Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CS(O)(=O)=O.[NH2:6][CH2:7][C:8]1[CH:9]=[C:10]2[C:14](=[CH:15][CH:16]=1)[C:13](=[O:17])[N:12]([CH:18]1[CH2:23][CH2:22][C:21](=[O:24])[NH:20][C:19]1=[O:25])[CH2:11]2.C1N=CN([C:31](N2C=NC=C2)=[O:32])C=1.[F:38][C:39]1[CH:44]=[C:43]([F:45])[CH:42]=[CH:41][C:40]=1[C:46]1[N:47]=[C:48]([NH2:51])[S:49][CH:50]=1.O>CN(C=O)C.C(OCC)(=O)C>[F:38][C:39]1[CH:44]=[C:43]([F:45])[CH:42]=[CH:41][C:40]=1[C:46]1[N:47]=[C:48]([NH:51][C:31]([NH:6][CH2:7][C:8]2[CH:9]=[C:10]3[C:14](=[CH:15][CH:16]=2)[C:13](=[O:17])[N:12]([CH:18]2[CH2:23][CH2:22][C:21](=[O:24])[NH:20][C:19]2=[O:25])[CH2:11]3)=[O:32])[S:49][CH:50]=1
Reactant: NCc1ccc2c(c1)CN(C1CCC(=O)NC1=O)C2=O
Reactant: Nc1nc(-c2ccc(F)cc2F)cs1
Reactant: O=C(n1ccnc1)n1ccnc1
Agent: CS(=O)(=O)O
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: O
Product: O=C1CCC(N2Cc3cc(CNC(=O)Nc4nc(-c5ccc(F)cc5F)cs4)ccc3C2=O)C(=O)N1
Temperature: 25 °C
Reaction time: 18 h
Yield: 12.4 %

Procedure:
A mixture of 3-(5-aminomethyl-1-oxo-1,3-dihydro-isoindol-2-yl)-piperidine-2,6-dione methanesulfonic acid salt (0.40 g, 1.1 mmol) and CDI (0.18 g, 1.1 mmol) in DMF (5 mL) was stirred at room temperature for 18 h. To the mixture was added 4-(2,4-difluoro-phenyl)-thiazol-2-ylamine (0.23 g, 1.1 mmol) at room temperature, and the mixture was stirred at 100° C. for 2 days. To the mixture was added water (25 mL) and ethyl acetate (20 mL). The mixture was stirred at room temperature for 2 h. The suspension was filtered and the solid was washed with water (20 mL), ethyl acetate (20 mL) and water (20 mL) to give a solid. The solid was purified with Prep HPLC to give 1-[4-(2,4-difluoro-phenyl)-thiazol-2-yl]-3-[2-(2,6-dioxo-piperidin-3-yl)-1-oxo-2,3-dihydro-1H-isoindol-5-ylmethyl]-urea as a white solid (70 mg, 13% yield): HPLC: Waters Symmetry C18, 5 μm, 3.9×150 mm, 1 mL/min, 240 nm, 40/60 CH3CN/0.1% H3PO4, 6.43 min (97.7%); mp: 264-266 0C; 1H NMR (DMSO-d6) □ 1.93-2.05 (m, 1H, CHH), 2.30-2.45 (m, 1H, CHH), 2.55-2.68 (m, 1H, CHH), 2.82-3.00 (m, 1H, CHH), 4.32 (d, J=17.4 Hz, 1H, CHH), 4.41-4.54 (m, 3H, CH2, CHH), 5.11 (dd, J=5.1, 13.2 Hz, 1H, NCH), 7.09-7.24 (m, 2H, Ar, NH), 7.28-7.41 (m, 2H, Ar), 7.46 (d, J=7.7 Hz, 1H, Ar), 7.53 (s, 1H, Ar), 7.71 (d, J=7.9 Hz, 1H, Ar), 7.93-8.10 (m, 1H, Ar), 10.85 (s, 1H, NH), 10.98 (s, 1H, NH); 13C NMR (DMSO-d6) □ 22.48, 31.18, 42.94, 47.12, 51.57, 104.54 (t, JC-F=26.4 Hz), 110.67 (d, JC-F=14.3 Hz), 111.81 (dd, JC-F=3.3, 20.9 Hz), 118.91 (dd, JC-F=2.8, 11.6 Hz), 121.95, 123.03, 126.95, 130.29 (dd, JC-F=4.4, 9.9 Hz), 130.49, 141.44, 142.45, 143.95, 154.02, 159.48 (dd, JC-F=252.2, 12.1 Hz), 159.36, 161.24 (dd, JC-F=246.9, 13.2 Hz), 167.88, 170.98, 172.85: LCMS MH=512: Anal. Calcd for C24H19N5O4F2S: C, 56.36; H, 3.74; N, 13.69. Found: C, 56.16; H, 3.80; N, 14.07.
