Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]1[N:11]=[C:6]2[CH:7]=[N:8][CH:9]=[CH:10][N:5]2[N:4]=1.[Br:14]Br>C(O)C>[BrH:14].[Br:14][C:10]1[N:5]2[N:4]=[C:3]([C:2]([F:12])([F:1])[F:13])[N:11]=[C:6]2[CH:7]=[N:8][CH:9]=1
Reactant: BrBr
Reactant: FC(F)(F)c1nc2cnccn2n1
Solvent: CCO
Product: Br
Product: FC(F)(F)c1nc2cncc(Br)n2n1
Reaction time: 0.33 h

Procedure:
A solution of 500 mg (2.66 mmol) of 2-(trifluoromethyl)[1,2,4]triazolo[1,5-a]pyrazine (Intermediate 7, Step C) in 2.5 mL of dry ethanol, stirred at 0° C. under protection from moisture, was treated dropwise with 0.151 mL (2.92 mmol) of bromine. After 20 minutes at 0° C., the solution was concentrated and dried to give the title compound as an orange solid. LC-MS 267, 269 (M+1).
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]2[CH2:14][CH2:13][CH:12]([C:15]([OH:17])=O)[CH2:11][CH2:10]2)=[CH:5][C:4]=1[C:18]1[NH:26][C:21]2[CH:22]=[N:23][CH:24]=[CH:25][C:20]=2[N:19]=1.CN(C(ON1N=N[C:37]2[CH:38]=[CH:39][CH:40]=[N:41][C:36]1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)CC)C.N1CCCCC1>ClCCl>[Cl:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]2[CH2:14][CH2:13][CH:12]([C:15]([N:41]3[CH2:36][CH2:37][CH2:38][CH2:39][CH2:40]3)=[O:17])[CH2:11][CH2:10]2)=[CH:5][C:4]=1[C:18]1[NH:26][C:21]2[CH:22]=[N:23][CH:24]=[CH:25][C:20]=2[N:19]=1
Reactant: O=C(O)C1CCN(c2ccc(Cl)c(-c3nc4ccncc4[nH]3)c2)CC1
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: C1CCNCC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(C1CCN(c2ccc(Cl)c(-c3nc4ccncc4[nH]3)c2)CC1)N1CCCCC1
Temperature: 35 °C
Yield: 37.7 %

Procedure:
Method C—Step f A mixture of 1-[4-Cloro-3-(3H-imidazo[4,5-c]pyridin-2-yl)-phenyl]-piperidine-4-carboxylic acid hydrochloride (0.09 g, 0.25 mmol), HATU (0.10 g, 0.26 mmol), triethylamine (TEA) (0.08 mL, 0.55 mmol), piperidine (0.03 g, 0.31 mmol) and dichloromethane (2 mL) was heated at 35° C. overnight. Reaction was cooled to room temperature, washed with ammonium chloride solution (3 mL) and the crude was purified by SCX (eluent: NH3 2N in MeOH) and flash chromatography (eluent: AcOEt:MeOH, 9:1), to obtain 0.04 g of the title compound (37%).
Reaction SMILES: [Br:1][C:2]1[C:7]([O:8][CH:9]([CH3:11])[CH3:10])=[CH:6][C:5]([N:12]2[C:17](=[O:18])[CH:16]=[C:15]([C:19]([F:22])([F:21])[F:20])[NH:14][C:13]2=O)=[C:4]([F:24])[CH:3]=1.P(Cl)(Cl)([Cl:27])=O>N1C=CC=CC=1>[Br:1][C:2]1[C:7]([O:8][CH:9]([CH3:11])[CH3:10])=[CH:6][C:5]([N:12]2[C:17](=[O:18])[CH:16]=[C:15]([C:19]([F:22])([F:21])[F:20])[N:14]=[C:13]2[Cl:27])=[C:4]([F:24])[CH:3]=1
Reactant: CC(C)Oc1cc(-n2c(=O)cc(C(F)(F)F)[nH]c2=O)c(F)cc1Br
Reactant: O=P(Cl)(Cl)Cl
Solvent: c1ccncc1
Product: CC(C)Oc1cc(-n2c(Cl)nc(C(F)(F)F)cc2=O)c(F)cc1Br

