Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([OH:11])=[N:7][NH:8]2)=[CH:4][CH:3]=1.[CH3:12][N:13]1C(=O)O[C:16](=[O:17])[C:15]2=[CH:21][CH:22]=[CH:23][CH:24]=[C:14]12>>[CH3:12][NH:13][C:14]1[CH:24]=[CH:23][CH:22]=[CH:21][C:15]=1[C:16]([N:8]1[C:9]2[C:5](=[CH:4][CH:3]=[C:2]([Cl:1])[CH:10]=2)[C:6]([OH:11])=[N:7]1)=[O:17]
Reactant: Oc1n[nH]c2cc(Cl)ccc12
Reactant: Cn1c(=O)oc(=O)c2ccccc21
Product: CNc1ccccc1C(=O)n1nc(O)c2ccc(Cl)cc21
Yield: 59 %

Procedure:
6-Chloro-1H-indazol-3-ol was reacted with N-methylisatoic anhydride according to the general procedure A above and afforded the desired amine as a yellow solid in 59.0% yield; m.p. 203°-205° C.
Reaction SMILES: [Br:1][CH:2]1[CH2:7][CH2:6][CH2:5][CH2:4][CH:3]1[C:8](Br)=[O:9].Cl.C(O[NH2:20])C1C=CC=CC=1.CCO[C:24](C)=[O:25]>>[Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][O:9][NH:20][CH:24]=[O:25]
Reactant: NOCc1ccccc1
Reactant: O=C(Br)C1CCCCC1Br
Reactant: CCOC(C)=O
Agent: Cl
Product: O=CNOCc1ccccc1Br
Yield: 72 %

Procedure:
Prepared in 72% yield (4.5 g, 14.5 mmol) from the reaction of 2-bromocyclohexanoyl bromide (4.53 g, 20.1 mmol) with O-benzylhydroxylamine, hydrochloride (3.21 g, 20.1 mmol) via general procedure A. Rf=0.47 (3:1; hexanes:EtOAc); mp=84.6-86.1° C.; 1H NMR (400 MHz, CDCl3) δ 8.98 (br s, 1H), 7.51-7.31 (m, 5H), 4.94 (s, 2H), 2.13 (ddd, J=14.6, 10.9, 4.0 Hz, 2H), 2.00 (dt, J=14.0, 4.1 Hz, 2H), 1.80-1.57 (m, 5H), 1.42-1.23 (m, 1H). 13C NMR (101 MHz, CDCl3) δ 169.6, 135.0, 129.6, 129.0, 128.7, 78.2, 38.1, 24.7, 22.6. IR (neat) 3235 (br), 3034, 2936, 2862, 1680, 1651 (s), 1470, 1459, 1270, 1249, 1210, 1122, 1025, 1000 cm-1; HR-APPIMS calculated for C14H16BrNO2 (M+H)+ 312.0594, observed 312.0206.
Reaction SMILES: [CH3:1][C:2]1[CH:17]=[CH:16][CH:15]=[C:14]([CH3:18])[C:3]=1[CH2:4][O:5][C:6]1[CH:7]=[C:8]([CH:11]=[CH:12][CH:13]=1)[C:9]#[N:10].[N-:19]=[N+:20]=[N-:21].[Na+].[Cl-].[NH4+]>CN(C)C=O>[CH3:1][C:2]1[CH:17]=[CH:16][CH:15]=[C:14]([CH3:18])[C:3]=1[CH2:4][O:5][C:6]1[CH:7]=[C:8]([C:9]2[NH:21][N:20]=[N:19][N:10]=2)[CH:11]=[CH:12][CH:13]=1
Reactant: Cc1cccc(C)c1COc1cccc(C#N)c1
Reactant: [N-]=[N+]=[N-]
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1cccc(C)c1COc1cccc(-c2nnn[nH]2)c1
Temperature: 110 °C