Reaction SMILES: [C:1](=[O:4])([O-])[O-:2].[K+].[K+].[CH3:7][O:8][C:9]1[CH:18]=[CH:17][C:12]([CH:13]=[CH:14][CH:15]=O)=[CH:11][CH:10]=1.[C:19](#[N:21])C>O>[C:19]([CH:15]([O:2][C:1](=[O:4])[C:9]1[CH:18]=[CH:17][CH:12]=[CH:11][CH:10]=1)[CH:14]=[CH:13][C:12]1[CH:17]=[CH:18][C:9]([O:8][CH3:7])=[CH:10][CH:11]=1)#[N:21]
Reactant: CC#N
Reactant: COc1ccc(C=CC=O)cc1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Product: COc1ccc(C=CC(C#N)OC(=O)c2ccccc2)cc1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
Acetonitrile (25 ml) is added to a solution of potassium carbonate (3.45 g; 0.025 mol) in 15 ml of water and the mixture is cooled to 0° C. 4-Methoxycinnamaldehyde (8.1 g; 0.05 mol) dissolved in acetonitrile (25 ml) is added dropwise under efficient stirring over 30 min, keeping the temperature between 0 and 2° C., and the yellow mixture is further stirred 2 h at the same temperature. The phases are separated, the organic layer is washed with brine, dried over magnesium sulfate, and evaporated. The crude benzoic acid 1-cyano-3-(4-methoxyphenyl)-allyl ester (15 g), obtained as a pale yellow oil, is used for the next step without further purification.
Reaction SMILES: [CH:1]1([OH:7])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.N1C=CC=CC=1.[C:14](Cl)(=[O:19])[O:15][CH:16]([Cl:18])[CH3:17].O>C(Cl)(Cl)Cl>[C:14](=[O:19])([O:7][CH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1)[O:15][CH:16]([Cl:18])[CH3:17]
Reactant: OC1CCCCC1
Reactant: CC(Cl)OC(=O)Cl
Solvent: ClC(Cl)Cl
Solvent: O
Solvent: c1ccncc1
Product: CC(Cl)OC(=O)OC1CCCCC1
Temperature: -78 °C
Reaction time: 24 h

Procedure:
Cyclohexanol (4.58 g) was dissolved in chloroform (75 ml), pyridine (3.63 g) was added, and the mixture was cooled to −78° C. 1-Chloroethyl chlorocarbonate (5.0 ml) was added. The reaction mixture was gradually returned to room temperature and stirred for one day. Water was added to the reaction mixture to separate the organic layer. The organic layer was washed successively with water and brine, dried over sodium sulfate, and concentrated under reduced pressure to give the title compound (8.85 g).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][NH:5][S:6]([C:9]1[CH:14]=[C:13]([F:15])[C:12]([CH2:16][S:17][C:18]2[N:19]([C:35]3[CH:40]=[CH:39][C:38]([F:41])=[CH:37][CH:36]=3)[C:20]([C:23]([C:26]3[CH:31]=[CH:30][C:29]([Cl:32])=[C:28]([O:33][CH3:34])[CH:27]=3)([CH3:25])[CH3:24])=[CH:21][N:22]=2)=[C:11]([F:42])[CH:10]=1)(=[O:8])=[O:7].C([NH:50][C:51](N1C=CC=N1)=[N:52]C(OC(C)(C)C)=O)(OC(C)(C)C)=O.CCN(CC)CC>CO>[Cl:32][C:29]1[CH:30]=[CH:31][C:26]([C:23]([C:20]2[N:19]([C:35]3[CH:40]=[CH:39][C:38]([F:41])=[CH:37][CH:36]=3)[C:18]([S:17][CH2:16][C:12]3[C:11]([F:42])=[CH:10][C:9]([S:6]([NH:5][CH2:4][CH2:3][CH2:2][NH:1][C:51]([NH2:52])=[NH:50])(=[O:7])=[O:8])=[CH:14][C:13]=3[F:15])=[N:22][CH:21]=2)([CH3:25])[CH3:24])=[CH:27][C:28]=1[O:33][CH3:34]
