Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[N:11]=[C:5]2[CH:6]=[C:7]([Br:10])[CH:8]=[CH:9][N:4]2[N:3]=1.[CH3:12][NH:13][CH2:14][CH3:15]>C(O)C>[Br:10][C:7]1[CH:8]=[CH:9][N:4]2[N:3]=[C:2]([N:13]([CH2:14][CH3:15])[CH3:12])[N:11]=[C:5]2[CH:6]=1
Reactant: Brc1ccn2nc(Br)nc2c1
Reactant: CCNC
Solvent: CCO
Product: CCN(C)c1nc2cc(Br)ccn2n1
Yield: 59.6 %

Procedure:
A mixture of 2,7-dibromo-[1,2,4]triazolo[1,5-a]pyridine (1 g, 3.61 mmol) and N-methylethanamine (4.00 ml, 46.6 mmol) in ethanol (4 ml) was heated for 4 hours to 120° C. in a high pressure vessel. The crude material was applied on silicagel and purified by flash chromatography over a 20 g silicagel column using heptane/ethyl acetate 10-30% as eluent affording (7-bromo-[1,2,4]triazolo[1,5-a]pyridin-2-yl)-ethyl-methyl-amine (549 mg, 59.6%) as a white solid. mp: 109-111° C., MS: m/z=255/257 (M+H+)
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]([S:7](Cl)(=[O:9])=[O:8])[S:5][CH:6]=1.[OH:11][N:12]1[C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=2[N:14]=[N:13]1.C(N(CC)CC)C.C(OCC)(=O)C>C(OC)(C)(C)C>[CH3:1][C:2]1[N:3]=[C:4]([S:7]([O:11][N:12]2[C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=3[N:14]=[N:13]2)(=[O:9])=[O:8])[S:5][CH:6]=1
Reactant: On1nnc2ccccc21
Reactant: Cc1csc(S(=O)(=O)Cl)n1
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: COC(C)(C)C
Product: Cc1csc(S(=O)(=O)On2nnc3ccccc32)n1

Procedure:
Under atmosphere of argon, to a solution of 4-methylthiazol-2-sulfonyl chloride in methyl t-butyl ether (0.20 M, 20 ml), 1-hydroxybenzotriazole (549 mg) and triethylamine (0.57 ml) were added under stirring with cooled on ice bath, and the mixture was stirred for 1 hour at room temperature. To the reaction mixture, ethyl acetate was added. The organic layer was washed with water three times, with a saturated aqueous solution of sodium chloride once successively, dried over an anhydrous magnesium sulfate and concentrated to give the compound of the present invention (1.1 g) having the following physical data.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7](Cl)=[CH:6][C:5]=1[C:11]([F:14])([F:13])[F:12])([O-:3])=[O:2].[C:15]1([SH:21])[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.C(O)C.[OH-].[Na+]>O>[N+:1]([C:4]1[CH:9]=[CH:8][C:7]([S:21][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[CH:6][C:5]=1[C:11]([F:14])([F:13])[F:12])([O-:3])=[O:2]
Reactant: O=[N+]([O-])c1ccc(Cl)cc1C(F)(F)F
Reactant: Sc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: O=[N+]([O-])c1ccc(Sc2ccccc2)cc1C(F)(F)F

Procedure:
A solution of 2-nitro-5-chlorobenzotrifluoride (33.8 g, 0.15 mole), benzenethiol (16.6 g, 0.15 mole) and ethanol (150 ml) is heated to its reflux temperature under nitrogen. To this solution is slowly added a solution of sodium hydroxide (6 g, 0.15 mole) and water (7 ml) at such a rate that refluxing continues with no external heating. the solution is then heated at its reflux temperature for an additional two hours, filtered hot and the filtrate cooled. The resulting precipitate is collected by filtration and recrystallized from hexene to afford a yellow solid, m.p. 65°-67° C.
