Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(O)=O.C([O:11][CH:12]1[CH2:15][CH:14]([C:16]2[C:21](=[O:22])[NH:20][N:19]3[C:23]([C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=4[F:32])=[N:24][N:25]=[C:18]3[CH:17]=2)[CH2:13]1)C1C=CC=CC=1.C([O-])=O.[NH4+]>CO>[F:32][C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][C:26]=1[C:23]1[N:19]2[NH:20][C:21](=[O:22])[C:16]([CH:14]3[CH2:13][CH:12]([OH:11])[CH2:15]3)=[CH:17][C:18]2=[N:25][N:24]=1
Reactant: O=c1[nH]n2c(-c3ccccc3F)nnc2cc1C1CC(OCc2ccccc2)C1
Agent: O=C[O-]
Agent: [NH4+]
Solvent: O=CO
Solvent: CO
Product: O=c1[nH]n2c(-c3ccccc3F)nnc2cc1C1CC(O)C1
Temperature: 60 °C
Reaction time: 2 h

Procedure:
Formic acid (8 ml) was added to a solution of 7-(3-benzyloxycyclobutyl)-3-(2-fluorophenyl)-1,2,4-triazolo[4,3-b]pyridazin-6-one (0.64 g, 1.64 mmol) and ammonium formate (1.034 g, 16.4 mmol) in methanol (40 ml). The solution was flushed with nitrogen and 10% palladium on carbon (0.3 g) was added. The resulting solution was stirred under an atmosphere of nitrogen for 2 hours at 60° C. The reaction was cooled, filtered, and concentrated under vacuum. The residue was purified by chromatography on silica using 0-10% methanol/dichloromethane as eluent to give the required product as a white solid. Data for the title compound: 1H NMR (360 MHz, DMSO), cis and traits isomers present in 5.5:1 ratio, δ1.89-1.98 (1.7H, m), 2.21-2.29 (0.3H, m), 2.40-2.48 (0.3H, m), 2.55-2.65 (1.7H, m), 2.88-3.00 (1H, m), 4.06-4.14 (0.85H, m), 4.20-4.30 (0.15H, m), 7.38-7.47 (2H, m), 7.60-7.65 (1H, m), 7.80-7.85 (1H, m), 7.97 (0.85H, s), 8.12 (0.15H, s); MS (ES+) m/e 301 [MH]+.
Reaction SMILES: C([O:3][C:4](=O)[C@@:5]([NH:25]C(OC(C)(C)C)=O)([CH3:24])[CH2:6][CH2:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:19]=[CH:18][C:17]([CH2:20][CH2:21][CH2:22][CH3:23])=[CH:16][CH:15]=2)=[CH:10][CH:9]=1)C.[BH4-].[Li+].C(OCC)(=O)C>C(OCC)C>[NH2:25][C@:5]([CH3:24])([CH2:6][CH2:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:15]=[CH:16][C:17]([CH2:20][CH2:21][CH2:22][CH3:23])=[CH:18][CH:19]=2)=[CH:10][CH:9]=1)[CH2:4][OH:3]
Reactant: CCCCc1ccc(-c2ccc(CC[C@@](C)(NC(=O)OC(C)(C)C)C(=O)OCC)cc2)cc1
Agent: [BH4-]
Agent: [Li+]
Solvent: CCOC(C)=O
Solvent: CCOCC
Product: CCCCc1ccc(-c2ccc(CC[C@@](C)(N)CO)cc2)cc1
Temperature: 25 °C
Reaction time: 9 h