Reactant: CC(C)(C)OC(=O)N=C(NC(=O)OC(C)(C)C)n1cccn1
Reactant: COc1cc(C(C)(C)c2cnc(SCc3c(F)cc(S(=O)(=O)NCCCN)cc3F)n2-c2ccc(F)cc2)ccc1Cl
Solvent: CO
Solvent: CCN(CC)CC
Product: COc1cc(C(C)(C)c2cnc(SCc3c(F)cc(S(=O)(=O)NCCCNC(=N)N)cc3F)n2-c2ccc(F)cc2)ccc1Cl
Reaction time: 18 h
Yield: 29.4 %

Procedure:
A solution of N-(3-aminopropyl)-4-((5-(2-(4-chloro-3-methoxyphenyl)propan-2-yl)-1-(4-fluorophenyl)-1H-imidazol-2-ylthio)methyl)-3,5-difluorobenzenesulfonamide (172 mg, 0.27 mmol), N,N′-di-Boc-1H-pyrazole-1-carboxamidine (100 mg, 0.32 mmol) and Et3N (190 μL, 1.35 mmol) in MeOH (10 mL) was stirred at 25° C. for 18 h. The reaction mixture was concentrated and reconstituted in EtOAc. The organic layer was washed with 1N HCl (3×5 mL), satd NaHCO3 (5 mL), dried over Na2SO4 and concentrated to a colorless oil. To the oil was added 4N HCl in dioxane (10 mL) at 25° C. and stirred for 18 h. Upon completion, the reaction mixture was concentrated and purified by preparatory HPLC (MeCN/H2O with 0.1% TFA, 10-99%) to give the title product (54 mg, 28% yield) as white solid. 1H NMR (400 MHz, MeOD) δ 7.99 (s, 1H), 7.51 (s, 2H), 7.37 (s, 1H), 7.28 (d, J=5.7 Hz, 1H), 6.98 (s, 2H), 6.62 (s, 2H), 6.56 (s, 2H), 4.14 (s, 2H), 3.73 (s, 3H), 3.70-3.54 (m, 3H), 3.30-3.21 (m, 2H), 3.00 (s, 2H), 1.80 (s, 2H), 1.63 (s, 6H); MS (EI) m/z 681 (MH+).
Reaction SMILES: C=O.[CH2:3]([NH:10][C:11]1[CH:12]=[C:13]([CH:23]=[CH:24][CH:25]=1)[CH2:14][NH:15][C:16](=[O:22])[O:17][C:18]([CH3:21])([CH3:20])[CH3:19])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[BH3-][C:27]#N.[Na+].CC(O)=O>CC#N>[CH2:3]([N:10]([CH3:27])[C:11]1[CH:12]=[C:13]([CH:23]=[CH:24][CH:25]=1)[CH2:14][NH:15][C:16](=[O:22])[O:17][C:18]([CH3:20])([CH3:21])[CH3:19])[C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: CC(C)(C)OC(=O)NCc1cccc(NCc2ccccc2)c1
Reactant: [BH3-]C#N
Agent: C=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CC#N
Product: CN(Cc1ccccc1)c1cccc(CNC(=O)OC(C)(C)C)c1
Yield: 100.9 %

Procedure:
CH2O (aq, 37%) (0.112 ml, 0.12 g, 1.51 mmol, 2 eq) was added to a stirred solution of tert-butyl 3-(benzylamino)benzylcarbamate (0.2353 g, 0.753 mmol, 1 eq) in 5 ml CH3CN. After 10 min NaBH3CN (0.0615 g, 0.98 mmol, 1.3 eq) was added. The reaction was adjusted to pH {tilde over ( )} 7 with HOAc. After 2 h the solvent was removed in vacuo. The residue was diluted with saturated aqueous NaHCO3/EtOAc, and the layers were separated. The organic layer was washed with water (×3), brine (×1), and dried over Na2SO4. The inorganics were filtered off, and the solvent was removed in vacuo to yield 0.2482 g (0.76 mmol, 100% yield) of tert-butyl 3-(benzyl(methyl)amino)benzylcarbamate.
