Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][CH2:2][CH2:3][N:4]([CH2:17][C:18]([F:21])([F:20])[F:19])[C:5]1[CH:12]=[CH:11][C:8]([C:9]#[N:10])=[C:7]([C:13]([F:16])([F:15])[F:14])[CH:6]=1.[F:22][C:23]1[CH:24]=[CH:25][C:26](=O)[NH:27][CH:28]=1>COCCOC>[F:22][C:23]1[CH:24]=[CH:25][C:26]([O:1][CH2:2][CH2:3][N:4]([CH2:17][C:18]([F:19])([F:20])[F:21])[C:5]2[CH:12]=[CH:11][C:8]([C:9]#[N:10])=[C:7]([C:13]([F:15])([F:16])[F:14])[CH:6]=2)=[N:27][CH:28]=1
Reactant: N#Cc1ccc(N(CCO)CC(F)(F)F)cc1C(F)(F)F
Reactant: O=c1ccc(F)c[nH]1
Solvent: COCCOC
Product: N#Cc1ccc(N(CCOc2ccc(F)cn2)CC(F)(F)F)cc1C(F)(F)F

Procedure:
Synthesized as described in Example 27B from 4-[(2-hydroxyethyl)(2,2,2-trifluoroethyl)amino]-2-(trifluoromethyl)benzonitrile (Example 15B) and 5-fluoro-2(1H)-pyridinone, using dry DME as the reaction solvent: MS (APCI) m/z 408 (M+1).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([C:8]([O:10]C)=O)[CH:5]=[C:4]([NH:12][C:13]2[CH:18]=[CH:17][C:16]([O:19][C:20]3[CH:25]=[CH:24][N:23]=[C:22]4[NH:26][CH:27]=[CH:28][C:21]=34)=[C:15]([F:29])[CH:14]=2)[N:3]=1.[OH-].[Na+].Cl.CN(C(ON1N=[N:48][C:43]2C=[CH:45][CH:46]=[N:47][C:42]1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C1C=NC2N(O)N=NC=2C=1.C(N(C(C)C)CC)(C)C.N1CCNCC1>O>[F:29][C:15]1[CH:14]=[C:13]([NH:12][C:4]2[CH:5]=[C:6]([C:8]([N:47]3[CH2:42][CH2:43][NH:48][CH2:45][CH2:46]3)=[O:10])[N:7]=[C:2]([NH2:1])[N:3]=2)[CH:18]=[CH:17][C:16]=1[O:19][C:20]1[CH:25]=[CH:24][N:23]=[C:22]2[NH:26][CH:27]=[CH:28][C:21]=12
Reactant: COC(=O)c1cc(Nc2ccc(Oc3ccnc4[nH]ccc34)c(F)c2)nc(N)n1
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: C1CNCCN1
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: Nc1nc(Nc2ccc(Oc3ccnc4[nH]ccc34)c(F)c2)cc(C(=O)N2CCNCC2)n1
Temperature: 100 °C
Reaction time: 18 h

Procedure:
0.072 g (0.18 mmol) of methyl 2-amino-6-{[3-fluoro-4-(1H-pyrrolo[2,3-b]pyridin-4-yl-oxy)phenyl]amino}pyrimidine-4-carboxylate (from example 53) is suspended in 3 ml of water. 0.9 ml of a 1 molar sodium hydroxide solution is added. The reaction mixture is stirred at 100° C. for 18 hours. After cooling, the mixture is adjusted to pH 4.5 using 0.95 ml of a 1N hydrochloric acid solution. The precipitate formed is filtered off with suction and dried. The solid is suspended in DMF. 0.066 mg (0.175 mmol) of HATU, 0.025 g (0.184 mmol) of HOAT, 0.064 ml (0.368 mmol) of diisopropylethylamine and 0.031 g (0.368 mmol) of piperazine are added successively. The reaction mixture is stirred at 40° C. for 5 hours. After cooling, the solution is purified by preparative HPLC. This gives 0.012 g (15% of theory) of product.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[CH2:10][C@:9]3([CH:15]4[CH2:16][CH2:17][N:12]([CH2:13][CH2:14]4)[CH2:11]3)[O:8][C:5]2=[N:6][CH:7]=1.C([Sn](CCCC)(CCCC)[C:23]1[C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][C:26]=2[O:25][CH:24]=1)CCC>>[O:25]1[C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=2[C:23]([C:2]2[CH:3]=[C:4]3[CH2:10][C@:9]4([CH:15]5[CH2:16][CH2:17][N:12]([CH2:13][CH2:14]5)[CH2:11]4)[O:8][C:5]3=[N:6][CH:7]=2)=[CH:24]1
Reactant: CCCC[Sn](CCCC)(CCCC)c1coc2ccccc12
Reactant: Brc1cnc2c(c1)C[C@@]1(CN3CCC1CC3)O2
Product: c1ccc2c(-c3cnc4c(c3)C[C@@]3(CN5CCC3CC5)O4)coc2c1