Procedure:
To a solution of (R)-2-tert-butoxycarbonylamino-4-(4′-butyl-biphenyl-4-yl)-2-methyl-butyric acid ethyl ester (22 mg) in diethylether is added lithium borohydride (20 mg). After stirring the suspension for 9 h at RT, ethyl acetate (5 ml) is added and the mixture is washed with water (2 ml), 1M citric acid (2×2 ml) and water (2 ml). The organic phase is dried over MgSO4, the solvent removed and the crude material purified by chromatography using diethyl ether/hexane (1/1) (Rf=0.31, MS: (ES+): 412.6 (M+H)+). The purified product is dissolved in dioxane containing 4M HCl and left at room temperature for 16 h. After lyophilisation, the desired compound is obtained as a white solid in the hydrochloride salt form (Rf=0.48 in DCM/methanol 100/15, MS: (ES+): 312.5 (M+H)+).
Reaction SMILES: [NH2:1][C:2]1[C:3]([I:18])=[C:4]([C:8]([I:17])=[C:9]([N:12]([CH3:16])[C:13](=[O:15])[CH3:14])[C:10]=1[I:11])[C:5]([OH:7])=O.S(Cl)(Cl)=O.[CH3:23][NH:24][CH3:25].[OH-].[Na+]>O>[NH2:1][C:2]1[C:3]([I:18])=[C:4]([C:8]([I:17])=[C:9]([N:12]([CH3:16])[C:13](=[O:15])[CH3:14])[C:10]=1[I:11])[C:5]([N:24]([CH3:25])[CH3:23])=[O:7]
Reactant: CC(=O)N(C)c1c(I)c(N)c(I)c(C(=O)O)c1I
Reactant: CNC
Agent: [Na+]
Agent: [OH-]
Solvent: O=S(Cl)Cl
Solvent: O
Product: CC(=O)N(C)c1c(I)c(N)c(I)c(C(=O)N(C)C)c1I

Procedure:
The acid chloride (16.23 g.) prepared from 3-amino-5-(N-methylacetamido)-2,4,6-triiodobenzoic acid and thionyl chloride was interacted with 60 ml. of dimethylamine (40% in water), 20 ml. of 35% aqueous sodium hydroxide and 30 ml. of water. The product was isolated and recrystallized from isopropyl alcohol to give 3-amino-2,4,6-triiodo-5-(N-methylacetamido)N,N-dimethylbenzamide as a pale yellow solid, m.p. 235°-240° C.
Reaction SMILES: [CH2:1]([C:3]1([C:18]2[CH:19]=[C:20]([NH2:24])[CH:21]=[CH:22][CH:23]=2)[CH:8]2[CH:4]1[CH2:5][N:6]([CH2:9][CH2:10][CH2:11][C:12]1C=CC=[CH:14][CH:13]=1)[CH2:7]2)[CH3:2].[CH2:25]([S:27](Cl)(=[O:29])=[O:28])[CH3:26]>N1C=CC=CC=1>[CH2:1]([C:3]1([C:18]2[CH:19]=[C:20]([NH:24][S:27]([CH2:25][CH3:26])(=[O:29])=[O:28])[CH:21]=[CH:22][CH:23]=2)[CH:8]2[CH:4]1[CH2:5][N:6]([CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14])[CH2:7]2)[CH3:2]
Reactant: CCS(=O)(=O)Cl
Reactant: CCC1(c2cccc(N)c2)C2CN(CCCc3ccccc3)CC21
Solvent: c1ccncc1
Product: CCCCCCN1CC2C(C1)C2(CC)c1cccc(NS(=O)(=O)CC)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 25.4 %

Procedure:
To a solution of 3-[6-ethyl-3-(3-phenylpropyl)-3-azabicyclo[3.1.0]hex-6-yl]phenylamine (Preparation 20, 500 mg, 1.56 mmol) in pyridine (5 ml), at 0° C. under nitrogen was added dropwise over 5 minutes ethanesulfonylchloride (0.25 ml, 0.34 g, 2.6 mmol). The mixture was allowed to warm to room temperature and was stirred for 18 hours. The mixture was concentrated in vacuo and the residue was purified by silica (25 g) column chromatography eluting with 50:50:1 ethyl acetate:hexane:ammonia solution (0.880). Product-containing fractions were combined and concentrated in vacuo to give the title compound as a pale yellow oil (150 mg, 31%).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([CH3:10])=[C:6]([O:11][CH3:12])[CH:5]=1)([O-:3])=[O:2].Br[N:14]1[C:18](=O)[CH2:17][CH2:16][C:15]1=O.N1CCCC1>N(C(C)(C)C#N)=NC(C)(C)C#N.C(Cl)(Cl)(Cl)Cl>[N+:1]([C:4]1[CH:9]=[CH:8][C:7]([CH2:10][N:14]2[CH2:18][CH2:17][CH2:16][CH2:15]2)=[C:6]([O:11][CH3:12])[CH:5]=1)([O-:3])=[O:2]
Reactant: COc1cc([N+](=O)[O-])ccc1C
Reactant: O=C1CCC(=O)N1Br
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)(Cl)Cl
Solvent: C1CCNC1
Product: COc1cc([N+](=O)[O-])ccc1CN1CCCC1
Temperature: 0 °C
Reaction time: 1 h
Yield: 80 %