Reaction SMILES: [CH3:1][N:2]1[C:7](=[O:8])[C:6]([C:9]2[CH:18]=[CH:17][C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[CH:10]=2)=[C:5]([C:19]2[CH:24]=[CH:23][N:22]=[CH:21][CH:20]=2)[N:4]=[C:3]1SC.C(Cl)Cl.C[OH:31].Cl>O1CCOCC1.[OH-].[Na+]>[OH:31][C:3]1[N:2]([CH3:1])[C:7](=[O:8])[C:6]([C:9]2[CH:18]=[CH:17][C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[CH:10]=2)=[C:5]([C:19]2[CH:24]=[CH:23][N:22]=[CH:21][CH:20]=2)[N:4]=1
Reactant: CO
Reactant: CSc1nc(-c2ccncc2)c(-c2ccc3ccccc3c2)c(=O)n1C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: ClCCl
Product: Cn1c(O)nc(-c2ccncc2)c(-c2ccc3ccccc3c2)c1=O
Temperature: 25 °C
Reaction time: 7 h

Procedure:
A suspension of 3-methyl-2-methylsulfanyl-5-naphthalen-2-yl-6-pyridin-4-yl-3H-pyrimidin-4-one (10.1 g, 28.1 mmol) was heated to 100° C. in 100 mL 1,4-dioxane and 60 mL 2.5M sodium hydroxide. After 7 h, TLC (95:5 DCM/MeOH) shows the solution to have no remaining starting material. The reaction was cooled to room temperature and acidified to pH 5 with 5M HCl. The resulting precipitate was collected by filtration, and then suspended in 100 mL hot methanol. The solid was cooled to room temperature then collected by filtration and washed with 100 mL diethylether. The product was air dried overnight to give a pale yellow solid. M+1=330.2.
Reaction SMILES: [CH2:1]([N:8]1[CH2:12][C@H:11]2/[C:13](=N/[S@](C(C)(C)C)=O)/[CH2:14][CH2:15][C@H:10]2[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[O:24]1CCCC1>>[CH2:1]([N:8]1[CH2:12][C@H:11]2[C:13](=[O:24])[CH2:14][CH2:15][C@H:10]2[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)[S@](=O)/N=C1\CC[C@H]2CN(Cc3ccccc3)C[C@@H]12
Reactant: C1CCOC1
Agent: Cl
Product: O=C1CC[C@H]2CN(Cc3ccccc3)C[C@@H]12
Temperature: 25 °C
Reaction time: 2 h

Procedure:
(S,E)-N-((3aS,6aR)-2-Benzylhexahydrocyclopenta[c]pyrrol-4(5H)-ylidene)-2-methylpropane-2-sulfinamide (2.67 g, 8.38 mmol) from Example 14 Step A and 2.0 N aqueous HCl (18.86 mL, 37.7 mmol) were combined in tetrahydrofuran (25 mL). The reaction was stirred at room temperature for 2 hours and the tetrahydrofuran was removed in vacuo and the remaining aqueous portion was made slightly basic with aqueous sodium bicarbonate solution. The aqueous layer was extracted with 3×200 mL of dichloromethane. The combined organic layers were separated, and the solvent was removed in vacuo. The crude material was purified on a silica gel cartridge (Analogix®, Burlington, Wis., RS25-25) eluting with ethyl acetate/hexanes to give (3aS,6aR)-2-benzylhexahydrocyclopenta[c]pyrrol-4(5H)-one: 1H NMR (300 MHz, CDCl3) δ ppm 7.35-7.16 (m, 5H), 3.61 (d, J=13.1, 1H), 3.48 (d, J=13.1, 1H), 3.02 (dd, J=1.8, 9.1, 1H), 2.96-2.82 (m, 1H), 2.71-2.56 (m, 2H), 2.43 (dt, J=8.2, 17.4, 3H), 2.34-2.21 (m, 1H), 2.12 (ddd, J=8.3, 13.0, 16.9, 1H), 1.79 (dddd, J=4.2, 6.4, 9.2, 13.2, 1H).