Procedure:
A mixture of 3-(2,6-Dimethylbenzyloxy)benzonitrile (Step A, 3 g, 11.8 mmol), sodium azide (0.847 g, 13 mmol) and ammonium chloride (0.697 g, 13 mmol) in dry dimethylformamide (30 ml) was heated under argon at 110° C. for 14 hours or until all the starting material is consumed. Water was added to the reaction mixture to dissolve all the solids; the solution was taken in brine and extracted with ethyl acetate (2×). The combined organic layer was washed with brine, dried over Na2SO4, filtered, concentrated and purified by flash chromatography on a silica gel column (chloroform:methanol 95:5) to give the title compound as a white solid.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:14]=[CH:13][C:12]([C:15]3[CH:20]=[CH:19][C:18]([C@H:21]4[CH2:26][CH2:25][C@H:24]([CH2:27]C)[CH2:23][CH2:22]4)=[CH:17][CH:16]=3)=[CH:11][N:10]=2)=[CH:5][C:4]=1[F:29])#[N:2].C(C1C=CC(C2N=CC(C3C=CC([C@H]4CC[C@H](CCCCCC)CC4)=CC=3)=CN=2)=CC=1F)#N>>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:10]=[CH:11][C:12]([C:15]3[CH:20]=[CH:19][C:18]([C@H:21]4[CH2:26][CH2:25][C@H:24]([CH3:27])[CH2:23][CH2:22]4)=[CH:17][CH:16]=3)=[CH:13][N:14]=2)=[CH:5][C:4]=1[F:29])#[N:2]
Reactant: CC[C@H]1CC[C@H](c2ccc(-c3cnc(-c4ccc(C#N)c(F)c4)nc3)cc2)CC1
Agent: CCCCCC[C@H]1CC[C@H](c2ccc(-c3cnc(-c4ccc(C#N)c(F)c4)nc3)cc2)CC1
Product: C[C@H]1CC[C@H](c2ccc(-c3cnc(-c4ccc(C#N)c(F)c4)nc3)cc2)CC1

Procedure:
2-(4'-cyano-3'-fluorophenyl)-5-[4'-(trans-4"-ethylcyclohexyl) phenyl] pyrimidine ##STR33## 2-(4'-cyano-3'-fluorophenyl)-5-[4'-(trans-4"-butylcyclohexyl) phenyl] pyrimidine ##STR34## 2-(4'-cyano-3'-fluorophenyl)-5-[4'-(trans-4"-pentylcyclohexyl) phenyl] pyrimidine ##STR35## 2-(4'-cyano-3'-fluorophenyl)-5-[4'-(trans-4"-hexylcyclohexyl) phenyl] pyrimidine
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][O:11][CH:10]([CH:14]([OH:21])[C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH2:9]1)=O)(C)(C)C.O[C:23]1[CH:31]=[CH:30][C:26]2[CH:27]=[CH:28][O:29][C:25]=2[CH:24]=1.S([O-])(=O)(=O)C>>[O:29]1[C:25]2[CH:24]=[C:23]([O:21][C@@H:14]([C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=3)[C@@H:10]3[O:11][CH2:12][CH2:13][NH:8][CH2:9]3)[CH:31]=[CH:30][C:26]=2[CH:27]=[CH:28]1
Reactant: CC(C)(C)OC(=O)N1CCOC(C(O)c2ccccc2)C1
Reactant: Oc1ccc2ccoc2c1
Agent: CS(=O)(=O)[O-]
Product: c1ccc([C@H](Oc2ccc3ccoc3c2)[C@H]2CNCCO2)cc1

Procedure:
(R)-2-[(S)-(Benzofuran-6-yloxy)-phenyl-methyl]-morpholine was synthesized from 2-(Hydroxy-phenyl-methyl)-morpholine-4-carboxylic acid tert-butyl ester and 6-hydroxybenzofuran according General Procedure C employing the alternate etherification sequence (via the mesylate) and was isolated as an oil. MS (APCI): 310 [M+H]+.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]([CH3:15])([CH3:14])[C:10]([CH3:13])([CH3:12])[CH3:11])[N:5]=[C:4]([NH:16][C:17]([CH3:23])([CH3:22])[C:18]([CH3:21])([CH3:20])[CH3:19])[N:3]=1.[CH3:24][O:25][C:26]1[CH:31]=[CH:30][C:29]([N:32]2[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]2)=[CH:28][CH:27]=1.C1(N)C(F)=C(F)C(F)=C(N)C=1F.Cl.Cl>ClC1C=CC=CC=1>[CH3:24][O:25][C:26]1[CH:27]=[CH:28][C:29]([N:32]2[CH2:37][CH2:36][N:35]([C:2]3[N:7]=[C:6]([NH:8][C:9]([CH3:15])([CH3:14])[C:10]([CH3:13])([CH3:11])[CH3:12])[N:5]=[C:4]([NH:16][C:17]([CH3:22])([CH3:23])[C:18]([CH3:19])([CH3:21])[CH3:20])[N:3]=3)[CH2:34][CH2:33]2)=[CH:30][CH:31]=1
Reactant: COc1ccc(N2CCNCC2)cc1
Reactant: CC(C)(C)C(C)(C)Nc1nc(Cl)nc(NC(C)(C)C(C)(C)C)n1
Agent: Cl
Agent: Nc1c(F)c(N)c(F)c(F)c1F
Solvent: Clc1ccccc1
Product: COc1ccc(N2CCN(c3nc(NC(C)(C)C(C)(C)C)nc(NC(C)(C)C(C)(C)C)n3)CC2)cc1