Procedure:
A mixture of 4-nitro-2-methoxytoluene (5 g, 30 mmol), N-bromosuccinimide (5.3 g, 30 mmol), azobisisobutyronitrile (AIBN, 10 mg) and CCl4 was refluxed for 60 h. The reaction mixture was cooled to 0° C., filtered through diatomaceous earth and concentrated under vacuum. The resulting oil was redissolved in THF (50 mL) and added portionwise to a cold (0° C.) stirred solution of pyrrolidine (10.65 g, 150 mmol). Afterwards, the cooling bath was removed and the reaction was stirred at ambient temperature for 1 h. It was then concentrated to an oil, diluted with 100 mL saturated aqueous NaHCO3 and 50 mL brine. Following extraction three times with 125 mL EtOAc, the combined organic layer was dried over MgSO4 and concentrated to 6.5 g of an oil. Purification by chromatography (SiO2 ; 30% EtOAc in hexanes) yielded 5.7 g (24 mmol, 80%) of the desired compound as an oil.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.[Mg].[O:12]1[CH2:15][CH2:14][CH2:13]1.[NH4+].[Cl-]>C1COCC1>[C:5]1([CH2:4][CH2:3][CH2:2][CH2:15][CH2:14][CH2:13][OH:12])[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1
Reactant: C1COC1
Reactant: BrCCCc1ccccc1
Agent: [Cl-]
Agent: [Mg]
Agent: [NH4+]
Solvent: C1CCOC1
Product: OCCCCCCc1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 33.8 %

Procedure:
(3-Bromopropyl)benzene (20 g) in THF (75 ml) was added dropwise to magnesium (2.43 g) at a rate to maintain gentle reflux. The mixture was stirred for 2 h at RT and oxetane (10 g) was added dropwise. The resulting suspension was stirred at RT for 2 h and at reflux for 16 h and poured into saturated aqueous NH4Cl (100 ml). The mixture was extracted with ER (3×75 ml) and the dried extract was evaporated to leave a yellow oil. Distillation of the oil gave the title compound as a colourless liquid (6.05 g) b.p. 100°-105°/0.4 mmHg. T.l.c. [O] Rf 0.3.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[N:12]3[CH:13]=[CH:14][C:15]([C:17]([CH3:27])([O:19][Si:20]([CH2:25][CH3:26])([CH2:23][CH3:24])[CH2:21][CH3:22])[CH3:18])=[N:16][C:11]3=[N:10][CH:9]=2)[CH:5]=[CH:4][N:3]=1.[F:28][C:29]1[CH:34]=[C:33]([F:35])[CH:32]=[CH:31][C:30]=1B(O)O>>[F:28][C:29]1[CH:34]=[C:33]([F:35])[CH:32]=[CH:31][C:30]=1[C:2]1[N:7]=[C:6]([C:8]2[N:12]3[CH:13]=[CH:14][C:15]([C:17]([CH3:27])([O:19][Si:20]([CH2:25][CH3:26])([CH2:23][CH3:24])[CH2:21][CH3:22])[CH3:18])=[N:16][C:11]3=[N:10][CH:9]=2)[CH:5]=[CH:4][N:3]=1
Reactant: OB(O)c1ccc(F)cc1F
Reactant: CC[Si](CC)(CC)OC(C)(C)c1ccn2c(-c3ccnc(Cl)n3)cnc2n1
Product: CC[Si](CC)(CC)OC(C)(C)c1ccn2c(-c3ccnc(-c4ccc(F)cc4F)n3)cnc2n1