Reaction SMILES: [CH:1]1([NH:4][C:5](=[O:31])[C:6]2[CH:11]=[C:10]([F:12])[C:9]([CH3:13])=[C:8]([C:14]3[CH:15]=[C:16]4[C:21](=[CH:22][CH:23]=3)[C:20](=[O:24])[N:19]([CH2:25][CH:26]3[CH2:28][CH2:27]3)[CH:18]=[C:17]4[CH:29]=O)[CH:7]=2)[CH2:3][CH2:2]1.[N:32]1([CH2:38][CH2:39][OH:40])[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]1>>[CH:1]1([NH:4][C:5](=[O:31])[C:6]2[CH:11]=[C:10]([F:12])[C:9]([CH3:13])=[C:8]([C:14]3[CH:15]=[C:16]4[C:21](=[CH:22][CH:23]=3)[C:20](=[O:24])[N:19]([CH2:25][CH:26]3[CH2:27][CH2:28]3)[CH:18]=[C:17]4[CH2:29][N:35]3[CH2:36][CH2:37][N:32]([CH2:38][CH2:39][OH:40])[CH2:33][CH2:34]3)[CH:7]=2)[CH2:3][CH2:2]1
Reactant: Cc1c(F)cc(C(=O)NC2CC2)cc1-c1ccc2c(=O)n(CC3CC3)cc(C=O)c2c1
Reactant: OCCN1CCNCC1
Product: Cc1c(F)cc(C(=O)NC2CC2)cc1-c1ccc2c(=O)n(CC3CC3)cc(CN3CCN(CCO)CC3)c2c1

Procedure:
The title compound was prepared as a solid according to the method of Example 75 step ii) using product of Example 75 step i) and 2-piperazin-1-yl-ethanol.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([NH:8][C:9]2[C:18]3[C:13](=[CH:14][C:15]([O:22][CH3:23])=[C:16]([N+:19]([O-])=O)[CH:17]=3)[N:12]=[CH:11][C:10]=2[C:24]#[N:25])[CH:5]=[CH:6][CH:7]=1.[Cl-].[NH4+].CO>O.C(OCC)(=O)C.[Fe]>[NH2:19][C:16]1[CH:17]=[C:18]2[C:13](=[CH:14][C:15]=1[O:22][CH3:23])[N:12]=[CH:11][C:10]([C:24]#[N:25])=[C:9]2[NH:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([Br:1])[CH:3]=1
Reactant: COc1cc2ncc(C#N)c(Nc3cccc(Br)c3)c2cc1[N+](=O)[O-]
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CO
Product: COc1cc2ncc(C#N)c(Nc3cccc(Br)c3)c2cc1N
Yield: 69 %

Procedure:
A mixture of 2.05 g (5.1 mmol) of 4-[(3-bromophenyl)amino]-7-methoxy-6-nitro-quinoline-3-carbonitrile, 1.37 g (25.7 mmol) of ammonium chloride, and 0.86 g (15.4 mmol) of powdered iron was stirred at reflux in 26 ml water and 26 ml methanol for 2 hours. The mixture was diluted with ethyl acetate and the hot mixture was filtered. The organic layer was separated from the filtrate and dried over magnesium sulfate. The solvent was removed and the residue was chromatographed on silica gel eluting with mixtures of chloroform and ethyl acetate. Product fractions were combined to give 1.3 g of 6-amino-4-[(3-bromophenyl)amino]-7-methoxy-quinoline-3-carbonitrile as a yellow solid: mass spectrum (electrospray, m/e): M+H 369.1, 371.1.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2([C:12]([O:14]C)=O)[CH2:11][CH2:10]2)=[CH:5][CH:4]=1.[NH2:16][NH2:17]>>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2([C:12]([NH:16][NH2:17])=[O:14])[CH2:11][CH2:10]2)=[CH:5][CH:4]=1
Reactant: NN
Reactant: COC(=O)C1(c2ccc(OC)cc2)CC1
Product: COc1ccc(C2(C(=O)NN)CC2)cc1
Temperature: 120 °C
Yield: 82.6 %

Procedure:
A mixture of methyl 1-(4-methoxyphenyl)cyclopropanecarboxylate (0.90 g, 4.4 mmol) and hydrazine (0.65 mL, 21 mmol) was heated at 120° C. for 2 h. After cooling, the excess hydrazine was removed under reduced pressure. The residue was treated with water, filtered and washed with water to give the desired product (750 mg, 83%). Analytical LCMS: (M+H)+=207.1.