Procedure:
using 3-(4-bromo-2-fluoro-5-isopropoxyphenyl)-6-trifluoromethyl-2,4(1H,3H)-pyrimidinedione with phosphorus oxychloride and pyridine there is obtained 1-(4-bromo-2-fluoro-5-isopropoxyphenyl)-2-chloro-4-trifluoromethyl-6(1H)-pyrimidinone, m.p. 102° C.;
Reaction SMILES: [NH2:1][C:2]1[C:7]2[C:8]([C:11]3[CH:16]=[CH:15][C:14]([NH:17][C:18]([C:20]4[N:21]([CH3:29])[C:22]5[C:27]([CH:28]=4)=[CH:26][CH:25]=[CH:24][CH:23]=5)=[O:19])=[C:13]([O:30][CH3:31])[CH:12]=3)=[CH:9][S:10][C:6]=2[C:5](I)=[CH:4][N:3]=1.[CH3:33][N:34]([CH3:44])[C:35]1[CH:36]=[C:37](B(O)O)[CH:38]=[CH:39][CH:40]=1.C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.O>[NH2:1][C:2]1[C:7]2[C:8]([C:11]3[CH:16]=[CH:15][C:14]([NH:17][C:18]([C:20]4[N:21]([CH3:29])[C:22]5[C:27]([CH:28]=4)=[CH:26][CH:25]=[CH:24][CH:23]=5)=[O:19])=[C:13]([O:30][CH3:31])[CH:12]=3)=[CH:9][S:10][C:6]=2[C:5]([C:39]2[CH:38]=[CH:37][CH:36]=[C:35]([N:34]([CH3:44])[CH3:33])[CH:40]=2)=[CH:4][N:3]=1
Reactant: CN(C)c1cccc(B(O)O)c1
Reactant: COc1cc(-c2csc3c(I)cnc(N)c23)ccc1NC(=O)c1cc2ccccc2n1C
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Product: COc1cc(-c2csc3c(-c4cccc(N(C)C)c4)cnc(N)c23)ccc1NC(=O)c1cc2ccccc2n1C
Reaction time: 0.42 h
Yield: 20.3 %

Procedure:
A mixture of 1-Methyl-1H-indole-2-carboxylic acid [4-(4-amino-7-iodo-thieno[3,2-c]pyridin-3-yl)-2-methoxy-phenyl]-amide (0.100 g, 0.18 mmol) in 1,2-dimethoxyethane (3 mL) and water (1.5 mL) was reacted with 3-(dimethylamino)phenylboronic acid (0.045 g, 0.27 mmol), sodium carbonate (0.06 g, 0.54 mmol) and tetrakis triphenylphosphine palladium (0) (0.017 g, 0.01 mmol) at reflux for two hours. The solvent was removed in vacuo and the residue was purified by preparative RP-HPLC (Hypersil-HS 100 A, C18, 8 μm, 100 Å, 25 cm; 5% acetonitrile-0.1M ammonium acetate 5-100% acetonitrile-0.1M ammonium acetate over 25 min, 21 ml/min). The acetonitrile was removed in vacuo and the aqueous mixture was lyophilized to provide the title compound (20 mg) as an off-white powder. 1H NMR (DMSO-d6, 400 MHz) δ 9.52 (s, 1H), 8.01 (t, 1H), 7.94 (s, 1H), 7.72 (d, 1H), 7.58 (m, 2H), 7.34 (m, 3H), 7.23 (s, 1H), 7.16 (t, 1H), 7.10 (d, 1H), 6.97 (s, 1H), 6.95 (d, 1H), 6.79 (d, 1H), 5.56 (bs, 2H), 4.04 (s, 3H), 3.92 (s, 3H), 2.97 (s, 6H); LCMS (Conditions b), Rt=6.22 min, MS m/e: 548 (M+H)+.
Reaction SMILES: [CH3:1][S:2]([C:4]([S:16][CH3:17])=[CH:5][C:6]1[CH:11]=[CH:10][C:9]([CH2:12][CH:13]([CH3:15])[CH3:14])=[CH:8][CH:7]=1)=O.C(N(CC)CC)C.S(Cl)([Cl:27])=O>C(Cl)(Cl)Cl>[CH3:1][S:2][C:4]([S:16][CH3:17])=[C:5]([Cl:27])[C:6]1[CH:11]=[CH:10][C:9]([CH2:12][CH:13]([CH3:15])[CH3:14])=[CH:8][CH:7]=1
Reactant: CSC(=Cc1ccc(CC(C)C)cc1)S(C)=O
Reactant: O=S(Cl)Cl
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: CSC(SC)=C(Cl)c1ccc(CC(C)C)cc1
Yield: 83.8 %