Reaction SMILES: F[C:2]1[N:7]=[C:6]([C:8]2[C:16]3[C:11](=[CH:12][N:13]=[C:14]([C:17]4[CH:18]=[N:19][N:20]([CH2:22][CH3:23])[CH:21]=4)[CH:15]=3)[N:10](C3CCCCO3)[N:9]=2)[CH:5]=[CH:4][CH:3]=1.[NH:30]1[CH2:35][CH2:34][CH2:33][C@@H:32]([NH:36]C(=O)OC(C)(C)C)[CH2:31]1>>[CH2:22]([N:20]1[CH:21]=[C:17]([C:14]2[CH:15]=[C:16]3[C:8]([C:6]4[N:7]=[C:2]([N:30]5[CH2:35][CH2:34][CH2:33][C@@H:32]([NH2:36])[CH2:31]5)[CH:3]=[CH:4][CH:5]=4)=[N:9][NH:10][C:11]3=[CH:12][N:13]=2)[CH:18]=[N:19]1)[CH3:23]
Reactant: CCn1cc(-c2cc3c(-c4cccc(F)n4)nn(C4CCCCO4)c3cn2)cn1
Reactant: CC(C)(C)OC(=O)N[C@@H]1CCCNC1
Product: CCn1cc(-c2cc3c(-c4cccc(N5CCC[C@@H](N)C5)n4)n[nH]c3cn2)cn1
Yield: 41.6 %

Procedure:
Following the procedures as described in Example 189, 3-(6-fluoropyridin-2-yl)-5-(1-ethyl-1H-pyrazol-4-yl)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3,4-c]pyridine and (R)-tert-butyl piperidin-3-ylcarbamate were reacted. The product was deprotected and purified to give 285 as a white solid (41.6% over two steps). 1H NMR (400 MHz, DMSO) δ 9.02 (s, 1H), 8.60 (s, 1H), 8.34 (s, 1H), 7.97 (s, 1H), 7.62 (t, J=8.0 Hz, 1H), 7.42 (d, J=7.4 Hz, 1H), 6.83 (d, J=8.5 Hz, 1H), 4.45 (d, J=8.7 Hz, 1H), 4.28-4.12 (m, 3H), 2.98 (t, J=10.9 Hz, 1H), 2.82-2.72 (m, 2H), 2.03-1.93 (m, 1H), 1.86-1.77 (m, 1H), 1.67-1.51 (m, 1H), 1.42 (t, J=7.3 Hz, 3H), 1.38-1.26 (m, 1H); 3 protons not seen. LC/MS: m/z 389.2 [M+1]
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11]([NH2:21])([CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:22]([C:24]1[N:29]=[C:28]([NH:30][CH2:31][CH:32]2[CH2:39][CH2:38][C:35]3([CH2:37][CH2:36]3)[CH2:34][CH2:33]2)[C:27]([C:40](O)=[O:41])=[CH:26][N:25]=1)#[N:23].C1C=NC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl>CN(C=O)C.CCOC(C)=O>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][C:11]([CH2:14][C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)([NH:21][C:40]([C:27]2[C:28]([NH:30][CH2:31][CH:32]3[CH2:39][CH2:38][C:35]4([CH2:37][CH2:36]4)[CH2:34][CH2:33]3)=[N:29][C:24]([C:22]#[N:23])=[N:25][CH:26]=2)=[O:41])[CH2:12][CH2:13]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCC(N)(Cc2ccccc2)CC1
Reactant: N#Cc1ncc(C(=O)O)c(NCC2CCC3(CC2)CC3)n1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2cccnc21
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CCC(Cc2ccccc2)(NC(=O)c2cnc(C#N)nc2NCC2CCC3(CC2)CC3)CC1
Temperature: 25 °C
Reaction time: 15 h

Procedure:
To a solution of the 4-amino-4-benzylpiperidine-1-carboxylic acid tert-butyl ester (0.38 mmol, step 66.1) and 2-cyano-4-[(spiro[2.5]oct-6-ylmethyl)amino]pyrimidine-5-carboxylic acid (0.38 mmol) in DMF (1.3 mL) are added HOAt (0.51 mmol) and EDCI-HCl (0.51 mmol) at 0° C. After warming to room temperature and stirring for 15 h, the reaction mixture is diluted with AcOEt and washed with 1N aq. KHSO4, sat. aq. NaHCO3, and brine. The organic layer is dried over MgSO4, filtered, and concentrated in vacuo. The residue is purified by silica gel column chromatography to give 4-benzyl-4-({2-cyano-4-[(spiro[2.5]oct-6-ylmethyl)-amino]-pyrimidine-5-carbonyl}amino)piperidine-1-carboxylic acid tert-butyl ester.