Reaction SMILES: C[O:2][C:3]([CH2:5][O:6][C:7]1[CH:8]=[C:9]([C:13]2[CH:18]=[CH:17][C:16]([CH2:19][NH:20][C:21]3[N:22]([C:32]4[N:33]=[CH:34][N:35]=[C:36]([NH2:39])[C:37]=4[N:38]=3)[C@@H:23]3[O:31][C@H:28]([CH2:29][OH:30])[C@@H:26]([OH:27])[C@H:24]3[OH:25])=[CH:15][CH:14]=2)[CH:10]=[CH:11][CH:12]=1)=O.CO.[NH3:42]>>[C:3]([CH2:5][O:6][C:7]1[CH:8]=[C:9]([C:13]2[CH:18]=[CH:17][C:16]([CH2:19][NH:20][C:21]3[N:22]([C:32]4[N:33]=[CH:34][N:35]=[C:36]([NH2:39])[C:37]=4[N:38]=3)[C@@H:23]3[O:31][C@H:28]([CH2:29][OH:30])[C@@H:26]([OH:27])[C@H:24]3[OH:25])=[CH:15][CH:14]=2)[CH:10]=[CH:11][CH:12]=1)(=[O:2])[NH2:42]
Reactant: COC(=O)COc1cccc(-c2ccc(CNc3nc4c(N)ncnc4n3[C@@H]3O[C@H](CO)[C@@H](O)[C@H]3O)cc2)c1
Reactant: N
Solvent: CO
Product: NC(=O)COc1cccc(-c2ccc(CNc3nc4c(N)ncnc4n3[C@@H]3O[C@H](CO)[C@@H](O)[C@H]3O)cc2)c1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
8-(3′-Methoxycarbonylmethoxybiphenyl-4-ylmethyl-amino)adenosine (0.080 g) was dissolved in 2.0 M ammonia methanol solution (3.0 mL), and the resulting mixture was stirred at room temperature for 18 hours. The reaction mixture was concentrated under reduced pressure to give the title compound (0.080 g).
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[C:9]([OH:10])=[CH:8][CH:7]=[CH:6][C:5]=1[C:11]([F:14])([F:13])[F:12].[CH3:15][O:16][CH2:17]Cl.[Cl-].[Na+]>C1COCC1>[Cl:3][C:4]1[C:5]([C:11]([F:12])([F:13])[F:14])=[CH:6][CH:7]=[CH:8][C:9]=1[O:10][CH2:15][O:16][CH3:17]
Reactant: COCCl
Reactant: Oc1cccc(C(F)(F)F)c1Cl
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COCOc1cccc(C(F)(F)F)c1Cl
Temperature: 12 °C
Reaction time: 16 h
Yield: 110.7 %

Procedure:
To a suspension of sodium hydride (3.78 g) in THF (150 mL) were added dropwise 2-chloro-3-hydroxybenzotrifluoride (12.4 g) and chloromethyl methyl ether (6.10 g) under ice-cooling, and the mixture was stirred at 12° C. for 16 hr. The reaction mixture was poured into saturated aqueous sodium chloride solution, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure to give the title compound (16.8 g) as a crude product.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([N:8]2[CH:12]=[C:11]([CH:13]=[O:14])[C:10]([CH3:15])=[N:9]2)[CH:5]=[CH:4][N:3]=1.[NH2:16][C:17]1[CH:18]=[C:19]2[C:23](=[CH:24][CH:25]=1)[N:22]([CH3:26])[CH:21]=[C:20]2C(C1CC1)=O.C(=O)([O-])[O-].[K+].[K+].CC1(C)C2C=CC=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=2OC2C1=CC=CC=2P(C1C=CC=CC=1)C1C=CC=CC=1>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.O1CCOCC1>[CH3:15][C:10]1[C:11]([CH2:13][OH:14])=[CH:12][N:8]([C:6]2[CH:5]=[CH:4][N:3]=[C:2]([NH:16][C:17]3[CH:18]=[C:19]4[C:23](=[CH:24][CH:25]=3)[N:22]([CH3:26])[CH:21]=[CH:20]4)[N:7]=2)[N:9]=1
Reactant: Cc1nn(-c2ccnc(Cl)n2)cc1C=O
Reactant: Cn1cc(C(=O)C2CC2)c2cc(N)ccc21
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Solvent: C1COCCO1
Product: Cc1nn(-c2ccnc(Nc3ccc4c(ccn4C)c3)n2)cc1CO
Temperature: 100 °C
Yield: 72.2 %

Procedure:
A round bottomed flask was charged with 1-(2-chloropyrimidin-4-yl)-3-methyl-1H-pyrazole-4-carbaldehyde (400 mg, 1.78 mmol), (5-amino-1-methyl-1H-indol-3-yl)(cyclopropyl)methanone (385 mg, 1.0 equiv.), potassium carbonate (0.74 g, 3.0 equiv), palladium acetate (20 mg, 0.05 equiv), (9,9-dimethyl-9H-xanthene-4,5-diyl)bis(diphenylphosphine) (Xantphos, 100 mg, 0.1 equiv.) and 40 mL of anhydrous dioxane. After being degassed by nitrogen bubbling, the reaction mixture was heated at 100° C. for 12 hours. To the reaction mixture, water was added to form solids. The resulting solids were collected by filtration, washed with water followed by ethyl acetate to give brown powder (430 mg, 60%). The collected solids were dried in vacuo and then used to next step without further purification; MS (ESI) m/z 401 [M+H]+.