Procedure:
Prepared by a method analogous to that described for the preparation of Example 4 from (2′R)-5′-bromospiro[1-azabicyclo[2.2.2]octane-3,2′(3′H)-furo[2,3-b]pyridine] and 3-tri-n-butylstannylbenzofuran. The title compound was obtained as a colourless solid; m/e 333 (MH+).
Reaction SMILES: Cl[CH2:2][NH:3][C:4](=[O:9])[C:5]([CH3:8])([CH3:7])[CH3:6].[CH3:10][C:11]1[C:19]2[C:14](=[CH:15][CH:16]=[C:17]([C:20]#[N:21])[CH:18]=2)[NH:13][C:12]=1[C:22]1[CH:23]=[N:24][CH:25]=[CH:26][CH:27]=1>>[C:20]([C:17]1[CH:18]=[C:19]2[C:14](=[CH:15][CH:16]=1)[N:13]([CH2:2][NH:3][C:4](=[O:9])[C:5]([CH3:8])([CH3:7])[CH3:6])[C:12]([C:22]1[CH:23]=[N:24][CH:25]=[CH:26][CH:27]=1)=[C:11]2[CH3:10])#[N:21]
Reactant: Cc1c(-c2cccnc2)[nH]c2ccc(C#N)cc12
Reactant: CC(C)(C)C(=O)NCCl
Product: Cc1c(-c2cccnc2)n(CNC(=O)C(C)(C)C)c2ccc(C#N)cc12

Procedure:
N-Chloromethyl-2,2-dimethyl-propionamide and 3-methyl-2-pyridin-3-yl-1H-indole-5-carbonitrile (Example 6) are processed according to the method described in Example 68 to give N-(5-cyano-3-methyl-2-pyridin-3-yl-indol-1-ylmethyl)-2,2-dimethyl-propionamide. 1H NMR (400 MHz, MeOD) δ ppm 1.06 (s, 9H), 2.27 (s, 3H), 5.54 (s, 2H), 7.55 (dd, J=8.6, 1.8 Hz, 1H), 7.66 (ddd, J=7.9, 5.0, 1.0 Hz, 1H), 7.81 (d, J=8.6 Hz, 1H), 8.01-8.09 (m, 2H), 8.65-8.73 (m, 2H). HRMS (ESI) m/z 347.1863 [(M+H)+ Calcd for C21H23N4O: 347.1872].
Reaction SMILES: [BrH:1].[C:2]12([CH2:12][OH:13])[CH2:11][CH:6]3[CH2:7][CH:8]([CH2:10][CH:4]([CH2:5]3)[CH2:3]1)[CH2:9]2>[Br-].[Zn+2].[Br-].O>[C:2]12([CH2:12][OH:13])[CH2:9][CH:8]3[CH2:7][CH:6]([CH2:5][CH:4]([CH2:10]3)[CH2:3]1)[CH2:11]2.[C:2]12([CH2:12][Br:1])[CH2:11][CH:6]3[CH2:7][CH:8]([CH2:10][CH:4]([CH2:5]3)[CH2:3]1)[CH2:9]2
Reactant: Br
Agent: OCC12CC3CC(CC(C3)C1)C2
Agent: [Br-]
Agent: [Zn+2]
Solvent: O
Product: BrCC12CC3CC(CC(C3)C1)C2