Procedure:
A mixture of 6.84 g. of 2-chloro-4,6-bis[(1,1,2,2-tetramethylpropyl)amino]-s-triazine and 7.69 g. of N-(p-methoxyphenyl)piperazine (prepared from the commercially available dihydrochloride salt) in 150 ml. of chlorobenzene is refluxed for 5 hours and then cooled. The reaction mixture is washed with two 25 ml. portions of water. The organic layer is dried over anhydrous potassium carbonate and magnesium sulfate and the solvent is stripped with a water pump. The residual amber oil is crystallized by slurrying in isopropanol. Recrystallization from 150 ml. of propanol (using charcoal for decolorization) gives the desired product as a white solid, m.p. 155°-157° C.
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][C:5]([N:8]2[CH2:13][CH2:12][CH:11]([N:14]3[CH2:18][CH2:17][C@H:16]([NH:19][C:20]4[CH:25]=[CH:24][C:23]([S:26]([CH3:29])(=[O:28])=[O:27])=[CH:22][C:21]=4[F:30])[C:15]3=[O:31])[CH2:10][CH2:9]2)=[N:6][CH:7]=1.CC1(C)C(C)(C)OB([C:40]2[CH:41]=[N:42][N:43](C(OC(C)(C)C)=O)[CH:44]=2)O1.C([O-])([O-])=O.[Na+].[Na+]>O1CCOCC1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[NH:42]1[CH:41]=[C:40]([C:2]2[CH:3]=[N:4][C:5]([N:8]3[CH2:13][CH2:12][CH:11]([N:14]4[CH2:18][CH2:17][C@H:16]([NH:19][C:20]5[CH:25]=[CH:24][C:23]([S:26]([CH3:29])(=[O:28])=[O:27])=[CH:22][C:21]=5[F:30])[C:15]4=[O:31])[CH2:10][CH2:9]3)=[N:6][CH:7]=2)[CH:44]=[N:43]1
Reactant: CC(C)(C)OC(=O)n1cc(B2OC(C)(C)C(C)(C)O2)cn1
Reactant: CS(=O)(=O)c1ccc(N[C@H]2CCN(C3CCN(c4ncc(Br)cn4)CC3)C2=O)c(F)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Product: CS(=O)(=O)c1ccc(N[C@H]2CCN(C3CCN(c4ncc(-c5cn[nH]c5)cn4)CC3)C2=O)c(F)c1
Temperature: 110 °C
Reaction time: 8 h
Yield: 43.6 %

Procedure:
(S)-1-(1-(5-Bromopyrimidin-2-yl)piperidin-4-yl)-3-(2-fluoro-4-(methylsulfonyl)phenylamino)pyrrolidin-2-one (Example 7; 0.090 g, 0.17 mmol), tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole-1-carboxylate (0.057 g, 0.19 mmol), Pd(PPh3)4 (0.020 g, 0.018 mmol) and Na2CO3 (0.44 mL, 0.88 mmol) were suspended in dioxane in a sealed tube and stirred at 110° C. overnight. The material was cooled and filtered through silica gel (10% MeOH/EtOAc). The material was purified by reverse phase HPLC purification (5 to 95% acetonitrile in water) to give (S)-1-(1-(5-(1H-pyrazol-4-yl)pyrimidin-2-yl)piperidin-4-yl)-3-(2-fluoro-4-(methylsulfonyl)phenylamino)pyrrolidin-2-one (0.037 g, 42% yield) as a white solid. Mass spectrum (apci) m/z=500.3 (M+H).
Reaction SMILES: [CH2:1]([O:4][C:5](=[O:40])[C@@H:6]([NH:32][C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])[CH2:7][C:8]1[CH:31]=[CH:30][C:11]([O:12][C:13]([NH:15][C@@H:16]([CH2:20][CH2:21][NH:22][C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[C:17](O)=[O:18])=[O:14])=[CH:10][CH:9]=1)[CH:2]=[CH2:3].[C:41]([S:60][CH2:61][C@@H:62]([C:64]([NH2:66])=[O:65])[NH2:63])([C:54]1[CH:59]=[CH:58][CH:57]=[CH:56][CH:55]=1)([C:48]1[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=1)[C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1.C(N(CC)C(C)C)(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>ClCCl>[CH2:1]([O:4][C:5](=[O:40])[C@H:6]([CH2:7][C:8]1[CH:9]=[CH:10][C:11]([O:12][C:13](=[O:14])[NH:15][C@@H:16]([CH2:20][CH2:21][NH:22][C:23](=[O:24])[O:25][C:26]([CH3:29])([CH3:28])[CH3:27])[C:17](=[O:18])[NH:63][C@H:62]([C:64](=[O:65])[NH2:66])[CH2:61][S:60][C:41]([C:48]2[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=2)([C:54]2[CH:55]=[CH:56][CH:57]=[CH:58][CH:59]=2)[C:42]2[CH:43]=[CH:44][CH:45]=[CH:46][CH:47]=2)=[CH:30][CH:31]=1)[NH:32][C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])[CH:2]=[CH2:3]
Reactant: C=CCOC(=O)[C@H](Cc1ccc(OC(=O)N[C@@H](CCNC(=O)OC(C)(C)C)C(=O)O)cc1)NC(=O)OC(C)(C)C
Reactant: NC(=O)[C@@H](N)CSC(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: C=CCOC(=O)[C@H](Cc1ccc(OC(=O)N[C@@H](CCNC(=O)OC(C)(C)C)C(=O)N[C@@H](CSC(c2ccccc2)(c2ccccc2)c2ccccc2)C(N)=O)cc1)NC(=O)OC(C)(C)C
Temperature: 60 °C