Reaction SMILES: C1OCCOCCOCCOCCOCCOC1.[Br:19][C:20]1[CH:25]=[CH:24][C:23](I)=[C:22]([O:27][C:28]([F:31])([F:30])[F:29])[CH:21]=1.[NH2:32][C@@H:33]1[CH2:38][CH2:37][C@H:36]([NH:39][C:40]2[N:49]=[C:48]([N:50]([CH2:53]C)[CH2:51]C)[C:47]3[C:42](=[CH:43][CH:44]=[CH:45][CH:46]=3)[N:41]=2)[CH2:35][CH2:34]1.CC(C)([O-])C.[Na+].C1C=CC(P(C2C=CC3C(=CC=CC=3)C=2C2C3C(=CC=CC=3)C=CC=2P(C2C=CC=CC=2)C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[ClH:107]>CCOCC.CCOC(C)=O.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C1COCC1>[ClH:107].[ClH:107].[Br:19][C:20]1[CH:25]=[CH:24][C:23]([NH:32][C@@H:33]2[CH2:34][CH2:35][C@H:36]([NH:39][C:40]3[N:49]=[C:48]([N:50]([CH3:53])[CH3:51])[C:47]4[C:42](=[CH:43][CH:44]=[CH:45][CH:46]=4)[N:41]=3)[CH2:37][CH2:38]2)=[C:22]([O:27][C:28]([F:31])([F:30])[F:29])[CH:21]=1
Reactant: FC(F)(F)Oc1cc(Br)ccc1I
Reactant: CCN(CC)c1nc(N[C@H]2CC[C@@H](N)CC2)nc2ccccc12
Agent: [Pd]
Agent: C1COCCOCCOCCOCCOCCO1
Agent: CC(C)(C)[O-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: CCOCC
Product: CN(C)c1nc(N[C@H]2CC[C@@H](Nc3ccc(Br)cc3OC(F)(F)F)CC2)nc2ccccc12
Yield: 18 %

Procedure:
To a glass flask were added 18-crown-6 (647 mg, 2.45 mmol), 4-Bromo-1-iodo-2-trifluoromethoxy-benzene (770 mg, 2.10 mmol), cis-N2-(4-amino-cyclohexyl)-N4,N4-dimethyl-quinazoline-2,4-diamine obtained in step C of example 9 (500 mg, 1.75 mmol), sodium tert-butoxide (235 mg, 2.45 mmol), tris(dibenzylideneacetone)dipalladium (160 mg, 0.175 mmol), (R)-(+)-2,2′-Bis(diphenylphosphino)-1,1′-binaphthyl (160 mg, 0.175 mmol) and THF (3.5 mL). The reaction mixture was stirred at reflux 18 hr. The mixture was filtered through a pad of celite, concentrated, and purified by flash chromatography (NH-silica gel, 33% EtOAc in hexane) to give a pale yellow oil. To a solution of above oil in Et2O (2 mL) was added 4 M hydrogen chloride in EtOAc (0.3 mL). The mixture was stirred at ambient temperature for 30 min and concentrated. A solution of the residue in Et2O (2 mL) was stirred at ambient tempareture for 15 min. The precipitate was collected by filtration, washed with Et2O, and dried under reduced pressure to give cis-N2-[4-(4-bromo-2-trifluoromethoxy-phenylamino)-cyclohexyl]-N4,N4-dimethyl-quinazoline-2,4-diamine dihydrochloride (189 mg, 18%) as a white solid.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]2[CH:10]=[C:9]([CH3:11])[C:8]([CH3:12])=[CH:7][C:5]=2[N:6]=1.[C:13]([O:16][CH2:17][C:18](Cl)=[O:19])(=[O:15])[CH3:14]>N1C=CC=CC=1>[C:13]([O:16][CH2:17][C:18]([NH:1][C:2]1[S:3][C:4]2[CH:10]=[C:9]([CH3:11])[C:8]([CH3:12])=[CH:7][C:5]=2[N:6]=1)=[O:19])(=[O:15])[CH3:14]
Reactant: Cc1cc2nc(N)sc2cc1C
Reactant: CC(=O)OCC(=O)Cl
Solvent: c1ccncc1
Product: CC(=O)OCC(=O)Nc1nc2cc(C)c(C)cc2s1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