Procedure:
To 39 g (0.17 moles) of zinc bromide, 29.8 g (0.17 mole) of hydrobromic acid were added. To the solution thus obtained, 11.5 g (0.069 mole) of 1-adamantyl methylalcohol which was prepared by the method shown in (1) was added and the mixture was refluxed for 11 hours. After the reaction mixture was brought to room temperature, 200 ml of water were added to this and extracted with two 300 ml portions of ether. After washing with 100 ml of water saturated with sodium bicarbonate and 100 ml of water, the resulting ether layer was dehydrated with anhydrous magnesium sulfate and was filtered. Ether was then distilled away. Residual solids were recrystallized from methanol or sublimed (1 mmHg, 75° C) to purify it, and 13 g of 1-adamantyl methyl bromide were obtained. Melting point of the product was 37°-39° C and the yield was 84%.
Reaction SMILES: C[Si]([N-][Si](C)(C)C)(C)C.[Li+].C1COCC1.[CH2:16]([Sn:20](Cl)([CH2:25][CH2:26][CH2:27][CH3:28])[CH2:21][CH2:22][CH2:23][CH3:24])[CH2:17][CH2:18][CH3:19].[F:30][C:31]1[N:32]=[CH:33][N:34]2[CH:38]=[CH:37][S:36][C:35]=12.O>C1COCC1>[F:30][C:31]1[N:32]=[CH:33][N:34]2[CH:38]=[C:37]([Sn:20]([CH2:25][CH2:26][CH2:27][CH3:28])([CH2:21][CH2:22][CH2:23][CH3:24])[CH2:16][CH2:17][CH2:18][CH3:19])[S:36][C:35]=12
Reactant: CCCC[Sn](Cl)(CCCC)CCCC
Reactant: Fc1ncn2ccsc12
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: CCCC[Sn](CCCC)(CCCC)c1cn2cnc(F)c2s1
Reaction time: 0.17 h

Procedure:
A 1.0 N lithiumbis(trimethylsilyl)amide/THF solution (3.2 ml) and 0.75 ml of tri-n-butylstannyl chloride were added in that order to a solution of 7-fluoroimidazo[5,1-b]thiazole in dry THF in an argon atmosphere at −78° C. The mixture was stirred at the same temperature for 10 min. Water was added thereto, followed by extraction with ethyl acetate and washing with saturated brine. The extract was dried over anhydrous magnesium sulfate and then filtered. The solvent was removed by distillation under the reduced pressure. The residue was purified by column chromatography on silica gel (hexane:ethyl acetate=7:1) to give 820 mg of the title compound.
Reaction SMILES: Br[CH2:2][C:3]([O:5][CH3:6])=[O:4].C([O-])(=O)C.[Na+].[CH3:12][O:13][C:14]1[CH:34]=[C:33]([O:35][CH3:36])[CH:32]=[C:31]([O:37][CH3:38])[C:15]=1/[CH:16]=[CH:17]/[S:18]([CH2:21][C:22]1[CH:23]=[CH:24][C:25]([O:29][CH3:30])=[C:26]([NH2:28])[CH:27]=1)(=[O:20])=[O:19]>CO>[CH3:12][O:13][C:14]1[CH:34]=[C:33]([O:35][CH3:36])[CH:32]=[C:31]([O:37][CH3:38])[C:15]=1[CH:16]=[CH:17][S:18]([CH2:21][C:22]1[CH:23]=[CH:24][C:25]([O:29][CH3:30])=[C:26]([NH:28][CH2:2][C:3]([O:5][CH3:6])=[O:4])[CH:27]=1)(=[O:20])=[O:19]
Reactant: COC(=O)CBr
Reactant: COc1cc(OC)c(/C=C/S(=O)(=O)Cc2ccc(OC)c(N)c2)c(OC)c1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CO
Product: COC(=O)CNc1cc(CS(=O)(=O)C=Cc2c(OC)cc(OC)cc2OC)ccc1OC
Yield: 85 %