Procedure:
1-Methylsulfinyl-1-methylthio-2-(p-isobutylphenyl)ethylene (701 mg) was dissolved in 2 ml of chloroform, and 0.50 ml of triethylamine was added. With stirring under ice cooling, 5 ml of a chloroform solution of 380 mg of thionyl chloride was added over the course of 10 minutes. The mixture was further stirred for 30 minutes under ice cooling, and chloroform was added in an amount sufficient to adjust the total amount of the mixture to 30 ml. The mixture was then washed twice with 10 ml of water. The organic layer was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and chromatographed on a Florisil (chromatographic magnesium silicate) column using benzene as an eluent to afford 628 mg of 1,1-bis (methylthio)-2-chloro-2-(p-isobutylphenyl) ethylene as a colorless oil in a yield of 84%.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([NH2:16])[CH2:11][C:10]([O:14][CH3:15])([O:12][CH3:13])[CH2:9]2)=[CH:4][CH:3]=1.[O:17]=[C:18]1[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[C:20](=[O:27])N1C(OCC)=O.C(N(CC)CC)C>C(Cl)(Cl)Cl>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2([N:16]3[C:18](=[O:17])[C:26]4[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=4)[C:20]3=[O:27])[CH2:11][C:10]([O:14][CH3:15])([O:12][CH3:13])[CH2:9]2)=[CH:6][CH:7]=1
Reactant: CCOC(=O)N1C(=O)c2ccccc2C1=O
Reactant: COC1(OC)CC(N)(c2ccc(Br)cc2)C1
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: COC1(OC)CC(c2ccc(Br)cc2)(N2C(=O)c3ccccc3C2=O)C1
Temperature: 70 °C
Yield: 40.6 %

Procedure:
A mixture of 1-(4-bromophenyl)-3,3-dimethoxycyclobutanamine (0.66 g, 2.306 mmol), ethyl 1,3-dioxoisoindoline-2-carboxylate (0.56 g, 2.55 mmol) and triethylamine (1.3 ml, 9.33 mmol) in CHCl3 (15 ml) was heated at 70° C. for 16 h. The reaction mixture was concentrated to as dry as possible. Methanol (˜5 ml) was added. The solution was concentrated to dryness. Methanol (˜5 ml) was added again and the resulted solid was collected by filtration to afford product as a white solid (0.39 g). 1H NMR (500 MHz, CDCl3): 7.70 (dd, 2H), 7.60 (dd, 2H), 7.44 (dd, 2H), 7.37 (dd, 2H), 3.18 (m, 4H), 3.10 (s, 3H), 3.02 (s, 3H).
Reaction SMILES: [NH2:1][C:2]1[C:3]2[C:13]([O:14][CH2:15][CH:16]3[CH2:20][CH2:19][CH2:18][CH2:17]3)=[CH:12][C:11]([CH2:21][CH2:22][NH2:23])=[CH:10][C:4]=2[S:5][C:6]=1[C:7]([NH2:9])=[O:8].C(N(CC)CC)C.[CH3:31][O:32][C:33](Cl)=[O:34]>CN(C=O)C>[CH3:31][O:32][C:33](=[O:34])[NH:23][CH2:22][CH2:21][C:11]1[CH:12]=[C:13]([O:14][CH2:15][CH:16]2[CH2:17][CH2:18][CH2:19][CH2:20]2)[C:3]2[C:2]([NH2:1])=[C:6]([C:7](=[O:8])[NH2:9])[S:5][C:4]=2[CH:10]=1
Reactant: COC(=O)Cl
Reactant: NCCc1cc(OCC2CCCC2)c2c(N)c(C(N)=O)sc2c1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COC(=O)NCCc1cc(OCC2CCCC2)c2c(N)c(C(N)=O)sc2c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 45.6 %