Procedure:
3-(2-Chloropyrimidin-4-yl)-7-(1-methyl-1-triethylsilanyloxyethyl)-imidazo[1,2-α]pyrimidine (250 mg, 0.62 mmol) and 2,4-difluorobenzeneboronic acid (196 mg, 1.24 mmol) were reacted together as described in Example 61. Purification by column chromatography on silica using 2.5% MeOH/CH2Cl2 gave 3-[2-(2,4-difluorophenyl)pyrimidin-4-yl]-7-(1-methyl-1-triethylsilanyloxyethyl)imidazo[1,2-α]pyrimidine: m/z (ES+) 482 (M+H+).
Reaction SMILES: Cl[C:2]1[N:10]=[C:9]([NH2:11])[N:8]=[C:7]2[C:3]=1[N:4]=[CH:5][NH:6]2.[IH:12]>O>[I:12][C:2]1[N:10]=[C:9]([NH2:11])[N:8]=[C:7]2[C:3]=1[N:4]=[CH:5][NH:6]2
Reactant: I
Reactant: Nc1nc(Cl)c2nc[nH]c2n1
Solvent: O
Product: Nc1nc(I)c2nc[nH]c2n1
Reaction time: 1.5 h

Procedure:
6-Chloro-9H-purin-2-amine (5.0 g., 29.5 mmole) was added to 47% hydrogen iodide (61 ml., 12.2 ml./g.) chilled in an ice bath. After 1.5 hours, water (61 ml.) was added and the mixture stirred in an ice- bath for 30 minutes. The yellow solid was filtered out and the filter cake was washed with water. The wet solid was transferred to a beaker and the residue in the funnel was washed into the beaker with water (30 ml.). 6M Sodium hydroxide (7 ml.) was added with stirring until all the solid had dissolved (pH 14). The solution was added to boiling water (30 ml.) containing acetic acid (3 ml.). The mixture was boiled briefly and allowed to stand at room temperature for one hour. The product was filtered off, washed with water, and dried under vacuum overnight to give 6.88 g. of the desired product; m.p. about 240° C. (dec.).
Reaction SMILES: [CH2:1]([Si:3]([CH2:7][CH3:8])([CH2:5][CH3:6])Cl)[CH3:2].[O:9]1[CH2:13][CH2:12][NH:11][C:10]1=[O:14]>>[CH2:1]([Si:3]([CH2:7][CH3:8])([CH2:5][CH3:6])[N:11]1[CH2:12][CH2:13][O:9][C:10]1=[O:14])[CH3:2]
Reactant: O=C1NCCO1
Reactant: CC[Si](Cl)(CC)CC
Product: CC[Si](CC)(CC)N1CCOC1=O

Procedure:
Following the previous example, but replacing the trimethylchlorosilane with triethylchlorosilane (63.3 g; 0.42 mol) and operating under similar conditions, the result is the compound of the above heading; a colorless fluid liquid, obtained with a similar yield. 2-oxazolidinone, calculated: 42.82%; found; 42.70%. Distills at 100°C between 2 and 4 mm.
Reaction SMILES: [H-].[Na+].[C:3](=[O:10])([O:7][CH2:8][CH3:9])OCC.[Br:11][C:12]1[CH:17]=[CH:16][C:15]([C:18](=[O:20])[CH3:19])=[CH:14][CH:13]=1.Cl>C(OCC)C.C(O)C>[Br:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]([CH2:19][C:3]([O:7][CH2:8][CH3:9])=[O:10])=[O:20])=[CH:14][CH:13]=1
Reactant: CC(=O)c1ccc(Br)cc1
Reactant: CCOC(=O)OCC
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CCO
Solvent: CCOCC
Product: CCOC(=O)CC(=O)c1ccc(Br)cc1
Temperature: 0 °C
Yield: 74.5 %