2-Amino-5,6-dimethylbenzothiazole (4.5 g) is dissolved in pyridine (80 ml) and thereto is added dropwise acetoxyacetyl chloride (3.0 ml) at room temperature. After the mixture is stirred at room temperature for 2 hours, the solvent is distilled off. The resulting oil is solidified with addition of water. The obtained solids are filtered off and washed with water, then with diethyl ether, dried and recrystallized from ethanol to give the title compound (5.4 g) having the following physical properties.
Reaction SMILES: [CH3:1][C@H:2]([NH:11][CH3:12])[C@H:3]([OH:10])[C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1.Cl.[OH-].[Na+].[CH:16](O)=O.C=O>O>[CH3:1][C@H:2]([N:11]([CH3:16])[CH3:12])[C@H:3]([OH:10])[C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: CN[C@@H](C)[C@H](O)c1ccccc1
Reactant: O=CO
Agent: C=O
Agent: Cl
Agent: [Na+]
Solvent: O
Product: C[C@@H]([C@H](O)c1ccccc1)N(C)C
Reaction time: 3 h

Procedure:
Ephedrine hydrochloride (30.3 g, 0.15 mol) was dissolved in warm water (60 ml) there was, then added thereto a 40% sodium hydroxide aqueous solution (15 ml, 0.15 mol) and 85% formic acid (21.7 g, 0.4 mol) and the mixture refluxed under heating, and to this solution was added dropwise at 35% formalin solution (15 g, 0.18 mol) over 20 minutes. Thereafter, refluxing under heating was continued for 3 hours and the reaction solution was concentrated to 1/2 of its original volume and then added thereto was a 40% sodium hydroxide aqueous solution to adjust the pH to about 11. The resultant precipitated crystals were filtered out and recrystallized from methanol. Yield: 23 g (84%); m.p.: 86.5°-87.5° C. [α]D20 =-29.5° (C=4.54, MeOH).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]#[N:9])=[N:6][CH:7]=1.[H-].[Na+].[F:12][C:13]([F:43])([F:42])[C:14]1[CH:19]=[CH:18][C:17]([C@@H:20]2[C:29]3[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=3)[CH2:23][CH2:22][N:21]2[C:30](OC2C=CC([N+]([O-])=O)=CC=2)=[O:31])=[CH:16][CH:15]=1.O>C1COCC1>[C:8]([C:5]1[N:6]=[CH:7][C:2]([NH:1][C:30]([N:21]2[CH2:22][CH2:23][C:24]3[C:29](=[CH:28][CH:27]=[CH:26][CH:25]=3)[C@H:20]2[C:17]2[CH:18]=[CH:19][C:14]([C:13]([F:42])([F:12])[F:43])=[CH:15][CH:16]=2)=[O:31])=[CH:3][CH:4]=1)#[N:9]
Reactant: N#Cc1ccc(N)cn1
Reactant: O=C(Oc1ccc([N+](=O)[O-])cc1)N1CCc2ccccc2[C@H]1c1ccc(C(F)(F)F)cc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: N#Cc1ccc(NC(=O)N2CCc3ccccc3[C@H]2c2ccc(C(F)(F)F)cc2)cn1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 5-amino-2-pyridinecarbonitrile (81 mg, 678 μmol) in THF (1.0 mL) was added sodium hydride, 60% dispersion in mineral oil (17 mg, 452 μmol). The resulting mixture was then subjected to a microwave irradiation at 160° C. for 15 min. Then, (R)-4-nitrophenyl 1-(4-(trifluoromethyl)phenyl)-3,4-dihydroisoquinoline-2(1H)-carboxylate (100 mg, 226 example 88) was added and the mixture was stirred at RT for overnight. Then, H2O (0.5 mL) was added and the mixture was extracted with EtOAc (2×1 mL). The combined organic extracts were dried over MgSO4 and concentrated. The residue