Procedure:
3.00 g (5.30 mmol) of the compound from example 13A was dissolved in 120 ml dichloromethane. 1.92 g (5.30 mmol) S-Trityl-L-cysteinamide, 0.92 ml (5.30 mmol) N,N-diisopropylethylamine and 2.02 g (5.30 mmol) HATU were added. The reaction mixture was split into 6 portions. The portions were heated for 30 min in a sealed tube at 60° C. in a microwave synthesizer. From the combined reaction mixture the solvent was removed by rotary evaporation (approx. 40° C., approx. 200 mbar, approx. 30 min.). The raw product was dissolved in dichloromethane and chromatographed over approx. 800 ml silica gel. Solvents used were dichloromethane/ethyl acetate 2/1, dichloromethane/ethyl acetate 1/1. The product-containing fractions were combined and concentrated to dryness under reduced pressure. This gave 4.91 g (3.73 mmol, 70% of theory, 69% purity) of the desired product.
Reaction SMILES: [NH2:1][C:2]1[N:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][N:8]=2)[NH:5][C:4](=[O:13])[CH:3]=1.[Br:14][C:15]1[CH:16]=[C:17]([CH:20]=[CH:21][C:22]=1[F:23])[CH:18]=O.[C:24]1(=O)[CH2:28][CH2:27][C:26](=[O:29])[CH2:25]1>C(O)C>[Br:14][C:15]1[CH:16]=[C:17]([CH:18]2[C:3]3[C:4](=[O:13])[NH:5][N:6]([C:7]4[CH:12]=[CH:11][CH:10]=[CH:9][N:8]=4)[C:2]=3[NH:1][C:24]3[CH2:28][CH2:27][C:26](=[O:29])[C:25]2=3)[CH:20]=[CH:21][C:22]=1[F:23]
Reactant: O=C1CCC(=O)C1
Reactant: O=Cc1ccc(F)c(Br)c1
Reactant: Nc1cc(=O)[nH]n1-c1ccccn1
Solvent: CCO
Product: O=C1CCC2=C1C(c1ccc(F)c(Br)c1)c1c(n(-c3ccccn3)[nH]c1=O)N2
Temperature: 80 °C
Yield: 30.2 %

Procedure:
5-Amino-1-(2-pyridyl)-1,2-dihydropyrazol-3-one (0.26 g, 1.5 mmol), prepared as described in (Weisberger A., Porter H. D., J. Am. Chem. Soc., (1944) 66, 1849), 3-bromo-4-fluorobenzaldehyde (0.3 g, 1.5 mmol), and 1,3-cyclopentanedione (0.147 g, 1.5 mmol) in ethyl alcohol (3 mL) were heated at 80° C. for 2 days in a sealed tube. The reaction mixture was cooled and the resulting precipitate was filtered off to provide 0.2 g of the title compound as a tan solid. 1H NMR (300 MHz, DMSO-d6) δ 2.32 (m, 2H), 2.8 (m, 2H), 4.82 (s, 1H), 7.22 (m, 3H), 7.48 (dd, 1H), 7.55 (dd, 1H), 7.92 (t, 1H), 8.41 (m, 1H), 10.42 (s, 1H), 10.55 (bs, 11H); MS (ESI−) m/z 439 (M−H)−; Anal. calcd for C20H14N4BrFO2.0.25H2O: C, 53.89; H, 3.28; N, 12.57. Found: C, 53.76; H, 3.01; N, 13.22.
Reaction SMILES: Cl[C:2]1[CH:11]=[C:10]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[Cl:18])[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:19]([F:22])([F:21])[F:20])[CH:8]=2)[N:3]=1.O.[NH2:24][NH2:25]>>[F:20][C:19]([F:22])([F:21])[C:7]1[CH:8]=[C:9]2[C:4](=[CH:5][CH:6]=1)[N:3]=[C:2]([NH:24][NH2:25])[CH:11]=[C:10]2[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[Cl:18]
Reactant: FC(F)(F)c1ccc2nc(Cl)cc(-c3ccccc3Cl)c2c1
Reactant: NN
Solvent: O
Product: NNc1cc(-c2ccccc2Cl)c2cc(C(F)(F)F)ccc2n1