Procedure:
Sodium hydride (5.2 g, 0.21 mol) was suspended in dry diethyl ether and cooled to 0° C. Diethyl carbonate (17.7 g, 0.15 mol) was added and the contents were stirred for ten minutes, at which time dropwise addition of p-bromoacetophenone (19.9 g, 0.1 mol) in diethyl ether (50 mL) and ethanol (0.2 mL) was initiated. Addition was continued for twenty minutes; the solution was refluxed for three hours, cooled to room temperature and poured onto cold 10% aqueous hydrochloric acid (250 mL). The aqueous solution was extracted twice with diethyl ether (750 mL) and the combined extracts were washed successively with water (250 mL), brine (250 mL) and dried (MgSO4). The solvent was removed in vacuo and the residue was purified on silica gel, eluting with hexane/ethyl acetate (4/1), to afford 20.2 g (74%) of the title compound as an oil. 1HNMR (60MHz, CDCl3): δ1.2 (t,3H), 3.9 (s, 2H), 4.1 (q, 2H), 7.55 (d, J=7 Hz, 2H), 7.75 (d, J=2 Hz, 2H).
Reaction SMILES: C[Si]([N-][Si](C)(C)C)(C)C.[Li+].[O:11]=[C:12]1[NH:18][C:17]2[CH:19]=[CH:20][CH:21]=[CH:22][C:16]=2[NH:15][CH2:14][C@@H:13]1[NH:23][C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25].Br[CH2:32][C:33]([O:35][CH3:36])=[O:34]>C1COCC1.CCOC(C)=O>[CH3:36][O:35][C:33](=[O:34])[CH2:32][N:18]1[C:17]2[CH:19]=[CH:20][CH:21]=[CH:22][C:16]=2[NH:15][CH2:14][C@H:13]([NH:23][C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[C:12]1=[O:11]
Reactant: CC(C)(C)OC(=O)N[C@H]1CNc2ccccc2NC1=O
Reactant: COC(=O)CBr
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COC(=O)CN1C(=O)[C@@H](NC(=O)OC(C)(C)C)CNc2ccccc21
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 83 %

Procedure:
A 1.0 M solution of lithium bis(trimethylsilyl)amide (3.4 ml, 3.4 mmol) in THF was added dropwise to a −78° C. solution of (3S)-2-oxo-3-tert-butoxycarbonylamino-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine (0.94 g, 3.38 mmol) in 20 ml of anhydrous THF and stirred for 30 min. Methyl bromoacetate (0.44 ml, 4 mmol) was added dropwise to the reaction mixture then warmed to RT. The reaction was diluted with 100 ml of EtOAc and washed with 0.3N KHSO4 (50 ml), H2O (2×50 ml, and brine. The combined organics were dried over anhydrous Na2SO4, filtered, and evaporated to afforded a gum that was purified by flash chromatography eluting with 3:7 EtOAc/Hex. to give 0.98 g (83%) of the title compound as a white solid. 1H NMR (CDCl3) δ7.15-7.07 (2H, m), 6.98-6.94 (1H, m), 6.88-6.84 (1H, d), 5.62-5.55 (1H, d), 4.71-4.65 (1H, d), 4.65-4.6 (1H, m), 4.33-4.27 (1H, d), 3.96-3.90 (1H, m), 3.78 (3H, s), 3.44-3.37 (1H, m), 1.4 (9H, s).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:10])[CH3:9])=[CH:4][CH:3]=1.[O:11]1[CH:15]=[CH:14][CH:13]=[C:12]1[CH:16]=O.CO[Na].Cl>CO>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:10])[CH:9]=[CH:16][C:12]2[O:11][CH:15]=[CH:14][CH:13]=2)=[CH:4][CH:3]=1
Reactant: O=Cc1ccco1
Reactant: CC(=O)c1ccc(Br)cc1
Agent: CO[Na]
Agent: Cl
Solvent: CO
Product: O=C(C=Cc1ccco1)c1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 57.1 %