Procedure:
To a stirred solution of 3-amino-6-(2-amino-ethyl)-4-cyclopentylmethoxy-benzo[b]thiophene-2-carboxylic acid amide (11) (HCl salt form, 0.050 g, 0.14 mmol) and triethylamine (0.07 mL, 0.5 mmol) in DMF (1 mL) at 0° C. was added methyl-chloroformate (0.02 mL, 0.3 mmol). The reaction was allowed to warm to room temperature and stirred for 1 h. The reaction was quenched with MeOH and the solvent was removed under reduced pressure. The residue was purified by flash silica gel chromatography to afford the title compound (0.025 g, 47%).
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[C:5]([CH3:12])[N:6]=[CH:7]2.N1C=CC=CC=1.Cl[C:20](OC1C=CC=CC=1)=[O:21].C(N(CC)CC)C.[F:36][C:37]([F:50])([F:49])[C:38]1[CH:39]=[CH:40][C:41]([N:44]2[CH2:47][CH:46]([NH2:48])[CH2:45]2)=[N:42][CH:43]=1>ClCCl>[CH3:12][C:5]1[N:6]=[CH:7][C:8]2[C:3]([CH:4]=1)=[C:2]([NH:1][C:20]([NH:48][CH:46]1[CH2:45][N:44]([C:41]3[CH:40]=[CH:39][C:38]([C:37]([F:36])([F:49])[F:50])=[CH:43][N:42]=3)[CH2:47]1)=[O:21])[CH:11]=[CH:10][CH:9]=2
Reactant: NC1CN(c2ccc(C(F)(F)F)cn2)C1
Reactant: Cc1cc2c(N)cccc2cn1
Reactant: O=C(Cl)Oc1ccccc1
Solvent: ClCCl
Solvent: c1ccncc1
Solvent: CCN(CC)CC
Product: Cc1cc2c(NC(=O)NC3CN(c4ccc(C(F)(F)F)cn4)C3)cccc2cn1
Temperature: 25 °C
Reaction time: 8 h
Yield: 69.9 %

Procedure:
D4 (73 mg, 0.46 mmol) in dry dichloromethane (5 ml) was treated with pyridine (45 ul, 0.55 mmol) and phenyl chloroformate (69 ul, 0.55 mmol). After 1 h triethylamine (128 ul, 0.92 mmol) was added, followed by D7 (100 mg, 0.46 mmol). The reaction mixture was then stirred overnight at ambient temperature. The precipitate was separated by centrifugation, washed with dichloromethane then diethyl ether and then dried to give the title compound as a yellow solid (129 mg). MH+ 402.
Reaction SMILES: [C:1](OC(N1CCNCC1)=O)(C)(C)C.[Cl:14]CC(Cl)=O.C(NC)(C)C.[ClH:24].Cl.CO[CH2:28][CH:29]([NH:31][C:32](=[O:40])[CH2:33][N:34]1[CH2:39][CH2:38][NH:37][CH2:36][CH2:35]1)[CH3:30]>>[ClH:14].[ClH:24].[CH:29]([N:31]([CH3:1])[C:32](=[O:40])[CH2:33][N:34]1[CH2:39][CH2:38][NH:37][CH2:36][CH2:35]1)([CH3:30])[CH3:28]
Reactant: O=C(Cl)CCl
Reactant: COCC(C)NC(=O)CN1CCNCC1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Agent: CNC(C)C
Agent: Cl
Product: CC(C)N(C)C(=O)CN1CCNCC1

Procedure:
N-Isopropyl-N-methyl-2-piperazin-1-yl-acetamide dihydrochloride was prepared from 1-tert-butyloxycarbonyl-piperazine, chloroacetylchloride and N-isopropyl-N-methylamine in an analogous manner as described for the preparation of N-(2-methoxy-1-methyl-ethyl)-2-piperazin-1-yl-acetamide dihydrochloride (example 40).
Reaction SMILES: O=[C:2]([CH:9]1[CH2:18][CH2:17][C:12]2([O:16][CH2:15][CH2:14][O:13]2)[CH2:11][CH2:10]1)[CH2:3][C:4]([O:6]CC)=O.[NH2:19][C:20]1[CH:24]=[CH:23][NH:22][N:21]=1>CCO>[O:13]1[C:12]2([CH2:11][CH2:10][CH:9]([C:2]3[CH:3]=[C:4]([OH:6])[N:21]4[N:22]=[CH:23][CH:24]=[C:20]4[N:19]=3)[CH2:18][CH2:17]2)[O:16][CH2:15][CH2:14]1
Reactant: CCOC(=O)CC(=O)C1CCC2(CC1)OCCO2
Reactant: Nc1cc[nH]n1
Solvent: CCO
Product: Oc1cc(C2CCC3(CC2)OCCO3)nc2ccnn12
Temperature: 100 °C

