulfonamide (122 mg, 77.2%) as a white solid. MS (ESI+APCI) M+1=475.2.
Reaction SMILES: C([O:3][C:4]([C:6]1([N:15]([CH3:28])[C:16]([C:18]2[C:27]3[CH2:26][CH2:25][CH2:24][CH2:23][C:22]=3[CH:21]=[CH:20][CH:19]=2)=[O:17])[CH2:14][C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH2:7]1)=[O:5])C.[OH-].[K+].O>CCO>[CH3:28][N:15]([C:16]([C:18]1[C:27]2[CH2:26][CH2:25][CH2:24][CH2:23][C:22]=2[CH:21]=[CH:20][CH:19]=1)=[O:17])[C:6]1([C:4]([OH:5])=[O:3])[CH2:7][C:8]2[C:13](=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH2:14]1
Reactant: CCOC(=O)C1(N(C)C(=O)c2cccc3c2CCCC3)Cc2ccccc2C1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CN(C(=O)c1cccc2c1CCCC2)C1(C(=O)O)Cc2ccccc2C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 71.5 %

Procedure:
The mixture of 2-[methyl-(5,6,7,8-tetrahydro-naphthalene-1-carbonyl)-amino]-indan-2-carboxylic acid ethyl ester (120) (226 mg, 0.60 mmol) and KOH (600 mg, 10.7 mmol) is dissolved in EtOH (5 mL) and water (0.5 mL) under a water bath. The water bath is removed when KOH is completely dissolved and the resulting reaction solution is stirred at RT for 8 h. After concentration in vacuo, the residue is dissolved in water (20 mL) and acidified with conc. HCl until pH˜3. The precipitate is filtered to give a pure product (121) as a pale orange solid (150 mg, 72%).
Reaction SMILES: [F:1][CH:2]([F:38])[CH2:3][N:4]1[CH:12]=[C:11]2[C:6]([C:7]([CH:14]([O:16][CH2:17][C:18]3([C:31]4[CH:36]=[CH:35][C:34]([F:37])=[CH:33][CH:32]=4)[CH2:23][CH2:22][N:21]([C:24](OC(C)(C)C)=O)[CH2:20][CH2:19]3)[CH3:15])=[CH:8][C:9]([CH3:13])=[CH:10]2)=[N:5]1.C([BH3-])#N.[Na+].C=O>FC(F)(F)C(O)=O.C(O)(=O)C>[F:38][CH:2]([F:1])[CH2:3][N:4]1[CH:12]=[C:11]2[C:6]([C:7]([CH:14]([O:16][CH2:17][C:18]3([C:31]4[CH:32]=[CH:33][C:34]([F:37])=[CH:35][CH:36]=4)[CH2:19][CH2:20][N:21]([CH3:24])[CH2:22][CH2:23]3)[CH3:15])=[CH:8][C:9]([CH3:13])=[CH:10]2)=[N:5]1
Reactant: Cc1cc(C(C)OCC2(c3ccc(F)cc3)CCN(C(=O)OC(C)(C)C)CC2)c2nn(CC(F)F)cc2c1
Agent: C=O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O=C(O)C(F)(F)F
Product: Cc1cc(C(C)OCC2(c3ccc(F)cc3)CCN(C)CC2)c2nn(CC(F)F)cc2c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
(±)-tert-Butyl 4-((1-(2-(2,2-difluoroethyl)-5-methyl-2H-indazol-7-yl)ethoxy)methyl)-4-(4-fluorophenyl)piperidine-1-carboxylate (10 mg, 0.02 mmol) was dissolved in trifluoroacetic acid (50% in dichloromethane, 1 mL) and stirred at room temperature for 1 h. The reaction was concentrated, loaded onto a strong cation exchange cartridge in methanol, and flushed with several volumes of methanol which were discarded. The crude secondary amine was eluted in 2 M ammonia in methanol and concentrated. The resulting residue was dissolved in acetonitrile (1 mL), cooled to 0° C., and treated with sodium cyanoborohydride (5.9 mg, 0.01 mmol) and formalin (0.52 mL). After 5 min, the reaction was treated with a few drops of acetic acid. The ice bath was removed and stirring continued for 1 h. The reaction was concentrated and purified by column chromatography (10% methanolic ammonia/methylene chloride) to afford 4.5 mg (54%) as a clear oil. 1H-NMR (CDCl3, 500 MHz) δ 7.83 (s, 1H), 7.30-7.34 (m, 2H), 7.22 (m, 1H), 6.99-7.02 (m, 2H), 6.67 (m, 1H), 6.05-6.29 (m, 1H), 4.86 (q, J=6.4 Hz, 1H), 4.64-4.71 (m, 2H), 3.33-3.38 (m, 2H), 2.57 (m, 2H), 2.28 (s, 3H), 2.20 (s, 3H), 2.15-2.24 (m, 6H), 1.44 (d, J=6.4 Hz, 3H). Mass spec.: 446.63(MH)+.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5](B(O)O)[CH:6]=[N:7][CH:8]=1)#[N:2].C(=O)([O-])[O-].[Na+].[Na+].C(OC([N:25]([C:33]1[S:34][CH2:35][C@@H:36]2[CH2:41][CH2:40][CH2:39][C@:37]2([C:42]2[CH:47]=[C:46](Br)[CH:45]=[CH:44][C:43]=2[F:49])[N:38]=1)C(OC(C)(C)C)=O)=O)(C)(C)C.O>CN(C=O)C.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>[NH2:25][C:33]1[S:34][CH2:35][C@@H:36]2[CH2:41][CH2:40][CH2:39][C@:37]2([C:42]2[CH:47]=[C:46]([C:5]3[CH:6]=[N:7][CH:8]=[C:3]([CH:4]=3)[C:1]#[N:2])[CH:45]=[CH:44][C:43]=2[F:49])[N:38]=1
Reactant: CC(C)(C)OC(=O)N(C(=O)OC(C)(C)C)C1=N[C@@]2(c3cc(Br)ccc3F)CCC[C@H]2CS1
Reactant: N#Cc1cncc(B(O)O)c1
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: CN(C)C=O
Solvent: O
Product: N#Cc1cncc(-c2ccc(F)c([C@]34CCC[C@H]3CSC(N)=N4)c2)c1
Temperature: 80 °C
Reaction time: 2 h