Procedure:
To a solution of 4-bromophenylethanone (112.6 g, 570 mmol) and furan-2-carbaldehyde (58.5 g, 610 mmol) in methanol (1.5 L) was added CH3ONa (31 g, 570 mmol) over 10 min and the reaction solution was stirred at room temperature overnight. The reaction mixture was neutralized with conc. HCl to pH=7, and the solvent was removed under reduced pressure. To the resultant residue was added EA and water. The aqueous layer was extracted with EA for 3 times. The combined layers were washed with brine, dried over MgSO4, concentrated and purified by silica gel column chromatography (PE:EA=10:1) to afford 1-(4-bromophenyl)-3-(furan-2-yl)prop-2-en-1-one (5A) as a yellow solid (90.2 g, 65%).
Reaction SMILES: [CH3:1][N:2]1[C:8](=O)[C:7]2[CH:10]=[CH:11][S:12][C:6]=2[N:5]2[CH:13]=[N:14][C:15](C(O)=O)=[C:4]2[CH2:3]1.C(=O)=[O:20]>ClC(Cl)Cl>[CH3:1][N:2]1[CH2:8][C:7]2[CH:10]=[CH:11][S:12](=[O:20])[C:6]=2[N:5]2[CH:13]=[N:14][CH:15]=[C:4]2[CH2:3]1
Reactant: O=C=O
Reactant: CN1Cc2c(C(=O)O)ncn2-c2sccc2C1=O
Solvent: ClC(Cl)Cl
Product: CN1CC2=C(n3cncc3C1)S(=O)C=C2

Procedure:
27 g of 5,6-dihydro-5-methyl-4-oxo-4H-imidazo[1,5-a]thieno[3,2-f][1,4]diazepine-7-carboxylic acid was immersed in a flask filled with argon in a heating bath pre-heated to 280°. The substance melts with decarboxylation. After completion of the evolution of carbon dioxide (about 7 to 8 min.) the flask was cooled slightly. Even before it had solidified, the reaction mixture was mixed with 250 ml of trichloromethane. The solution was evaporated in a vacuum and the residue was recrystallized from ethyl acetate/diisopropyl ether. There was obtained 5,6-dihydro-5-methyl-4H-imidazo[1,5-a]thieno[3,2-f][1,4]diazepine-one of melting point 160°-163°. After recrystallization from ethyl acetate the melting point was 163°-164°.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4](Cl)[CH:3]=1.[C@H:9]1([NH2:16])[CH2:14][CH2:13][C@H:12]([NH2:15])[CH2:11][CH2:10]1>CS(C)=O>[Br:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([NH:15][C@H:12]2[CH2:13][CH2:14][C@H:9]([NH2:16])[CH2:10][CH2:11]2)[CH:3]=1
Reactant: Clc1cc(Br)ccn1
Reactant: N[C@H]1CC[C@H](N)CC1
Solvent: CS(C)=O
Product: N[C@H]1CC[C@H](Nc2cc(Br)ccn2)CC1
Temperature: 100 °C

Procedure:
A mixture of 4-bromo-2-chloropyridine (1500 mg, 7.79 mmol), DMSO (15 ml), and trans-cyclohexane-1,4-diamine (4450 mg, 39.0 mmol) was stirred at 100° C. until the formation of the product, as indicated by LCMS. The reaction mixture was cooled to room temperature, filtered and purified by prep LC, and lyapholized to yield 393 mg of the title compound as a TFA salt. LCMS (m/z): 270.2/272.2 (MH+), retention time=0.31 min.
Reaction SMILES: Cl.[OH:2][C:3]1[CH:11]=[CH:10][C:6]([C:7]([OH:9])=[O:8])=[CH:5][N:4]=1.[CH3:12]O>>[CH3:12][O:8][C:7](=[O:9])[C:6]1[CH:10]=[CH:11][C:3]([OH:2])=[N:4][CH:5]=1
Reactant: O=C(O)c1ccc(O)nc1
Reactant: CO
Agent: Cl
Product: COC(=O)c1ccc(O)nc1