Procedure:
To a 20 mL scintillation vial containing ethyl 3-oxo-3-(1,4-dioxaspiro[4.5]decan-8-yl)propanoate (11.7 mmol, 3.00 g) is added 3-amino-1H-pyrazole (11.7 mmol, 973 mg). The two oils were mixed and heated neat at 100° C. for 3 hours. The resulting off-white solid was dissolved up in EtOH (100 mL) and reduced in vacuo to remove water formed during cyclization. This solid was used in the next step without further purification.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([CH2:9][CH2:10][CH2:11][CH2:12][NH:13][C:14]2[NH:15][CH:16]=[CH:17][C:18](=[O:20])[N:19]=2)=[N:5][CH:6]=[CH:7][CH:8]=1.[N:21]1[CH:26]=[CH:25][C:24]([CH:27]=[O:28])=[CH:23][CH:22]=1.C(=O)(O)[O-].[K+].O>Cl>[CH3:1][O:2][C:3]1[C:4]([CH2:9][CH2:10][CH2:11][CH2:12][NH:13][C:14]2[NH:15][CH:16]=[C:17]([CH:27]([C:24]3[CH:25]=[CH:26][N:21]=[CH:22][CH:23]=3)[OH:28])[C:18](=[O:20])[N:19]=2)=[N:5][CH:6]=[CH:7][CH:8]=1
Reactant: O=Cc1ccncc1
Reactant: COc1cccnc1CCCCNc1nc(=O)cc[nH]1
Agent: Cl
Agent: O=C([O-])O
Agent: [K+]
Solvent: O
Product: COc1cccnc1CCCCNc1nc(=O)c(C(O)c2ccncc2)c[nH]1

Procedure:
2-[[4-(3-Methoxy-2-pyridyl)butyl]amino]-4-(1H)-pyrimidinone (0.14 g) and pyridine-4-aldehyde (0.06 g) were refluxed in concentrated hydrochloric acid (1 ml) for 5 hours. The solution was cooled and neutralised by the addition of potassium bicarbonate. Water (2 ml) was added, the aqueous layer was then decanted from the red coloured oil which was washed with more water. The oil was subjected to chromatography on silica gel using gradient elution (100% chloroform→2% Methanol in chloroform). The fractions containing the desired product were collected, combined and evaporated under reduced pressure to afford the title compound as an oil; δ(CDCl3) 1.67 (4H, m), 2.80 (2H, t), 3.36 (2H, m), 3.80 (3H, s), 5.72 (1H, s), 7.07 (2H, d), 7.35 (2H, d), 7.49 (1H, s), 7.87 (1H, t), 8.43 (2H, m) ppm.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]2[N:8]([CH:9]=1)[C:7]1[CH:10]=[CH:11][CH:12]=[CH:13][C:6]=1[S:5]2.CN(C)[CH:16]=[O:17].P(Cl)(Cl)(Cl)=O.[OH-].[NH4+]>O>[CH3:1][C:2]1[N:3]=[C:4]2[N:8]([C:9]=1[CH2:16][OH:17])[C:7]1[CH:10]=[CH:11][CH:12]=[CH:13][C:6]=1[S:5]2
Reactant: CN(C)C=O
Reactant: Cc1cn2c(n1)sc1ccccc12
Agent: [NH4+]
Agent: [OH-]
Solvent: O=P(Cl)(Cl)Cl
Solvent: O
Product: Cc1nc2sc3ccccc3n2c1CO
Temperature: 60 °C
Reaction time: 2 h