Reaction SMILES: [Br:1][C:2]1[C:7](=[O:8])[N:6]2[CH:9]([CH3:15])[CH2:10][CH2:11][C:12](Br)(Br)[C:5]2=[N:4][CH:3]=1.CS(C)=O.[C:20]1([NH:26][NH2:27])[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>O>[Br:1][C:2]1[C:7](=[O:8])[N:6]2[CH:9]([CH3:15])[CH2:10][CH2:11][C:12](=[N:27][NH:26][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[C:5]2=[N:4][CH:3]=1
Reactant: CC1CCC(Br)(Br)c2ncc(Br)c(=O)n21
Reactant: NNc1ccccc1
Solvent: O
Solvent: CS(C)=O
Product: CC1CCC(=NNc2ccccc2)c2ncc(Br)c(=O)n21
Reaction time: 72 h
Yield: 34.7 %

Procedure:
4.0 g. (0.01 moles) of 3,9,9-tribromo-6-methyl-6,7,8,9-tetrahydro-4H-pyrido[1,2-a]pyrimidine-4-one are dissolved in 10 ml. of dimethyl sulfoxide. To the solution 2.8 ml. (0.03 moles) of phenylhydrazine are added. The reaction mixture is allowed to stand for three days whereupon 20 ml. of water are added. The solvent is decanted from the precipitated substance and the product is recrystallized from methanol. 1.3 g. (34.7%) of 3-bromo-9-(phenylhydrazono)-6-methyl-6,7,8,9-tetrahydro-4H-pyrido[1,2-a]pyrimidine-4-one are obtained, melting at 190° to 192° C.
Reaction SMILES: [C:1]1([S:7]([OH:10])(=[O:9])=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Cl-].[Cl-].[Ca+2].[F:14][C:15]1[CH:40]=[CH:39][C:18]([O:19][CH2:20][CH:21]2[CH2:25][CH2:24][CH:23](C#CCCOC(C3CCCCO3)=O)[O:22]2)=[CH:17][CH:16]=1>C(Cl)Cl>[C:1]1([S:7]([CH:23]2[O:22][C@H:21]([CH2:20][O:19][C:18]3[CH:17]=[CH:16][C:15]([F:14])=[CH:40][CH:39]=3)[CH2:25][CH2:24]2)(=[O:9])=[O:10])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=S(=O)(O)c1ccccc1
Reactant: O=C(OCCC#CC1CCC(COc2ccc(F)cc2)O1)C1CCCCO1
Agent: [Ca+2]
Agent: [Cl-]
Solvent: ClCCl
Product: O=S(=O)(c1ccccc1)C1CC[C@@H](COc2ccc(F)cc2)O1
Temperature: 0 °C
Reaction time: 3 h

Procedure:
To benzenesulfonic acid sodium salt (10.0 g, 0.061 mol), 25% HCl was added dropwise with stirring until the solid dissolved. The reaction mixture was extracted (100 mL each, 3 times) with EtOAc, dried over Na2SO4 and concentrated to give benzenesulfonic acid (7.8 g, 90%). To a 100 mL round bottom with a magnetic stir bar, benzenesulfonic acid (4.61 g, 0.0324 mol), CaCl2(3.6 g, 0.0324 mol) and dry dichloromethane (30 mL) were added. The reaction mixture was cooled to 0° C. and (2S) (5RS)-2-(4-fluorophenoxymethyl)-5-hydroxy-tetrahydrofuran (4.6 g, 0.0216 mol) in dry CH2Cl2 (20 mL) was added. The reaction mixture was stirred for 3 h and monitored by TLC (EtOAc-light petroleum ether 1:4, Rf=0.25). The reaction mixture was filtered through celite and washed with CH2Cl2 (3 times). The combined organic layer was washed with saturated aqueous Na2CO3, water brine and dried over Na2SO4. Solvent was removed under reduced pressure to afford the crude (2S)(5RS)-5-benzenesulfonyl-2-(4-fluorophenoxymethyl)tetrahydrofuran 14 which was crystallized from chloroform-hexane to give pure white solid, yield 6.8 g (93%), m.p. 102° C.-104° C. 1H NMR (200 MHz, CDCl3): δ 1.90-3.0 (m, 4H), 3.85-5.0 (m, 4H), 6.70-7.05 (m, 4H), 7.45-7.72 (m, 3H), 7.77-8.0 (m, 2H).
Reaction SMILES: [C:1]1([CH3:11])[CH:6]=[CH:5][C:4]([S:7](Cl)(=[O:9])=[O:8])=[CH:3][CH:2]=1.[Br:12][C:13]1[CH:19]=[CH:18][C:16]([OH:17])=[CH:15][C:14]=1[OH:20].C([O-])([O-])=O.[K+].[K+].[CH2:27](Br)[CH:28]=[CH2:29]>CC(C)=O>[CH3:11][C:1]1[CH:6]=[CH:5][C:4]([S:7]([O:17][C:16]2[CH:18]=[CH:19][C:13]([Br:12])=[C:14]([O:20][CH2:29][CH:28]=[CH2:27])[CH:15]=2)(=[O:9])=[O:8])=[CH:3][CH:2]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: C=CCBr
Reactant: Oc1ccc(Br)c(O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: C=CCOc1cc(OS(=O)(=O)c2ccc(C)cc2)ccc1Br
Temperature: 60 °C
Yield: 81.5 %

Procedure:
p-Toluenesulfonylchloride (2.14 g, 11.2 mmoles) was added to a solution of 4-bromoresorcinol (2.12 g, 11.2 mmoles) and K2CO3 (10.0 g, 72.4 mmoles) in acetone (150 mL). The reaction was heated to 60° C. overnight, treated with allyl bromide (2.6 mL, 30.3 mmoles), and heated to 60° C. for 24 h (according to Bos, M. E.; Wulff, W. D.; Miller, R. A.; Chamberlin, S.; Brandvoid, T. A. J. Am. Chem. Soc. 1991, 113, 9293). The reaction was cooled to room temperature, quenched with aqueous NH4Cl, and concentrated under reduced pressure. The crude products were diluted with diethyl ether, extracted with H2O, washed with brine, dried (Na2SO4), and concentrated under reduced pressure. The residue was purified by flash chromatography on a prepacked Biotage colum (hexane to 4:1 hexane:ethyl acetate) on silica gel to provide the title compound (3.50 g, 81%) as a clear colorless oil.