Procedure:
In the manner given in Example 1, 2-chloro-6 -(trifluoromethyl)-4-(o-chlorophenyl)quinoline is reacted with hydrazine hydrate at reflux to give 6-(trifluoromethyl)- 4-(o-chlorophenyl)-2-hydrazinoquinoline.
Reaction SMILES: Br[C:2]1[N:7]=[CH:6][C:5]([CH:8]=[O:9])=[CH:4][CH:3]=1.[C:10]([C:13]1[CH:14]=[CH:15][C:16]([F:22])=[C:17](B(O)O)[CH:18]=1)(=[O:12])[NH2:11].C([O-])([O-])=O.[Na+].[Na+]>COCCOC.CCO>[F:22][C:16]1[CH:17]=[CH:18][C:13]([C:10]([NH2:11])=[O:12])=[CH:14][C:15]=1[C:2]1[CH:3]=[CH:4][C:5]([CH:8]=[O:9])=[CH:6][N:7]=1
Reactant: O=Cc1ccc(Br)nc1
Reactant: NC(=O)c1ccc(F)c(B(O)O)c1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: CCO
Product: NC(=O)c1ccc(F)c(-c2ccc(C=O)cn2)c1
Temperature: 80 °C

Procedure:
To a solution of 6-bromo-3-pyridinecarboxaldehyde (336 mg, 1.80 mmol) in DME (8 mL) and EtOH (4 mL) under argon, was added (5-carbamoyl-2-fluorophenyl)boronic acid (300 mg, 1.64 mmol) followed by palladium tetrakistriphenylphosphine (190 mg, 0.16 mmol) and 2M Na2CO3 (4 mL). The mixture was heated to 80° C. for 16 h and then allowed to cool to rt. The mixture was partitioned between EtOAc (50 mL), THF (50 mL) and Na2CO3 (20 mL). The aqueous was extracted with EtOAc (50 mL) and the combined organics washed with brine (30 mL) and dried (MgSO4). The solvent was removed in vacuo and the residue purified by column chromatography (0.4% NH3: 4% MeOH: DCM) to give the title compound: RT=2.50 min; m/z (ES+)=245.0 [M+H]+.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([C:9]2[N:10]=[C:11]([NH2:20])[S:12][C:13]=2[C:14]2[CH:19]=[CH:18][N:17]=[CH:16][CH:15]=2)[CH:5]=[C:6]([CH3:8])[CH:7]=1.[C:21]1([CH2:27][C:28](Cl)=[O:29])[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.C(=O)([O-])O.[Na+]>CN(C)C1C=CN=CC=1.CN(C)C(=O)C>[CH3:1][C:2]1[CH:3]=[C:4]([C:9]2[N:10]=[C:11]([NH:20][C:28](=[O:29])[CH2:27][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[S:12][C:13]=2[C:14]2[CH:19]=[CH:18][N:17]=[CH:16][CH:15]=2)[CH:5]=[C:6]([CH3:8])[CH:7]=1
Reactant: Cc1cc(C)cc(-c2nc(N)sc2-c2ccncc2)c1
Reactant: O=C(Cl)Cc1ccccc1
Agent: CN(C)c1ccncc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)N(C)C
Product: Cc1cc(C)cc(-c2nc(NC(=O)Cc3ccccc3)sc2-c2ccncc2)c1
Temperature: 80 °C
Reaction time: 14 h
Yield: 45.9 %