Procedure:
In 100 ml of n-butanol were heated 30.0 g of 2-aminobenzothiazole and 25.0 g of propargyl bromide at 100° C. for 6 hours. After cooling, the precipitated crystals were taken out by filtration and recrystallized from water to give 40.0 g of the intermediate. Next, the intermediate was added to 250 ml of sodium ethoxideethanol solution (Na, 3.3 g). The mixture was heated under reflux for one hour. After completion of the reaction, the solvent was removed and water was added to the residue. The precipitated crystals were taken out by filtration to give 22.4 g of 2-methylimidazo[2,1-b]benzothiazole. The benzothiazole was added to a mixture of 300 ml of dry dimethylformamide and 30.0 ml of phosphorus oxychloride followed by heating at 60° C. for 6 hours. After completion of the reaction, the reaction mixture was poured onto 1 liter of chilled water and then was neutralized with ammonium hydroxide. Then, the precipitated crystals were taken out by filtration. The thus obtained formyl compound, 20.5 g, was suspended in 300 ml of methanol and 1.5 g of sodium borohydride was added to the suspension followed by stirring at room temperature for 2 hours. After methanol was removed, the residue was treated with 200 ml of water and filtered to give 20.0 g of the title compound.
Reaction SMILES: Br[C:2]1[N:3]=[C:4]([CH:26]([C:40]2[CH:45]=[C:44]([O:46][CH2:47][CH3:48])[CH:43]=[C:42]([O:49][CH:50]([CH3:52])[CH3:51])[C:41]=2[F:53])[NH:27][C:28]2[CH:33]=[CH:32][C:31]([C:34]3[N:38]=[C:37]([CH3:39])[O:36][N:35]=3)=[CH:30][CH:29]=2)[N:5]([C:7]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:6]=1.[CH:54]([C:56]1[CH:61]=[CH:60][CH:59]=[CH:58][C:57]=1B(O)O)=[O:55].C([O-])([O-])=O.[Na+].[Na+]>COCCOC.O>[CH2:47]([O:46][C:44]1[CH:43]=[C:42]([O:49][CH:50]([CH3:51])[CH3:52])[C:41]([F:53])=[C:40]([CH:26]([NH:27][C:28]2[CH:29]=[CH:30][C:31]([C:34]3[N:38]=[C:37]([CH3:39])[O:36][N:35]=3)=[CH:32][CH:33]=2)[C:4]2[N:5]([C:7]([C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=3)([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[C:8]3[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=3)[CH:6]=[C:2]([C:57]3[CH:58]=[CH:59][CH:60]=[CH:61][C:56]=3[CH:54]=[O:55])[N:3]=2)[CH:45]=1)[CH3:48]
Reactant: O=Cc1ccccc1B(O)O
Reactant: CCOc1cc(OC(C)C)c(F)c(C(Nc2ccc(-c3noc(C)n3)cc2)c2nc(Br)cn2C(c2ccccc2)(c2ccccc2)c2ccccc2)c1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: CCOc1cc(OC(C)C)c(F)c(C(Nc2ccc(-c3noc(C)n3)cc2)c2nc(-c3ccccc3C=O)cn2C(c2ccccc2)(c2ccccc2)c2ccccc2)c1
Temperature: 150 °C
Yield: 96.4 %

Procedure:
A suspension of Intermediate 66.3 (100 mg, 0.13 mmol), 2-formyl phenylboronic acid (30 mg, 0.2 mmol), Na2CO3 (56 mg, 0.52 mmol) in 3:1 DME/H2O (4 mL) was degassed and then added in Pd(PPh3)4 (10 mg). The reaction mixture was heated to 150° C. for 8 min in microwave. The reaction mixture was then partionated between EtOAc and sat. NaCl, the organic layer was collected and dried over (Na2SO4), filtered and concentrated. The residue was subject to chromatographic purification (0-30% EtOAc/hexanes gradient), 100 mg (65%) of Intermediate 122.1 was obtained. LCMS (2 min gradient) RT 2.35 min, 798.3 (M+H).
Reaction SMILES: C([Li])CCC.[CH3:6][N:7]1[CH:11]=[CH:10][N:9]=[N:8]1.[CH3:12][C:13]1[C:18]([CH:19]=[O:20])=[CH:17][CH:16]=[C:15]([CH3:21])[N:14]=1>O1CCCC1>[CH3:12][C:13]1[C:18]([CH:19]([C:11]2[N:7]([CH3:6])[N:8]=[N:9][CH:10]=2)[OH:20])=[CH:17][CH:16]=[C:15]([CH3:21])[N:14]=1
Reactant: Cn1ccnn1
Reactant: Cc1ccc(C=O)c(C)n1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: Cc1ccc(C(O)c2cnnn2C)c(C)n1
Reaction time: 0.08 h