Reaction SMILES: [CH:1]1([Mg]Cl)[CH2:5][CH2:4][CH2:3][CH2:2]1.[C:8]1([CH2:14][C:15]#N)[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.Cl.[O:18]1CCCC1>CC(C)[O-].[Ti+4].CC(C)[O-].CC(C)[O-].CC(C)[O-]>[CH:1]1([C:15](=[O:18])[CH2:14][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: C1CCOC1
Reactant: Cl[Mg]C1CCCC1
Reactant: N#CCc1ccccc1
Agent: [Ti+4]
Agent: CC(C)[O-]
Agent: Cl
Product: O=C(Cc1ccccc1)C1CCCC1
Temperature: -50 °C
Reaction time: 2 h
Yield: 66.5 %

Procedure:
To a solution of titanium(IV) isopropoxide (5.13 mmol, 1.46 g) in anhydrous tetrahydro-furan (10 mL) was added a solution of cyclopentylmagnesium chloride in THF (7.69 mmol) at −78° C. Reaction was warmed to −50° C. in 5 min, then maintained at that temperature for 8 min and reaction became dark-brown to black. After cooling back to −78° C., 2-phenylacetonitrile (600 mg, 5.13 mmol) was added by a syringe, and the mixture was stirred at −78° C. for 2 h. 1 N HCl aqueous solution was added to quench the reaction. The mixture was extracted with acetic acid ethyl ester (40 mL) for three times, the combined organic layer was washed with brine (30 mL), dried over Na2SO4, filtered and concentrated. The residue was purified by silica gel column chromatography to give Intermediate 91 (320 mg, yield: 66.5%) as light green oil.
Reaction SMILES: [CH3:1][N:2]1[CH:15]=[C:5]2[CH2:6][CH2:7][NH:8][C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=3[C:4]2=[N:3]1.[C:16]1([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[C:22]([NH:24][C:25]1[N:30]=[CH:29][C:28]([C:31](Cl)=[O:32])=[CH:27][CH:26]=1)=[O:23]>>[CH3:1][N:2]1[CH:15]=[C:5]2[CH2:6][CH2:7][N:8]([C:31]([C:28]3[CH:27]=[CH:26][C:25]([NH:24][C:22]([C:17]4[C:16]([C:34]5[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=5)=[CH:21][CH:20]=[CH:19][CH:18]=4)=[O:23])=[N:30][CH:29]=3)=[O:32])[C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=3[C:4]2=[N:3]1
Reactant: Cn1cc2c(n1)-c1ccccc1NCC2
Reactant: O=C(Cl)c1ccc(NC(=O)c2ccccc2-c2ccccc2)nc1
Product: Cn1cc2c(n1)-c1ccccc1N(C(=O)c1ccc(NC(=O)c3ccccc3-c3ccccc3)nc1)CC2

Procedure:
As described for Example 12, 2,4,5,6-tetrahydro-2-methylpyrazolo[4,3-d][1]benzazepine is reacted with 6-[([1,1'biphenyl]-2-ylcarbonyl)amino]-3-pyridinecarbonyl chloride to give the product as a solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:13]=[C:12]([NH:14][C:15]3[CH:16]=[N:17][C:18]([O:21][CH3:22])=[CH:19][CH:20]=3)[C:11]([C:23]3[N:28]=[C:27]([CH3:29])[N:26]=[C:25](SC)[N:24]=3)=[CH:10][N:9]=2)=[CH:4][CH:3]=1.[NH3:32]>O1CCOCC1>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:13]=[C:12]([NH:14][C:15]3[CH:16]=[N:17][C:18]([O:21][CH3:22])=[CH:19][CH:20]=3)[C:11]([C:23]3[N:28]=[C:27]([CH3:29])[N:26]=[C:25]([NH2:32])[N:24]=3)=[CH:10][N:9]=2)=[CH:4][CH:3]=1
Reactant: COc1ccc(Nc2nc(-c3ccc(F)cc3)ncc2-c2nc(C)nc(SC)n2)cn1
Reactant: N
Solvent: C1COCCO1
Product: COc1ccc(Nc2nc(-c3ccc(F)cc3)ncc2-c2nc(C)nc(N)n2)cn1
Temperature: 100 °C

Procedure:
A glass microwave reaction vessel was charged with 2-(4-fluorophenyl)-N-(6-methoxypyridin-3-yl)-5-(4-methyl-6-(methylthio)-1,3,5-triazin-2-yl)pyrimidin-4-amine (12 mg, 0.028 mmol), ammonia (0.5 mL, 30% in water) and dioxane (1 mL). The reaction mixture was stirred and heated in a oil bath at 100° C. for 17 h. The solvent was removed in vacuo and the residue was purified by silica gel chromatography eluting with 80% EtOAc/hexanes to give 4-(2-(4-fluorophenyl)-4-(6-methoxypyridin-3-ylamino)pyrimidin-5-yl)-6-methyl-1,3,5-triazin-2-amine. 1H NMR (300 MHz, CDCl3) δ 9.60 (s, 1H); 8.35-8.54 (m, 3H); 8.12 (dd, J=8.84, 2.41 Hz, 1H); 7.15 (t, J=8.62 Hz, 2H); 6.86 (d, J=8.92 Hz, 1H); 5.44 (s, 2H); 3.99 (s, 3H); 2.56 (s, 3H). m/z (ESI, +ve ion) 405.0 (M+H)+.