Procedure:
To a solution of [4-(3,5-dimethylphenyl)-5-(4-pyridyl)-1,3-thiazol-2-yl]amine (0.51 g, 1.8 mmol) and 4-dimethylaminopyridine (0.06 g, 0.52 mmol) in N,N-dimethylacetamide (15 mL) was added 2-phenylacetyl chloride (0.32 g, 2.0 mmol) and the mixture was stirred at 80° C. for 14 h. To the reaction mixture was poured aqueous sodium hydrogencarbonate solution and the precipitated solid was collected by filtration. The obtained solid was washed with water and dried. The crude crystals were recrystallized from ethanol to give the title compound (0.33 g, yield 46%).
Reaction SMILES: Cl.[F:2][C:3]1[C:4]([F:19])=[CH:5][C:6]2[N:15]=[C:14]([NH2:16])[C:13]3[CH:12]=[C:11]([CH3:17])[S:10][C:9]=3[NH:8][C:7]=2[CH:18]=1.[CH3:20][O:21][CH2:22][CH2:23][CH:24]1[CH2:29]N[CH2:27][CH2:26][NH:25]1.CS(C)=O>C1(C)C=CC=CC=1>[F:2][C:3]1[C:4]([F:19])=[CH:5][C:6]2[N:15]=[C:14]([N:16]3[CH2:27][CH2:26][NH:25][C@@H:24]([CH2:23][CH2:22][O:21][CH3:20])[CH2:29]3)[C:13]3[CH:12]=[C:11]([CH3:17])[S:10][C:9]=3[NH:8][C:7]=2[CH:18]=1
Reactant: COCCC1CNCCN1
Reactant: Cc1cc2c(s1)Nc1cc(F)c(F)cc1N=C2N
Agent: Cl
Solvent: Cc1ccccc1
Solvent: CS(C)=O
Product: COCC[C@H]1CN(C2=Nc3cc(F)c(F)cc3Nc3sc(C)cc32)CCN1
Temperature: 115 °C
Yield: 66.4 %

Procedure:
Add 6,7-difluoro-2-methyl-4H-3-thia-4,9-diaza-benzo[f]azulen-10-ylamine hydrochloride (65.0 g, 215 mmol) and 2-(2-methoxy-ethyl)-piperazine (96.3 g, 668 mmol) to a solution of DMSO (650 mL) and toluene (1300 mL) with stirring under nitrogen. Heat at gentle reflux (115° C.) for 2 days, and then allow cooling to ambient temperature. Remove most of the organic portion under reduced pressure, and then partition the residue between ethyl acetate (450 mL) and aqueous saturated ammonium chloride solution (450 mL). Separate the layers, and then extract the aqueous layer with ethyl acetate (3×200 mL). Extract the combined organic layers with brine (3×200 mL). Concentrate the organic layer under reduced pressure. Purify the crude product by flash chromatography, eluting with 90:10/methylene chloride:MeOH to give 56 g (66%) of the title compound. 1H NMR (400 MHz, DMSO-d6) δ 7.70 (s, 1H), 6.74 (m, 2H), 6.36 (s, 1H), 3.86 (bm, 2H), 3.39 (m, 2H), 3.23 (s, 3H), 2.88 (bd, 1H), 2.72 (bm, 3H), 2.44 (bt, 1H), 2.31 (s, 3H), 2.31 (bm, 1H), 1.53 (m, 2H). HRMS (ES) exact mass M+H calcd for C19H22F2N4OS 393.1561; found 393.1554.
Reaction SMILES: [F:1][C:2]1[C:3]([C:24]2[CH2:29][CH2:28][CH2:27][C@@H:26]([NH:30][C:31]([NH:33][C:34]3[S:35][CH:36]=[CH:37][N:38]=3)=[O:32])[CH:25]=2)=[N:4][C:5]([NH:11][C:12]2[CH:17]=[CH:16][C:15]([N:18]3[CH2:23][CH2:22][O:21][CH2:20][CH2:19]3)=[CH:14][CH:13]=2)=[C:6]([CH:10]=1)[C:7]([NH2:9])=[O:8].FC1C(C2CCC[C@H](NC(NC3SC=CN=3)=O)C=2)=NC(NC2C=CC(N3CCOCC3)=CC=2)=C(C=1)C(N)=O>>[F:1][C:2]1[C:3]([C:24]2[CH2:29][CH2:28][CH2:27][CH:26]([NH:30][C:31]([NH:33][C:34]3[S:35][CH:36]=[CH:37][N:38]=3)=[O:32])[CH:25]=2)=[N:4][C:5]([NH:11][C:12]2[CH:17]=[CH:16][C:15]([N:18]3[CH2:23][CH2:22][O:21][CH2:20][CH2:19]3)=[CH:14][CH:13]=2)=[C:6]([CH:10]=1)[C:7]([NH2:9])=[O:8]
Reactant: NC(=O)c1cc(F)c(C2=C[C@H](NC(=O)Nc3nccs3)CCC2)nc1Nc1ccc(N2CCOCC2)cc1
Agent: NC(=O)c1cc(F)c(C2=C[C@@H](NC(=O)Nc3nccs3)CCC2)nc1Nc1ccc(N2CCOCC2)cc1
Product: NC(=O)c1cc(F)c(C2=CC(NC(=O)Nc3nccs3)CCC2)nc1Nc1ccc(N2CCOCC2)cc1