was dissolved in DMSO (1.0 mL) and the solution was then purified by preparative HPLC (0%-100% MeCN 0.1% TFA/H2O 0.1% TFA) to give the desired compound, which was dissolved in MeOH (1.0 mL). The solution was then washed through PL-HCO3 MP-Resin (200 mg per 6 mL tube) and the resin was washed with MeOH (2×0.3 mL). The combined washings were concentrated and dried under vacuum to give the title compound as a light yellow solid. MS (ESI, positive ion) m/z: 423 (M+H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:11][C:12]([NH:14][NH:15][C:16](=[S:25])[NH:17][C:18]2[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=2)=O)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].Cl>[OH-].[Na+]>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:6]=[CH:7][C:8]=1[O:9][CH3:10])[CH2:11][C:12]1[N:17]([C:18]2[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=2)[C:16]([SH:25])=[N:15][N:14]=1
Reactant: COc1ccc(CC(=O)NNC(=S)Nc2ccc(F)cc2)cc1OC
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: COc1ccc(Cc2nnc(S)n2-c2ccc(F)cc2)cc1OC
Yield: 80.9 %

Procedure:
A solution of 2-(2-(3,4-dimethoxyphenyl)acetyl)-N-(4-fluorophenyl)hydrazine-carbothioamide (2.03 g) in 2N NaOH (200 mL) was heated at reflux 3 h. The reaction was cooled and acidified to pH 5 with 2N HCl. White solids precipitated, were collected by filtration and washed with water. The solids were dried under vacuum to yield the title compound (1.56 g, 81%).
Reaction SMILES: S(Cl)([Cl:3])=O.O[CH2:6][C:7]1[C:12]([CH3:13])=[C:11]([S:14][CH2:15][CH2:16][N:17]2[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]2)[CH:10]=[CH:9][N:8]=1>>[Cl:3][CH2:6][C:7]1[C:12]([CH3:13])=[C:11]([S:14][CH2:15][CH2:16][N:17]2[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]2)[CH:10]=[CH:9][N:8]=1
Reactant: Cc1c(SCCN2CCCCC2)ccnc1CO
Reactant: O=S(Cl)Cl
Product: Cc1c(SCCN2CCCCC2)ccnc1CCl
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Thionyl chloride (15 ml) was dropwise added to 2-hydroxymethyl-3-methyl-4-(2-piperidinoethylthio)pyridine (2.5 g) under ice-cooling and the mixture was stirred at room temperature for 3 hours. After the completion of the reaction, thionyl chloride was distilled away. The residue was alkali-oversaturated with potassium carbonate and extracted with chloroform. The chloroform layer was dried over anhydrous magnesium sulfate and the solvent was distilled away to give 2.0 g of 2-chloromethyl-3-methyl-4-(2-piperidinoethylthio)pyridine as an oily substance. The substance was added to ethanol (50 ml) containing a solution of 2-mercaptobenzimidazole (1.0 g) and sodium hydroxide (0.6 g) in water (10 ml) and the mixture was refluxed under heating for 5 hours. After the completion of the reaction, the ethanol was distilled away and water was added to the residue, followed by extraction with chloroform. The extract was dried over anhydrous magnesium sulfate and the solvent was distilled away. The residue was recrystallized to give 2-((3-methyl-4-(2-piperidinoethylthio)-2-pyridyl)methylthio)-1H-benzimidazole, melting point 138°-140° C.