Procedure:
To a stirred solution of methyl bromoacetate (5 mmol) and sodium acetate (5 mmol) in methanol (20 mL) was added (E)-5-((2,4,6-trimethoxystyrylsulfonyl)methyl)-2-methoxybenzenamine (1 mmol). The resulting mixture was heated to reflux temperature. The heated mixture was stirred at reflux temperature for 12 to 15 h. The heated mixture was then cooled and poured onto water ice (about 100 g). A precipitate formed. The precipitate was separated by filtration to provide the product in 85% yield. m.p. 182-185° C.
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][CH:15]=1)[N:12]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:11][CH2:10][N:9]2[S:23]([C:26]1[CH:31]=[C:30]([Cl:32])[CH:29]=[CH:28][C:27]=1[O:33][CH3:34])(=[O:25])=[O:24])=[O:5])C.[OH-].[Na+]>O1CCCC1.CO>[C:19]([O:18][C:16]([N:12]1[C:13]2[C:8](=[CH:7][C:6]([C:4]([OH:5])=[O:3])=[CH:15][CH:14]=2)[N:9]([S:23]([C:26]2[CH:31]=[C:30]([Cl:32])[CH:29]=[CH:28][C:27]=2[O:33][CH3:34])(=[O:25])=[O:24])[CH2:10][CH2:11]1)=[O:17])([CH3:22])([CH3:21])[CH3:20]
Reactant: CCOC(=O)c1ccc2c(c1)N(S(=O)(=O)c1cc(Cl)ccc1OC)CCN2C(=O)OC(C)(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: COc1ccc(Cl)cc1S(=O)(=O)N1CCN(C(=O)OC(C)(C)C)c2ccc(C(=O)O)cc21
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of 4-(5-chloro-2-methoxy-benzenesulfonyl)-3,4-dihydro-2H-quinoxaline-1,6-dicarboxylic acid 1-tert-butyl ester 6-ethyl ester (430 mg, 0.84 mmol) in tetrahydrofuran (10 mL) and methanol (10 mL) was treated with 2N NaOH (5 mL). The mixture was stirred at room temperature for 1 hour. The organic solvents were then partially removed and the residue acidified with HCl 1N (10 mL). The precipitate which formed was filtered, washing with water, and dried under high vacuum. 4-(5-Chloro-2-methoxy-benzenesulfonyl)-3,4-dihydro-2H-quinoxaline-1,6-dicarboxylic acid 1-tert-butyl ester was obtained as a light yellow gum, 386 mg (95%), MS (ISP): m/e=481.1 (M−H), which was used crude in the following reaction.
Reaction SMILES: [CH2:1]([N:8]([CH2:30][C@@H:31]([C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1)[O:32][CH:33]1[CH2:38][CH2:37][CH2:36][CH2:35][O:34]1)[CH2:9][CH2:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]2[CH:22]=[CH:21][C:20]([C:23]([O:25][CH3:26])=[O:24])=[C:19]([N+:27]([O-])=O)[CH:18]=2)=[CH:13][CH:12]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl-].[NH4+]>C(O)C.O.[Fe]>[NH2:27][C:19]1[CH:18]=[C:17]([C:14]2[CH:15]=[CH:16][C:11]([CH2:10][CH2:9][N:8]([CH2:1][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)[CH2:30][C@@H:31]([C:39]3[CH:40]=[CH:41][CH:42]=[CH:43][CH:44]=3)[O:32][CH:33]3[CH2:38][CH2:37][CH2:36][CH2:35][O:34]3)=[CH:12][CH:13]=2)[CH:22]=[CH:21][C:20]=1[C:23]([O:25][CH3:26])=[O:24]
Reactant: COC(=O)c1ccc(-c2ccc(CCN(Cc3ccccc3)C[C@H](OC3CCCCO3)c3ccccc3)cc2)cc1[N+](=O)[O-]
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCO
Solvent: O
Product: COC(=O)c1ccc(-c2ccc(CCN(Cc3ccccc3)C[C@H](OC3CCCCO3)c3ccccc3)cc2)cc1N
Yield: 86.3 %

Procedure:
To a solution of methyl 4′[2-[benzyl[(2R)-2-phenyl-2-(tetrahydro-2H-pyran-2-yloxy)ethyl]amino]ethyl]-3-nitro-4-biphenylcarboxylate (1.44 g) in ethanol (30 ml) and water (10 ml) were added iron (406 mg) and ammonium chloride (65 mg) and stirred under reflux for 1.5 hours. The mixture was filtrated through Celite pad and evaporated. The residue was dissolved with ethyl acetate, chloroform and methanol, washed with saturated sodium bicarbonate aqueous solution and brine, dried over magnesium sulfate and evaporated to give methyl 3-amino-4′-[2-[benzyl[(2R)-2-phenyl-2-(tetrahydro-2H-pyran-2-yloxy)ethyl]amino]ethyl]-4-biphenylcarboxylate (1.18 g).
Reaction SMILES: [I:1][C:2]1[CH:3]=[CH:4][C:5]2[CH:30]3[CH2:31][CH:28]([CH2:29]3)[C:8]3[N:9]([CH2:17][C:18]4[C:26]5[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=5)[N:20]([CH3:27])[N:19]=4)[C:10]([C:12]([O:14]CC)=O)=[N:11][C:7]=3[C:6]=2[CH:32]=1.[NH3:33]>>[I:1][C:2]1[CH:3]=[CH:4][C:5]2[CH:30]3[CH2:31][CH:28]([CH2:29]3)[C:8]3[N:9]([CH2:17][C:18]4[C:26]5[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=5)[N:20]([CH3:27])[N:19]=4)[C:10]([C:12]([NH2:33])=[O:14])=[N:11][C:7]=3[C:6]=2[CH:32]=1
Reactant: CCOC(=O)c1nc2c(n1Cc1nn(C)c3ccccc13)C1CC(C1)c1ccc(I)cc1-2
Reactant: N
Product: Cn1nc(Cn2c(C(N)=O)nc3c2C2CC(C2)c2ccc(I)cc2-3)c2ccccc21
Temperature: 50 °C
Yield: 86 %