Procedure:
The sample was separated on a chiral column: Chiralpak AS-H 25×3 cm, 5 μm; Column Temp. 40° C.; Flow rate: 150 mL/min; Mobile Phase: CO2/MeOH=65/35; to give the two enantiomers. Example 33: (R)-5-fluoro-2-(4-morpholinophenylamino)-6-(3-(3-thiazol-2-ylureido)cyclohex-1-enyl)nicotinamide and Example 440: (S)-5-fluoro-2-(4-morpholinophenylamino)-6-(3-(3-thiazol-2-ylureido)cyclohex-1-enyl)nicotinamide.
Reaction SMILES: [CH2:1]([O:3][C:4]([NH:6][CH:7]=[CH:8][C:9]1[CH:19]=[CH:18][C:12]([O:13][CH2:14][CH:15]2[O:17][CH2:16]2)=[CH:11][CH:10]=1)=[O:5])[CH3:2].[C:20]([NH2:24])([CH3:23])([CH3:22])[CH3:21]>C(O)(C)C>[C:4]([NH:6][CH:7]=[CH:8][C:9]1[CH:19]=[CH:18][C:12]([O:13][CH2:14][CH:15]([OH:17])[CH2:16][NH:24][C:20]([CH3:23])([CH3:22])[CH3:21])=[CH:11][CH:10]=1)([O:3][CH2:1][CH3:2])=[O:5]
Reactant: CC(C)(C)N
Reactant: CCOC(=O)NC=Cc1ccc(OCC2CO2)cc1
Solvent: CC(C)O
Product: CCOC(=O)NC=Cc1ccc(OCC(O)CNC(C)(C)C)cc1

Procedure:
Analogously to the description in Example 2, 2.5 g (0.01 mol) of 1-[p-(2-ethoxycarbonylaminovinyl)-phenoxy]-2,3-epoxy-propane, on reaction with 1.0 ml (0.01 mol) of tert.-butylamine in 50 ml of isopropanol, yield 1-[p-(2-carbethoxyaminovinyl)-phenoxy]-2-hydroxy-3-tertiary-butylaminopropane as an oil. Its N-cyclohexyl-sulphamate, prepared in acetone, shows a melting point of 99°-100° C. (from ether).
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[C:3]1[C:4](=[O:10])[NH:5][C:6](=[O:9])[NH:7][CH:8]=1.C(=O)([O-])[O-].[K+].[K+].I[CH2:20][CH3:21]>CN(C=O)C>[CH2:20]([N:7]1[CH:8]=[C:3]([C:2]([F:11])([F:1])[F:12])[C:4](=[O:10])[NH:5][C:6]1=[O:9])[CH3:21]
Reactant: CCI
Reactant: O=c1[nH]cc(C(F)(F)F)c(=O)[nH]1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCn1cc(C(F)(F)F)c(=O)[nH]c1=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 27 %