Procedure:
A solution of n-butyllithium in hexanes (2.5 M, 22.5 mL, 56.3 mmol) was added dropwise by syringe to a stirring solution of 1-methyl-1H-1,2,3-triazole (5.00 g, 60.2 mmol, prepared according to PCT Int. Appl., 2008098104) in dry tetrahydrofuran (400 mL) at −55° C. The resulting off-white slurry was stirred at −45° C. for 20 min, whereupon a solution of 2,6-dimethyl-pyridine-3-carbaldehyde (8.33 g, 61.7 mmol) in dry tetrahydrofuran (10 mL) was added dropwise by syringe. After 5 min, the cooling bath was removed and the reaction mixture was allowed to slowly warm. After 45 min, saturated aqueous ammonium chloride solution (10 mL) and ethyl acetate (100 mL) were added. The whole was concentrated by rotary evaporation. The residue was dissolved in ethyl acetate (300 mL). The organic solution was washed with saturated aqueous sodium chloride solution (100 mL, containing excess solid sodium chloride). The aqueous layer was extracted with ethyl acetate (2×100 mL). The organic layers were combined and the combined solution was concentrated. Ether (100 mL) was added to the residue and the mixture was sonicated for 20 min during which time a white solid crashed out. The solids were collected by filtration. Ether (100 mL) was added to the collected solids and the mixture sonicated a second time. After 20 min, the mixture was filtered and the solids were collected to provide the title compound as a fine powder.
Reaction SMILES: [C:1]([S:4][CH:5]1[CH2:10][CH2:9][N:8](C(OC(C)(C)C)=O)[CH2:7][CH2:6]1)(=[O:3])[CH3:2].C(OCC)(=O)C.[ClH:24]>C(OCC)(=O)C>[ClH:24].[C:1]([S:4][CH:5]1[CH2:10][CH2:9][NH:8][CH2:7][CH2:6]1)(=[O:3])[CH3:2]
Reactant: CC(=O)SC1CCN(C(=O)OC(C)(C)C)CC1
Agent: Cl
Solvent: CCOC(C)=O
Product: CC(=O)SC1CCNCC1
Temperature: 50 °C
Reaction time: 4 h
Yield: 94 %

Procedure:
In 45 ml of ethyl acetate were dissolved 1.25 g (4.82 mmol) of 4-(acetylthio)-1-(tert-butoxycarbonyl)piperdine as described in Reference example 11, and 12.0 ml (48.2 mmol) of a 4N hydrogen chloride-ethyl acetate solution were added to the solution, followed by stirring of the resulting mixture at 50° C. for 4 hours. After cooling, the precipitated solid was collected by filtration and washed with hexane to obtain 885 mg (yield: 94%) of the desired compound as a slightly yellow powder.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([CH:12]([C:14]3[CH:21]=[C:20]([Cl:22])[C:17]([C:18]#[N:19])=[C:16]([CH:23]4[CH2:26][NH:25][CH2:24]4)[C:15]=3[O:27][CH2:28][CH3:29])[CH3:13])[N:9]=[C:10]([CH3:11])[C:3]=12.[CH3:30][C@H:31]1[CH2:33][O:32]1>C(O)C.CO>[NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([CH:12]([C:14]3[CH:21]=[C:20]([Cl:22])[C:17]([C:18]#[N:19])=[C:16]([CH:23]4[CH2:24][N:25]([CH2:30][C@@H:31]([OH:32])[CH3:33])[CH2:26]4)[C:15]=3[O:27][CH2:28][CH3:29])[CH3:13])[N:9]=[C:10]([CH3:11])[C:3]=12
Reactant: CCOc1c(C(C)n2nc(C)c3c(N)ncnc32)cc(Cl)c(C#N)c1C1CNC1
Reactant: C[C@H]1CO1
Solvent: CO
Solvent: CCO
Product: CCOc1c(C(C)n2nc(C)c3c(N)ncnc32)cc(Cl)c(C#N)c1C1CN(C[C@H](C)O)C1
Temperature: 125 °C
Yield: 47.9 %