Procedure:
A pressure tube containing a solution of ethyl 9-iodo-3((1-methyl-1H-indazol-3-yl)methyl)-3,4,5,6-tetrahydro-4,6-methanobenzo[3,4]cyclohepta[1,2-d]imidazole-2-carboxylate (198 mg, 0.37 mmol) in methanolic ammonia (7 mL of 7.0M ammonia in methanol) was warmed to 50° C. for 8 days. After evaporation of the reaction mixture in vacuo, the residue was suspended in methanol (0.8 mL) and the solid collected by vacuum filtration to furnish the title compound as an off-white solid (164 mg, 0.32 mmol, 86%): 1H NMR (250 MHz, CDCl3) δ1.48-1.57 (m, 2H), 2.71-2.87 (m, 2H), 3.52 (td, J=8.15, 4.42 Hz, 1H), 3.79 (td, J=7.54, 3.81 Hz, 1H), 3.99 (s, 3H), 5.44 (br. s., 3H), 6.24 (s, 2H), 6.78 (d, J=7.92 Hz, 1H), 7.03-7.11 (m, 1H), 7.31-7.41 (m, 3H), 7.53 (dt, J=8.22, 0.91 Hz, 1H), 8.71 (d, J=1.83 Hz, 1H); M+H=510.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([S:8]([NH:11][C:12]2[CH:17]=[C:16]([CH3:18])[N:15]=[C:14]3[S:19][C:20]([C:30]([OH:32])=O)=[C:21]([C:22]4[CH:27]=[CH:26][CH:25]=[C:24]([O:28][CH3:29])[CH:23]=4)[C:13]=23)(=[O:10])=[O:9])[CH:5]=[CH:6][CH:7]=1.C(Cl)(=O)C(Cl)=O.[CH3:39][NH2:40].C([O-])(O)=O.[Na+]>C(Cl)Cl.CN(C=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([S:8]([NH:11][C:12]2[CH:17]=[C:16]([CH3:18])[N:15]=[C:14]3[S:19][C:20]([C:30]([NH:40][CH3:39])=[O:32])=[C:21]([C:22]4[CH:27]=[CH:26][CH:25]=[C:24]([O:28][CH3:29])[CH:23]=4)[C:13]=23)(=[O:9])=[O:10])[CH:5]=[CH:6][CH:7]=1
Reactant: CN
Reactant: COc1cccc(-c2c(C(=O)O)sc3nc(C)cc(NS(=O)(=O)c4cccc(Cl)c4)c23)c1
Agent: O=C(Cl)C(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CNC(=O)c1sc2nc(C)cc(NS(=O)(=O)c3cccc(Cl)c3)c2c1-c1cccc(OC)c1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 54.7 %