Procedure:
To 500 ml of methyl alcohol, cooled to 0°-5° C. is added HCl gas over 30 minutes. The solution is allowed to reach room temperature and 50 g of 6-hydroxynicotinic acid added. The reaction mixture is stirred at reflux for 2 days. The methyl alcohol is removed in vacuo and the residue suspended in 200 ml of water and poured into 300 ml of saturated aqueous NaHCO3. The insoluble crystals are collected by filtration, washed with 500 ml of water and dried under vacuum at 60° C. to give 53.9 g of the desired product
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][N:11]=[C:10]([CH3:13])[C:9]=2[NH2:14])=[CH:4][CH:3]=1.[CH2:15]([N:22]1[CH2:27][CH2:26][C:25](=O)[CH2:24][CH2:23]1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.C(O)(=O)C.C([BH3-])#N.[Na+]>CO>[CH2:15]([N:22]1[CH2:27][CH2:26][CH:25]([NH:14][C:9]2[C:10]([CH3:13])=[N:11][O:12][C:8]=2[C:5]2[CH:4]=[CH:3][C:2]([Br:1])=[CH:7][CH:6]=2)[CH2:24][CH2:23]1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: O=C1CCN(Cc2ccccc2)CC1
Reactant: Cc1noc(-c2ccc(Br)cc2)c1N
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: Cc1noc(-c2ccc(Br)cc2)c1NC1CCN(Cc2ccccc2)CC1
Temperature: 0 °C

Procedure:
5-(4-Bromo-phenyl)-3-methyl-isoxazol-4-ylamine (0.500 g, 1.73 mmol) and 1-benzyl-piperidin-4-one were mixed with acetic acid (0.200 mL) in MeOH (8 mL). The reaction was cooled to 0° C. and stirred for one hour before sodium cyanoborohydride (0.108 g, 1.74 mmol) was added. The reaction was allowed to warm to room temperature and was monitored by analytical LCMS. When complete, the reaction was quenched with aqueous sodium bicarbonate then submitted to standard workup procedures. The crude material was purified by silica gel chromatography (0-100% EtOAc in hexanes) to afford the title compound
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8](Cl)(=[O:10])=[O:9].[NH2:12][C:13]1[C:14]2[C:21]([C:22]([C:24]3[CH:29]=[CH:28][CH:27]=[C:26]([NH2:30])[N:25]=3)=[O:23])=[CH:20][N:19]([CH:31]([CH3:33])[CH3:32])[C:15]=2[N:16]=[CH:17][N:18]=1>N1C=CC=CC=1>[NH2:12][C:13]1[C:14]2[C:21]([C:22]([C:24]3[N:25]=[C:26]([NH:30][S:8]([C:3]4[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=4[F:1])(=[O:10])=[O:9])[CH:27]=[CH:28][CH:29]=3)=[O:23])=[CH:20][N:19]([CH:31]([CH3:33])[CH3:32])[C:15]=2[N:16]=[CH:17][N:18]=1
Reactant: O=S(=O)(Cl)c1ccccc1F
Reactant: CC(C)n1cc(C(=O)c2cccc(N)n2)c2c(N)ncnc21
Solvent: c1ccncc1
Product: CC(C)n1cc(C(=O)c2cccc(NS(=O)(=O)c3ccccc3F)n2)c2c(N)ncnc21
Temperature: 40 °C
Yield: 38.8 %

Procedure:
2-Fluoro-benzenesulfonyl chloride (72 mg, 0.37 mmol) was added to a solution of (4-Amino-7-isopropyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-(6-amino-pyridin-2-yl)-methanone (100 mg 0.34 mmol) in pyridine (2 mL). The resulting solution was heated to 40° C. in a sealed tube for 12 h. The reaction mixture was concentrated in vacuo and the residue was triturated with MeOH and filtered to provide a crude yellow solid. Purification by flash column chromatography (hexanes/ethyl acetate 5:5-1:9) afforded the title compound as a yellow solid (60 mg, 40%). MS: 455.1 (MH+); HPLC Rf: 4.67 min. (HPLC method 4); HPLC purity: 100%.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10]([CH2:13][C:14]#[N:15])[S:11][CH:12]=2)=[CH:4][CH:3]=1.CO.Cl>O1CCCC1>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:9]=[C:10]([CH2:13][CH2:14][NH2:15])[S:11][CH:12]=2)=[CH:6][CH:7]=1
Reactant: N#CCc1nc(-c2ccc(F)cc2)cs1
Agent: Cl
Solvent: C1CCOC1
Solvent: CO
Product: NCCc1nc(-c2ccc(F)cc2)cs1
Temperature: 25 °C
Reaction time: 1 h
Yield: 25 %