Procedure:
A solution of 4-[1-(4-amino-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl]-2-azetidin-3-yl-6-chloro-3-ethoxybenzonitrile (50 mg, 0.12 mmol, chiral intermediate from example 212) in ethanol (1.7 mL) was treated with (S)-(−)-methyloxirane (21 μL, 0.30 mmol) and heated in the microwave at 125° C. for 15 min. The reaction mixture was diluted with methanol and purified by preparative LCMS (XBridge C18 column, eluting with a gradient of acetonitrile/water containing 0.1% ammonium hydroxide, at flow rate of 60 mL/min) to give the desired product (27 mg, 47%). The product was isolated as a single diastereomer. 1H NMR (300 MHz, DMSO-d6) δ 8.11 (s, 1H), 7.48 (s, 1H), 6.23 (q, J=6.9 Hz, 1H), 4.35 (d, J=4.5 Hz, 1H), 4.13-3.99 (m, 1H), 3.97-3.88 (m, 2H), 3.85-3.63 (m, 2H), 3.61-3.51 (m, 1H), 3.15-2.99 (m, 2H), 2.55 (s, 3H), 2.28 (d, J=5.9 Hz, 2H), 1.71 (d, J=7.0 Hz, 3H), 1.32 (t, J=6.9 Hz, 3H), 1.00 (d, J=6.2 Hz, 3H). LCMS for C23H29ClN7O2 (M+H)+: m/z=470.2; Found: 470.2.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:18])[CH2:5][C@@H:6]1[CH2:10][CH2:9][N:8]([C:11]([O:13]C(C)(C)C)=O)[CH2:7]1)[CH3:2].O1CCOCC1.C(N(CC)[CH:29]([CH3:31])[CH3:30])(C)C.C1(C(Cl)=O)CC1>Cl.ClCCl.O>[CH2:1]([O:3][C:4](=[O:18])[CH2:5][C@@H:6]1[CH2:10][CH2:9][N:8]([C:11]([CH:29]2[CH2:31][CH2:30]2)=[O:13])[CH2:7]1)[CH3:2]
Reactant: CCN(C(C)C)C(C)C
Reactant: CCOC(=O)C[C@@H]1CCN(C(=O)OC(C)(C)C)C1
Agent: Cl
Agent: O=C(Cl)C1CC1
Solvent: ClCCl
Solvent: C1COCCO1
Solvent: O
Product: CCOC(=O)C[C@@H]1CCN(C(=O)C2CC2)C1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 100 %

Procedure:
In a round bottom flask, a solution of 1,1-dimethylethyl (3S)-3-[2-(ethyloxy)-2-oxoethyl]-1-pyrrolidinecarboxylate (64.1 g, 249 mmol) in 4M HCl in dioxane (600 mL, 2400 mmol) was stirred at room temperature for 1 h. Analysis of an aliquot by LCMS confirmed complete removal of the BOC group from the starting material. The reaction was concentrated in vacuo to give a pale orange liquid. A solution of this intermediate as the HCl salt in dichloromethane (500 mL) was treated with N,N-diisopropylethylamine (87 mL, 498 mmol) and stirred for 5 min at room temperature. The yellow solution was cooled to 0° C. and was treated with cyclopropanecarbonyl chloride (24.9 mL, 274 mmol) by syringe. The resultant orange solution was allowed to warm to room temperature and stirred for 1 h. The reaction was diluted with water (400 mL), the layers were separated, and the aqueous layer was extracted with 200 mL dichloromethane. The organic layers were combined, dried over MgSO4, concentrated in vacuo, and pumped under high vacuum to give the title compound as an orange liquid (249 mmol, quantitative). MS(ES)+ m/e 226.2 [M+H]+, 451.1 [2M+H]+.
Reaction SMILES: [C:1]([NH:4][CH2:5][C:6]1[N:11]=[C:10]([C:12]2[N:13]=[C:14]([N:17]=[C:18]([NH2:20])[NH2:19])[S:15][CH:16]=2)[CH:9]=[C:8](Cl)[CH:7]=1)(=[O:3])[CH3:2].[H][H]>[Pd].CO>[C:1]([NH:4][CH2:5][C:6]1[N:11]=[C:10]([C:12]2[N:13]=[C:14]([N:17]=[C:18]([NH2:19])[NH2:20])[S:15][CH:16]=2)[CH:9]=[CH:8][CH:7]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)NCc1cc(Cl)cc(-c2csc(N=C(N)N)n2)n1
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: CC(=O)NCc1cccc(-c2csc(N=C(N)N)n2)n1
Yield: 90.9 %

Procedure:
4-(6-Acetylaminomethyl-4-chloropyridin-2-y1)-2-(diaminomethyleneamino)thiazole (160 mg) was hydrogenated over 10% palladium on carbon (50% wt) (50 mg) in methanol (5 ml) at atmospheric pressure of hydrogen for 8 hours at ambient temperature. After the catalyst was removed by filtration, the solvent was evaporated in vacuo and the residue was mixed with water. The solution was adjusted to pH 10 with aqueous potassium carbonate and the free base was extracted with ethyl acetate. The extract was washed with water, dried over magnesium sulfate and evaporated in vacuo to give 4-(6-acetylaminomethylpyridin-2-yl)-2-(diaminomethyleneamino)thiazole (0.13 g).