Procedure:
In an dried round bottom flask was added 4-{[(3-chlorophenyl)sulfonyl]amino}-6-methyl-3-[3-(methyloxy)phenyl]thieno[2,3-b]pyridine-2-carboxylic acid (50 mg, 0.102 mmol) (Example 35), DCM (1 mL), oxalyl chloride (0.013 mL, 0.153 mmol) and DMF (10 μL). The resulting mixture was stirred at RT for 10 min. Methylamine (2M in THF) (0.256 mL, 0.511 mmol) was then added dropwise and the mixture stirred at RT for 30 min. Aqueous NaHCO3 solution (25 mL) and DCM (25 mL) were then added and the organic layer separated. The aqueous was re-extracted with DCM (2×20 mL) and the combined organics washed with brine (30 mL), dried and concentrated. Purification by chromatography on silica gel, eluting with a gradient of 0-10% MeOH in DCM was followed by further purification by chromatography on silica gel, eluting with a gradient of 20-50% ethyl acetate in DCM, to give the title compound (28 mg). LCMS (A) m/z: 502 [M+1]+, Rt 1.21 min (acidic), Rt 0.91 min (basic).
Reaction SMILES: [NH2:1][C:2]([C@@H:4]1[CH2:8][C@@H:7]([OH:9])[CH2:6][N:5]1[C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])=O.FC(F)(F)C(OC(=O)C(F)(F)F)=O.O.C(OCC)(=O)C>N1C=CC=CC=1>[C:13]([O:12][C:10]([N:5]1[CH2:6][C@H:7]([OH:9])[CH2:8][C@H:4]1[C:2]#[N:1])=[O:11])([CH3:16])([CH3:14])[CH3:15]
Reactant: CC(C)(C)OC(=O)N1C[C@H](O)C[C@H]1C(N)=O
Solvent: O
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Product: CC(C)(C)OC(=O)N1C[C@H](O)C[C@H]1C#N
Temperature: 25 °C

Procedure:
7.82 g (34 mmol) of tert-butyl (2S,4R)-2-(aminocarbonyl)-4-hydroxypyrrolidine-1-carboxylate was dissolved in 80 ml of pyridine and 12 ml (84 mmol) of trifluoroacetic anhydride was added to the solution dropwise, at −20 C□. The mixture was stirred at room temperature for a day. The excess of anhydride was hydrolised by addition of some drops of water. To this mixture 200 ml of ethyl acetate was added and it was washed with 10% aqueous hydrogen chloride (to pH 3-5), 50 ml 2 N solution of sodium hydroxide and 50 ml brine. The organic solution was dried over sodium sulphate and evaporated to result in an oil. Yield: 5.35 g (74%). (MH30)=213, (MH+)2=426.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([C:10]2[C:14]([C:15]3[CH:20]=[CH:19][N:18]=[CH:17][CH:16]=3)=[CH:13][NH:12][N:11]=2)[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[C:40]([O:44][C:45]([N:47]1[CH2:52][CH2:51][CH:50](O)[CH2:49][CH2:48]1)=[O:46])([CH3:43])([CH3:42])[CH3:41].CCOC(/N=N/C(OCC)=O)=O.C1(P(=O)(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>O1CCCC1>[C:40]([O:44][C:45]([N:47]1[CH2:52][CH2:51][CH:50]([N:12]2[CH:13]=[C:14]([C:15]3[CH:20]=[CH:19][N:18]=[CH:17][CH:16]=3)[C:10]([C:6]3[CH:7]=[CH:8][CH:9]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=3)=[N:11]2)[CH2:49][CH2:48]1)=[O:46])([CH3:43])([CH3:41])[CH3:42]
Reactant: O=[N+]([O-])c1cccc(-c2n[nH]cc2-c2ccncc2)c1
Reactant: CC(C)(C)OC(=O)N1CCC(O)CC1
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: O=P(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(n2cc(-c3ccncc3)c(-c3cccc([N+](=O)[O-])c3)n2)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a suspension of 4-[3-(3-nitro-phenyl)-1H-pyrazol-4-yl]-pyridine (200 mg, 0.750 mmol) in anhydrous tetrahydrofuran (3 mL) at 0° C. triphenylphosphine (293 mg, 1.12 mmol, 1.5 eq), 4-hydroxy-piperidine-1-carboxylic acid tert-butyl ester (150 mg, 0.750 mmol, 1 eq) and DEAD (176 μL, 1.12 mmol, 1.5 eq) were added. The reaction was allowed to warm to room temperature and stirred under nitrogen atmosphere overnight. The regioisomeric ratio was 1:4 at 254 nm in favor of the N1-alkylated product. The solvent was removed under reduced pressure and the residue was purified by silica gel column chromatography (DCM/ethanol 97:3) to give 950 mg of major regioisomer contaminated with triphenylphosphinoxide.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([O:11][CH2:12][CH:13]2[CH2:17][C:16]3[C:18](Br)=[CH:19][CH:20]=[CH:21][C:15]=3[O:14]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[F:23][C:24]([F:35])([F:34])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1B(O)O.C(=O)([O-])[O-].[K+].[K+]>CC1C=CC=CC=1[P](C1C=CC=CC=1C)([Pd](Cl)(Cl)[P](C1=C(C)C=CC=C1)(C1C=CC=CC=1C)C1C=CC=CC=1C)C1C=CC=CC=1C>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([O:11][CH2:12][CH:13]2[CH2:17][C:16]3[C:18]([C:26]4[CH:27]=[CH:28][CH:29]=[CH:30][C:25]=4[C:24]([F:35])([F:34])[F:23])=[CH:19][CH:20]=[CH:21][C:15]=3[O:14]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: Cc1ccc(S(=O)(=O)OCC2Cc3c(Br)cccc3O2)cc1
Reactant: OB(O)c1ccccc1C(F)(F)F
Agent: Cc1ccccc1[P](c1ccccc1C)(c1ccccc1C)[Pd](Cl)(Cl)[P](c1ccccc1C)(c1ccccc1C)c1ccccc1C
Agent: O=C([O-])[O-]
Agent: [K+]
Product: Cc1ccc(S(=O)(=O)OCC2Cc3c(cccc3-c3ccccc3C(F)(F)F)O2)cc1
Yield: 76.9 %