Reaction SMILES: C1(C)C=CC(S(O)(=O)=O)=CC=1.C([O:14][C:15](=O)[CH:16]=[C:17]([NH2:21])OCC)C.[Cl:23][C:24]1[CH:25]=[C:26]([CH:30]=[C:31]([Cl:33])[CH:32]=1)[CH2:27][NH:28][NH2:29]>C(O)C>[NH2:21][C:17]1[NH:29][N:28]([CH2:27][C:26]2[CH:25]=[C:24]([Cl:23])[CH:32]=[C:31]([Cl:33])[CH:30]=2)[C:15](=[O:14])[CH:16]=1
Reactant: CCOC(=O)C=C(N)OCC
Reactant: NNCc1cc(Cl)cc(Cl)c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCO
Product: Nc1cc(=O)n(Cc2cc(Cl)cc(Cl)c2)[nH]1
Reaction time: 8 h

Procedure:
After adding 1 g of p-toluenesulphonic acid to a solution of 49.6 g of β-amino-β-ethoxyacrylic acid ethyl ester in 220 ml of ethanol, 59 g of 3,5-dichlorobenzylhydrazine were added dropwise under nitrogen. The solution was left to stand overnight and the solids which precipitated melted at 175°-176° after recrystallisation from ethanol. Yield: 40 g (48%) of the compound identified above.
Reaction SMILES: [Mg].Br[C:3]1[CH:8]=[CH:7][C:6]([F:9])=[CH:5][C:4]=1[CH3:10].C[O:12][C:13]1[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=1.[CH2:19]([O:26][C:27](Cl)=[O:28])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>O1CCCC1>[CH2:19]([O:26][C:27]([N:16]1[CH:17]=[CH:18][C:13](=[O:12])[CH2:14][CH:15]1[C:3]1[CH:8]=[CH:7][C:6]([F:9])=[CH:5][C:4]=1[CH3:10])=[O:28])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: Cc1cc(F)ccc1Br
Reactant: COc1ccncc1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [Mg]
Solvent: C1CCOC1
Product: Cc1cc(F)ccc1C1CC(=O)C=CN1C(=O)OCc1ccccc1
Temperature: -50 °C
Reaction time: 0.33 h

Procedure:
To Grignard reagent prepared from 14.2 g of magnesium, 93.1 g of 2-bromo-5-fluorotoluene and 500 ml of tetrahydrofuran was added dropwise 50 ml of 4-methoxypyridine at −20° C. under nitrogen atmosphere. After completion of dripwise addition, the mixture was stirred at the same temperature for 20 minutes. Further, the reaction mixture was cooled down to −50° C., and 85 ml of benzylchlorocarbonate was added dropwise, while keeping the temperature at −40° C. or below. After completion of dropwise addition, the temperature of the reaction mixture was slowly raised, 200 g of ice was added thereto at −15C, and the mixture was stirred for 30 minutes. Further, 200 ml of a 5M aqueous citric acid solution was added thereto and the mixture was stirred at room temperature for an hour. From the reaction mixture tetrahydrofuran was removed by distillation under reduced pressure. To the residue was added 200 ml of ethyl acetate and the mixture was extracted twice. The organic layers were combined and washed with an aqueous sodium hydrogen carbonate solution and saturated brine, dried over magnesium sulfate, and the solvent was removed by distillation under reduced pressure. The residue was collected by filtration and washed with isopropyl ether, to give 146.5 g of 1-benzyloxycarbonyl-2-(4-fluoro-2-methylphenyl)-4-oxo-3,4-dihydro-2H-pyridine as shown in Table 125 below.