Procedure:
2-(4-(4-fluorophenyl)thiazol-2-yl)acetonitrile (400 mg, 1.83 mmol) was dissolved in tetrahydrofuran (10 mL) at room temperature. Borane tetrahydrofuran complex solution (1M in tetrahydrofuran, 9.16 mL, 9.16 mmol) was added and the reaction mixture was stirred for 1 h at room temperature. The reaction mixture was cooled to 0° C. and quenched with methanol (5 eq., 0.4 mL). The reaction was allowed to warm to room temperature and 2N HCl was added until the reaction mixture was confirmed acidic by a pH paper. The reaction mixture was then refluxed at 65° C. for 30 min. The reaction mixture was then allowed to cool to room temperature and was concentrated under reduced pressure. The solid obtained was triturated with ether (2×20 mL) and dichloromethane (2×20 mL). The remaining solid was dissolved in water (50 mL) and basified to pH ˜11 with NaOH pellets. The aqueous mixture was then extracted with ether (2×100 mL). The organic layer was dried over anhdrous sodium sulfate and concentrated under reduced pressure to give the crude product, which was used directly without any purification in the next step (100 mg, 25% yield). MS (ESI) m/z: Calculated for C11H11FN2S: 222.06. found: 223.1 (M+H)+.
Reaction SMILES: C(N(C(C)C)CC)(C)C.[CH2:10]([O:14][C:15]1[CH:20]=[C:19](Cl)[N:18]=[CH:17][N:16]=1)[C:11]#[C:12][CH3:13].[Cl:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[SH:29].[Cl-].[NH4+]>C(Cl)(Cl)Cl>[CH2:10]([O:14][C:15]1[CH:20]=[C:19]([S:29][C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=2[Cl:22])[N:18]=[CH:17][N:16]=1)[C:11]#[C:12][CH3:13]
Reactant: CC#CCOc1cc(Cl)ncn1
Reactant: Sc1ccccc1Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: ClC(Cl)Cl
Solvent: CCN(C(C)C)C(C)C
Product: CC#CCOc1cc(Sc2ccccc2Cl)ncn1
Temperature: 25 °C
Reaction time: 7 h
Yield: 64.1 %

Procedure:
To 5 ml of chloroform were added 0.95 ml of diisopropylethylamine, 0.5 g of 4-(2-butynyloxy)-6-chloropyrimidine, and 0.42 g of 2-chlorothiophenol, followed by stirring at room temperature for 7 hours. The reaction mixture was then poured into a saturated aqueous ammonium chloride solution and extracted three times with chloroform. The chloroform layers were combined, washed with water, dried over anhydrous magnesium sulfate, and then concentrated. The residue was subjected to silica gel column chromatography to give 0.51 g of 4-(2-butynyloxy)-6-(2-chlorothiophenoxy)pyrimidine (the present compound (142)).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:7][C:8]([O:10][CH2:11]C)=[O:9].CO[CH:15](OC)[N:16]([CH3:18])[CH3:17].[NH4+].[Cl-]>CCOC(C)=O>[CH3:15][N:16]([CH3:18])[CH:17]=[C:7]([C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=1)[C:8]([O:10][CH3:11])=[O:9]
Reactant: COC(OC)N(C)C
Reactant: CCOC(=O)Cc1ccccn1
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCOC(C)=O
Product: COC(=O)C(=CN(C)C)c1ccccn1
Temperature: 130 °C

Procedure:
10 g of ethyl 2-(2-pyridinyl)acetate, 39 ml of dimethoxy-N,N-dimethylmethanamine and 1.5 ml of N,N,N′,N′-tetramethylenediamine are mixed and the mixture is heated at 130° C. for 18 hours. The mixture is taken up in 120 ml of a mixture of equal volumes of AcOEt and of a saturated NH4Cl solution. The organic phase is separated by settling, washed with a saturated NaCl solution, dried over Na2SO4 and evaporated to produce the expected product in the form of an oil.