Procedure:
5-Cyano-3-pyridinylboronic acid (37.9 mg), tetrakis(triphenylphosphine)palladium and a 1 N sodium carbonate solution (256 μL) were added to a solution of (±)-N,N-bis(tert-butoxycarbonyl) [(4aR*,7aS*)-7a-(5-bromo-2-fluorophenyl)-4,4a,5,6,7,7a-hexahydrocyclopenta[d][1,3]thiazin-2-yl]amine (70.0 mg) in DMF (5 mL). After replacement with nitrogen, the mixture was stirred at 80° C. for two hours. After cooling to room temperature, water was added to the reaction mixture. The aqueous layer was extracted with ethyl acetate, and the organic layer was washed with water and brine. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was dissolved in dichloromethane (3 mL). Trifluoroacetic acid (1 mL) was added and the mixture was stirred at room temperature for two hours. The reaction mixture was diluted with water, followed by neutralization with a saturated sodium bicarbonate solution. The aqueous layer was extracted with ethyl acetate, and the organic layer was dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by NH-silica gel column chromatography to obtain the title compound.
Reaction SMILES: [CH3:1][C:2]([CH3:22])([CH2:5][O:6][CH2:7][C:8]1[CH:13]=[CH:12][C:11]([F:14])=[C:10]([CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH:9]=1)[CH:3]=O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[C:42](Cl)(Cl)([Cl:44])[Cl:43]>ClCCl.[Zn]>[CH3:1][C:2]([CH3:22])([CH:3]=[C:42]([Cl:44])[Cl:43])[CH2:5][O:6][CH2:7][C:8]1[CH:13]=[CH:12][C:11]([F:14])=[C:10]([CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH:9]=1
Reactant: CC(C)(C=O)COCc1ccc(F)c(Cc2ccccc2)c1
Reactant: ClC(Cl)(Cl)Cl
Agent: [Zn]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: CC(C)(C=C(Cl)Cl)COCc1ccc(F)c(Cc2ccccc2)c1
Temperature: 25 °C
Reaction time: 14 h

Procedure:
A mixture of 2,2-dimethyl-3-(3-benzyl-4-fluorobenzyloxy)propan-1-al (0.4 g), triphenylphosphine (0.77 g), zinc dust (0.10 g) and carbon tetrachloride (3 cm3) in dichloromethane (3 ml) was heated at the reflux temperature for five hours. After cooling to the ambient temperature (ca 25° C.), the mixture was allowed to stand for 14 hours where upon it was triturated with diethylether. The solvent was evaporated under reduced pressure and the residue was passed through a short plug of silica gel using petroleum ether (boiling range 40°-60° C.) containing diethyl ether (10% by volume) as eluent to give 2,2-dimethyl-1-(3-benzyl-4-fluorobenzyloxy)-4,4-dichlorobut-3-ene (0.44 g).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]([CH3:10])[CH3:9].[Mg].[Cl:12][C:13]1[CH:14]=[C:15]2[C:19](=[CH:20][CH:21]=1)[NH:18][C:17](=[O:22])[C:16]2=[O:23].Cl>O1CCCC1.C(OCC)(=O)C>[Cl:12][C:13]1[CH:14]=[C:15]2[C:19](=[CH:20][CH:21]=1)[NH:18][C:17](=[O:22])[C:16]2([OH:23])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]([CH3:10])[CH3:9]
Reactant: O=C1Nc2ccc(Cl)cc2C1=O
Reactant: CC(C)c1ccccc1Br
Agent: Cl
Agent: [Mg]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC(C)c1ccccc1C1(O)C(=O)Nc2ccc(Cl)cc21
Temperature: 25 °C
Reaction time: 2 h
Yield: 98.3 %

Procedure:
Several drops of a 12 mL tetrahydrofuran solution of 8.2 g of 1-bromo-2-isopropylbenzene were added to a 5 mL tetrahydrofuran solution of 1.2 g of magnesium under a nitrogen atmosphere to initiate the reaction, after which the rest was gradually added drop-wise at a rate at which heating reflux was maintained. Upon completion of the dropping, the reaction mixture was refluxed for 0.5 hour in an oil bath, and then cooled to room temperature. A reagent prepared as above was gradually added drop-wise under ice cooling and a nitrogen atmosphere to a suspension of 3 g of 5-chloro-1H-indol-2,3-dione in 22 mL of tetrahydrofuran. Upon completion of the dropping, the temperature was raised to room temperature, and then the reaction mixture was stirred for 2 hours at that temperature. A 3N hydrochloric acid aqueous solution was poured into the reaction solution, and extraction was performed with ethyl acetate. The organic layer was washed with water and saturated brine and dried with magnesium sulfate, and the drying agent was then filtered off and the solvent was distilled off under reduced pressure. The residue was purified by column chromatography (silica gel 60, mobile phase: ethyl acetate/hexane=1/2; v/v) to obtain 4.9 g of the titled compound (pale yellow, amorphous).