Procedure:
Treatment of (±)-(4-bromo-2,3-dihydro-1-benzofuran-2-yl)methyl 4-methylbenzenesulfonate (5.0 g, 13.05 mmol) with 2-(trifluoromethyl)phenylboronic acid (3.72 g, 17.57 mmol), dichlorobis(tri-o-tolylphosphine)-palladium(II) (0.512 g, 0.652 mmol), and potassium carbonate (4.5 g, 32.62 mmol) generally according to the procedure described for Intermediate 37 provided 4.5 g (77%) of (±)-{4-[2-(trifluoromethyl)phenyl]-2,3-dihydro-1-benzofuran-2-yl}methyl 4-methylbenzenesulfonate as a yellow oil. Treatment of (±)-{4-[2-(trifluoromethyl)phenyl]-2,3-dihydro-1-benzofuran-2-yl}methyl 4-methylbenzenesulfonate (4.3 g, 9.59 mmol) with sodium azide (2.5 g, 38.46 mmol) generally according to the procedure described for Intermediate 98 gave 2.88 g (94%) of (±)-{4-[2-(trifluoromethyl)phenyl]-2,3-dihydro-1-benzofuran-2-yl}methyl azide. Treatment of the azide with palladium on carbon (0.28 g, 10 wt. %) generally according to the procedure described for Example 1 provided 2.46 g (83%) of (±)-1-{4-[2-(trifluoromethyl)phenyl]-2,3-dihydro-1-benzofuran-2-yl}methanamine as a white solid, hydrochloride salt. mp 213-215° C.; Anal. calcd. for C16H14F3NOHCl: C, 58.28; H, 4.59; N, 4.25. Found: C, 58.13; H, 4.65; N, 4.13.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:9]2[CH:18]=[CH:17][C:12]3[N:13]=[C:14]([NH2:16])[S:15][C:11]=3[CH:10]=2)[CH:6]=[N:7][CH:8]=1.C(=O)([O-])[O-].[Cs+].[Cs+].Cl[C:26]1[CH:31]=[N:30][CH:29]=[CH:28][N:27]=1>CC(N(C)C)=O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:9]2[CH:18]=[CH:17][C:12]3[N:13]=[C:14]([NH:16][C:26]4[CH:31]=[N:30][CH:29]=[CH:28][N:27]=4)[S:15][C:11]=3[CH:10]=2)[CH:6]=[N:7][CH:8]=1
Reactant: Clc1cnccn1
Reactant: COc1cncc(-c2ccc3nc(N)sc3c2)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC(=O)N(C)C
Product: COc1cncc(-c2ccc3nc(Nc4cnccn4)sc3c2)c1
Temperature: 200 °C
Yield: 15 %