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5]2[O:8][C:9]3[C:14]([C@@:15]4([CH2:19][S:18][C:17]([NH:20][C:21](=[O:27])[O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[N:16]4)[C:4]=2[CH:3]=1)=[CH:13][C:12]([C:28]1[C:29]([F:34])=[N:30][CH:31]=[CH:32][CH:33]=1)=[CH:11][CH:10]=3.Cl.[F:36][C:37]1([F:42])[CH2:41][CH2:40][NH:39][CH2:38]1.C[Si]([N-][Si](C)(C)C)(C)C.[Li+]>O.CCOC(C)=O>[F:36][C:37]1([F:42])[CH2:41][CH2:40][N:39]([C:2]2[N:7]=[CH:6][C:5]3[O:8][C:9]4[C:14]([C@@:15]5([CH2:19][S:18][C:17]([NH:20][C:21](=[O:27])[O:22][C:23]([CH3:24])([CH3:25])[CH3:26])=[N:16]5)[C:4]=3[CH:3]=2)=[CH:13][C:12]([C:28]2[C:29]([F:34])=[N:30][CH:31]=[CH:32][CH:33]=2)=[CH:11][CH:10]=4)[CH2:38]1
Reactant: CC(C)(C)OC(=O)NC1=N[C@@]2(CS1)c1cc(-c3cccnc3F)ccc1Oc1cnc(Cl)cc12
Reactant: FC1(F)CCNC1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: Cl
Agent: [Li+]
Solvent: O
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)NC1=N[C@@]2(CS1)c1cc(-c3cccnc3F)ccc1Oc1cnc(N3CCC(F)(F)C3)cc12
Temperature: 25 °C
Reaction time: 20 h
Yield: 22.4 %

Procedure:
A vial was charged with (S)-tert-butyl (3-chloro-7-(2-fluoropyridin-3-yl)-5′H-spiro[chromeno[2,3-c]pyridine-5,4′-thiazol]-2′-yl)carbamate (290 mg, 0.58 mmol), RuPhos-precatalyst (42.4 mg, 0.058 mmol) and 3,3-difluoropyrrolidine hydrochloride (167 mg, 1.16 mmol). The vial was sealed before evacuating and backfilling with nitrogen. The solids were suspended in 1,4-dioxane (2 mL) before adding lithium bis(trimethylsilyl)amide solution (1.0M in THF; 2.33 mL, 2.33 mmol) at ambient temperature. The reaction was stirred at ambient temperature for 20 h. Additional amounts of 3,3-difluoropyrolidine HCl (167 mg, 1.16 mmol), lithium bis(trimethylsilyl)amide solution (1.0M in THF; 1.16 mL, 1.162 mmol), and RuPhos-precatalyst (42.4 mg, 0.058 mmol) were added. After 23 h total reaction time, additional amounts of 3,3-difluoropyrrolidine hydrochloride (167 mg, 1.16 mmol), lithium bis(trimethylsilyl)amide solution (1.0M in THF; 1.16 mL, 1.16 mmol), and RuPhos-precatalyst (42.4 mg, 0.058 mmol) were added. After 29 h total reaction time, additional amounts of 3,3-difluoropyrrolidine hydrochloride (167 mg, 1.16 mmol), lithium bis(trimethylsilyl)amide solution (1.0M in THF; 1.16 mL, 1.16 mmol), and RuPhos-precatalyst (42.4 mg, 0.058 mmol) were added. After 45 h total reaction time, the reaction was diluted with water and EtOAc. The organic layer was separated, washed with brine, and dried over sodium sulfate. The solvent was removed under reduced pressure and the crude was purified by silica gel chromatography to afford (S)-tert-butyl (3-(3,3-difluoropyrolidin-1-yl)-7-(2-fluoropyridin-3-yl)-5′H-spiro[chromeno[2,3-c]pyridine-5,4′-thiazol]-2′-yl)carbamate (76.1 mg, 0.13 mmol, 23.0% yield).