Procedure:
To a stirred mixture of 5-trifluoromethyl uracil (1.8 g, 10 mmol) and powdered anhydrous potassium carbonate (1.38 g, 10 mmol) in DMF (50 mL), was added iodoethane (0.8 mL, 10 mmol). After stirring overnight at room temperature, the mixture was evaporated in vacuo and the residue was purified by silica gel column chromatography (eluent ethyl acetate:hexane (1:1)) to afford 563 mg (27%) of 1-ethyl-5-trifluoromethyl uracil as a white solid. m.p. 259-260° C.; 1H-NMR (200 MHz, CDCl3/CD3OD) δ 1.35 (3H, d, J=7.2 Hz), 3.87 (2H, q, J=7.2 Hz), 7.94 (1H, s); m/z (EI) 208 (M+).
Reaction SMILES: CC(C)([O-])C.[K+].[Br-].[CH2:8]([O:12][C:13]1[CH:38]=[CH:37][C:16]([CH2:17][P+](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=[CH:15][CH:14]=1)[CH2:9][CH2:10][CH3:11].[CH:39]([CH:41]1[CH:46]2[CH2:47][CH2:48][N:43]([CH2:44][CH2:45]2)[CH2:42]1)=O.O>O1CCCC1>[CH2:8]([O:12][C:13]1[CH:14]=[CH:15][C:16](/[CH:17]=[CH:39]\[CH:41]2[CH:46]3[CH2:47][CH2:48][N:43]([CH2:44][CH2:45]3)[CH2:42]2)=[CH:37][CH:38]=1)[CH2:9][CH2:10][CH3:11]
Reactant: CCCCOc1ccc(C[P+](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Reactant: O=CC1CN2CCC1CC2
Agent: CC(C)(C)[O-]
Agent: [Br-]
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Product: CCCCOc1ccc(/C=C\C2CN3CCC2CC3)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Potassium-tert-butoxide (2.46 g) was added to a stirred, ice-cooled suspension of (4-butoxybenzyl)-triphenylphosphonium bromide (10.1 g) in dry tetrahydrofuran (300 ml) under an atmosphere of argon. The reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was cooled to -10° C. and a solution of 3-formylquinuclidine (750 mg) in dry tetrahydrofuran (20 ml) was added dropwise over 15 minutes. The reaction mixture was stirred at room temperature overnight and water (1.0 ml) was then added. The tetrahydrofuran was evaporated and the residue was triturated several times with ether and filtered. The ether extracts were combined and evaporated to give an oil which was purified by flash column chromatography, using 10% methanol in dichloromethane containing 1% 0.880 ammonia as eluent, to give Z-3-[2-(4-butoxyphenyl)vinyl]-quinuclidine (Rf=0.3). This was dissolved in ether and an excess of a solution of hydrogen chloride in ether added to give a solid which was collected by filtration. There was thus obtained Z-3-[2-(4-butoxyphenyl)vinyl]quinuclidine hydrogen chloride as a colourless solid, m.p. 146°-149° C. (220 mg); microanalysis, found: C, 68.2; H, 8.4; N, 4.2%; C19H27NO.HCl.0.75H2O requires: C, 68.06; H, 8.8; N, 4.18%; NMR (DMSO-d6): 0.9-0.97(3H, t), 1.35-1.49(2H, m), 1.66-2.16(8H, m), 2.82-2.95(1H, m), 3.08-3.3(4H, m), 3.41-3.58(1H, t), 3.9-4.03(2H, t), 5.65-5.78(1H, d of d), 6.43-6.53(1H, d, J=11 Hertz), 6.9-7.0(2H, d) and 7.16-7.26(2H, d); m/Z 286 (M+H).
Reaction SMILES: [NH2:1][C:2]1[C:3]2[N:11]=[C:10](C3C=C(C=C(F)C=3)C(NCC3CCN(C)CC3)=O)[CH:9]=[CH:8][C:4]=2[N:5]=[CH:6][N:7]=1.Cl.[NH:31]1[CH:35]=[CH:34][N:33]=[C:32]1[CH:36]1[CH2:41][CH2:40][CH2:39][NH:38][CH2:37]1.C(N(CC)CC)C.CC(N(C)C)=O>ClCCl>[NH:31]1[CH:35]=[CH:34][N:33]=[C:32]1[CH:36]1[CH2:41][CH2:40][CH2:39][N:38]([C:10]2[CH:9]=[CH:8][C:4]3[N:5]=[CH:6][N:7]=[C:2]([NH2:1])[C:3]=3[N:11]=2)[CH2:37]1
Reactant: c1c[nH]c(C2CCCNC2)n1
Reactant: CN1CCC(CNC(=O)c2cc(F)cc(-c3ccc4ncnc(N)c4n3)c2)CC1
Agent: Cl
Solvent: ClCCl
Solvent: CC(=O)N(C)C
Solvent: CCN(CC)CC
Product: Nc1ncnc2ccc(N3CCCC(c4ncc[nH]4)C3)nc12
Temperature: 100 °C
Reaction time: 8 h
Yield: 8 %

Procedure:
To an 8 mL screw-cap vial was added 6-chloropyrido[3,2-d]pyrimidin-4-amine 10 (1 equiv., 0.68 mmol, 123 mg), 3-(1H-imidazol-2-yl)piperidine hydrochloride (1 equiv., 0.68 mmol, 128 mg), triethylamine (3 equiv., 2.05 mmol, 0.287 mL) and DMA (2 mL). The reaction was capped and shaken at 100° C. overnight. The reaction was then cooled to room temperature, diluted with dichloromethane, and washed with water. The organic was then concentrated, then purified by reverse phase HPLC, yielding 16 mg of product. 1H NMR (400 MHz, DMSO) δ 8.20-8.14 (m, 3H), 7.82-7.77 (m, 1H), 7.54-7.49 (d, J=9.4 Hz, 1H), 7.38-7.28 (d, J=8.1 Hz, 2H), 6.96-6.94 (s, 2H), 4.79-4.71 (d, J=12.7 Hz, 1H), 4.53-4.46 (d, J=17.4 Hz, 1H), 3.17-3.07 (m, 1H), 3.07-2.96 (m, 1H), 2.96-2.84 (m, 1H), 2.18-2.08 (m, 1H), 1.91-1.77 (m, 2H), 1.66-1.51 (m, 1H). LCMS M/Z (M+H)=296.