Procedure:
As shown in step 8-iii of Scheme 8, of 6-(5-methoxypyridin-3-yl)benzo[d]thiazol-2-amine (250 mg; 0.97 mmol) was dissolved in 4.0 mL of dry DMA. Cesium carbonate (650 mg; 2.0 mmol] and 2-chloropyrazine (Aldrich Chemical Co. Cat. No. 13, 248-9, 250 mg; 2.35 mmol) were added and the mixture heated in a sealed tube under microwave irradiation at 200° C. for 15 minutes. After cooling, the volatiles were removed under reduced pressure and residue purified via reversed-phase HPLC using an acetonitrile/water gradient (0.1% TFA). Fractions containing pure product were combined and lyophilized to provide (Compound 1, 50 mg, 15% yield) as an off-white powder: LCMS (M+H) 336.
Reaction SMILES: C[Si]([N-][Si](C)(C)C)(C)C.[K+].[O:11]1[CH2:16][CH2:15][CH:14]([NH:17][C:18]2[N:23]=[C:22]([C:24]3[CH:29]=[CH:28][NH:27][C:26](=[O:30])[CH:25]=3)[CH:21]=[CH:20][N:19]=2)[CH2:13][CH2:12]1.CS(O[C@H:36]([C:47]1[CH:52]=[CH:51][C:50]([Cl:53])=[C:49]([F:54])[CH:48]=1)[CH2:37][CH2:38][O:39][Si:40]([C:43]([CH3:46])([CH3:45])[CH3:44])([CH3:42])[CH3:41])(=O)=O>CC1CCCO1>[Si:40]([O:39][CH2:38][CH2:37][C@@H:36]([N:27]1[CH:28]=[CH:29][C:24]([C:22]2[CH:21]=[CH:20][N:19]=[C:18]([NH:17][CH:14]3[CH2:15][CH2:16][O:11][CH2:12][CH2:13]3)[N:23]=2)=[CH:25][C:26]1=[O:30])[C:47]1[CH:52]=[CH:51][C:50]([Cl:53])=[C:49]([F:54])[CH:48]=1)([C:43]([CH3:46])([CH3:45])[CH3:44])([CH3:42])[CH3:41]
Reactant: O=c1cc(-c2ccnc(NC3CCOCC3)n2)cc[nH]1
Reactant: CC(C)(C)[Si](C)(C)OCC[C@H](OS(C)(=O)=O)c1ccc(Cl)c(F)c1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [K+]
Solvent: CC1CCCO1
Product: CC(C)(C)[Si](C)(C)OCC[C@H](c1ccc(Cl)c(F)c1)n1ccc(-c2ccnc(NC3CCOCC3)n2)cc1=O
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 66.5 %

Procedure:
Potassium bis(trimethylsilyl)amide (0.91M in THF, 0.202 mL) was added to a cooled to 0° C. suspension of 4-(2-((tetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)pyridin-2(1H)-one (40 mg, 0.147 mmol) in 2-methyltetrahydrofuran (4 mL) The mixture was agitated 15 minutes, and (S)-3-(tert-butyldimethylsilyloxy)-1-(4-chloro-3-fluorophenyl)propyl methanesulfonate (81.6 mg, 0.206 mmol) in 2-methyltetrahydrofuran (1 mL) was added. The mixture was then heated to 75° C. and agitated overnight. The reaction was quenched with saturated sodium bicarbonate solution and diluted with ethyl acetate (5 mL). The organic layer was washed with water (2×) and evaporated. Purified by chromatography on silica gel, eluted with 50-75% ethyl acetate/hexanes to give (R)-1-(3-(tert-butyldimethylsilyloxy)-1-(4-chloro-3-fluorophenyl)propyl)-4-(2-((tetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)pyridin-2(1H)-one (0.056 g, 0.0977 mmol, 66.5% yield) as thick oil.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH:5]=[O:6].[CH2:10](O)[CH2:11][OH:12].O.C1(C)C=CC(S(O)(=O)=O)=CC=1.O>C1C=CC=CC=1>[O:6]1[CH2:10][CH2:11][O:12][CH:5]1[C:4]1[CH:3]=[C:2]([Br:1])[CH:9]=[CH:8][CH:7]=1
Reactant: O=Cc1cccc(Br)c1
Reactant: OCCO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: c1ccccc1
Solvent: O
Product: Brc1cccc(C2OCCO2)c1
Temperature: 25 °C

Procedure:
A solution of 3-bromobenzaldehyde (15.87 g, 85.78 mmol), 1,2-ethyleneglycol (8.01 g, 128.7 mmol) and p-toluenesulfonic acid hydrate (100 mg ) in benzene (200 ml) was refluxed at 110° C. under nitrogen for 3 hours, and the water formed in the reaction was collected through a Dean Stark trap. The resulting solution was cooled to room temperature, and washed with 10% sodium hydroxide (2×100 ml), water (4×100 ml) and brine (1×100 ml), and dried over magnesium sulfate. Removal of the solvent under reduced pressure gave the title compound as an oily material (16.8 g, 86%).