Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[N:11]=[C:10](Cl)[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([N:13]3[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]3)[CH:8]=2)[N:3]=1.[CH:19]1([C:22]2[CH:23]=[C:24]([NH2:27])[NH:25][N:26]=2)[CH2:21][CH2:20]1>C(O)C>[Cl:1][C:2]1[N:11]=[C:10]([NH:27][C:24]2[NH:25][N:26]=[C:22]([CH:19]3[CH2:21][CH2:20]3)[CH:23]=2)[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([N:13]3[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]3)[CH:8]=2)[N:3]=1
Reactant: Clc1nc(Cl)c2cc(N3CCCCC3)ccc2n1
Reactant: Nc1cc(C2CC2)n[nH]1
Solvent: CCO
Product: Clc1nc(Nc2cc(C3CC3)n[nH]2)c2cc(N3CCCCC3)ccc2n1
Reaction time: 10 h
Yield: 61 %

Procedure:
To 2,4-Dichloro-6-piperidin-1-yl-quinazoline (100 mg, 0.365 mmol), in ethanol (5 omL) was added 5-Cyclopropyl-2H-pyrazol-3-ylamine (88 mg 0.71 mmol). The additional resulted in the formation of a white precipitate. The partial solution was stirred for 10 hr and (2-Chloro-6-piperidin-1-yl-quinazolin-4-yl)-(5-cyclopropyl-2H-pyrazol-3-yl)-amine was colleted by filtration to give 80 mg (61% yield). HPLC tr=4.90 min (100%), LCMS m/e 369.31 (M+H), 367.28 (M-H) tr=3.41 min, HNMR (500 MHz, dmso): 12.30-12.25 (1H, bs), 10.67 (1H, s), 7.80-7.85 (1H, s), 7.65 91H, d), 7.50 (1H, d), 6.50 (1H, bs), 3.40 (4H, m0, 2.90 (1H, m), 1.70-1.55 (6H, m), 0.95 (2H, m), 0.70 (2H, m).
Reaction SMILES: O=[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([C:12]3[CH:13]=[C:14]([CH:17]=[CH:18][CH:19]=3)[C:15]#[N:16])[CH:10]=2)[O:5][CH:4]([C:20]2[CH:21]=[N:22][CH:23]=[CH:24][CH:25]=2)[CH2:3]1.C[Si]([N:30]=[C:31]=[N:32][Si](C)(C)C)(C)C>C(Cl)Cl.Cl[Ti](Cl)(Cl)Cl>[C:15]([C:14]1[CH:13]=[C:12]([C:9]2[CH:10]=[C:11]3[C:6](=[CH:7][CH:8]=2)[O:5][CH:4]([C:20]2[CH:21]=[N:22][CH:23]=[CH:24][CH:25]=2)[CH2:3]/[C:2]/3=[N:32]\[C:31]#[N:30])[CH:19]=[CH:18][CH:17]=1)#[N:16]
Reactant: C[Si](C)(C)N=C=N[Si](C)(C)C
Reactant: N#Cc1cccc(-c2ccc3c(c2)C(=O)CC(c2cccnc2)O3)c1
Agent: Cl[Ti](Cl)(Cl)Cl
Solvent: ClCCl
Product: N#C/N=C1\CC(c2cccnc2)Oc2ccc(-c3cccc(C#N)c3)cc21
Temperature: 0 °C
Reaction time: 1 h
Yield: 90.8 %

Procedure:
To a solution of 3-(4-oxo-2-(pyridine-3-yl)chroman-6-yl)benzonitrile (70 mg, 0.22 mmol) in anhydrous DCM (3 mL) was added TiCl4 (1 M solution in DCM, 293 mg, 1.54 mmol) dropwise within 15 minutes at room temperature in the absence of light. The resulting mixture was stirred for 1 h after the addition. To this mixture was added bis-trimethylsilylcarbodiimide (164 mg, 0.88 mmol) dropwise. The resulting mixture was stirred overnight. The reaction mixture was poured into ice-water and extracted with DCM. The combined organic phases were dried over anhydrous Na2SO4, and filtered. The filtrate was concentrated to give (E)-N-(6-(3-cyanophenyl)-2-(pyridine-3-yl)chroman-4-ylidene)cyanamide (70 mg, 93%), which was used in next step without further purification.
Reaction SMILES: [CH:1]1([C:6]2[N:11]=[C:10](O)[C:9]3[CH2:13][CH2:14][CH2:15][C:8]=3[N:7]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.P(Cl)(Cl)([Cl:18])=O>>[Cl:18][C:10]1[C:9]2[CH2:13][CH2:14][CH2:15][C:8]=2[N:7]=[C:6]([CH:1]2[CH2:5][CH2:4][CH2:3][CH2:2]2)[N:11]=1
Reactant: Oc1nc(C2CCCC2)nc2c1CCC2
Reactant: O=P(Cl)(Cl)Cl
Product: Clc1nc(C2CCCC2)nc2c1CCC2
Reaction time: 1 h
Yield: 85.7 %

Procedure:
A mixture of 2-cyclopentyl-6,7-dihydro-5H-cyclopentapyrimidin-4-ol (4.5 g, 22 mmol) and phosphorus oxychloride (13 mL, 130 mmol) was heated to reflux for 4 hours. Thereafter, volatiles were evaporated under reduced pressure and the mixture was poured over ice-water. After stirring for 1 hour, the product was extracted with dichloromethane (3×50 mL). The combined organic extracts were washed with water, treated with activated charcoal, dried over anhydrous Na2SO4, filtered, and the filtrate was concentrated under reduced pressure to afford the title compound as a light yellow solid (4.2 g, 86% yield)
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC3C(=CC=CC=3)C=2C2C3C(=CC=CC=3)C=CC=2P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(=O)([O-])[O-].[Cs+].[Cs+].[C:53]1([S:59]([C:62]2[CH:63]=[C:64](Br)[CH:65]=[CH:66][CH:67]=2)(=[O:61])=[O:60])[CH:58]=[CH:57][CH:56]=[CH:55][CH:54]=1.[C:69]([O:73][C:74]([N:76]1[CH2:81][CH2:80][NH:79][CH2:78][CH2:77]1)=[O:75])([CH3:72])([CH3:71])[CH3:70]>O1CCOCC1>[C:53]1([S:59]([C:62]2[CH:63]=[C:64]([N:79]3[CH2:78][CH2:77][N:76]([C:74]([O:73][C:69]([CH3:72])([CH3:71])[CH3:70])=[O:75])[CH2:81][CH2:80]3)[CH:65]=[CH:66][CH:67]=2)(=[O:61])=[O:60])[CH:58]=[CH:57][CH:56]=[CH:55][CH:54]=1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: O=S(=O)(c1ccccc1)c1cccc(Br)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Agent: c1ccc(P(c2ccccc2)c2ccc3ccccc3c2-c2c(P(c3ccccc3)c3ccccc3)ccc3ccccc23)cc1
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)N1CCN(c2cccc(S(=O)(=O)c3ccccc3)c2)CC1
Temperature: 100 °C
Yield: 71.2 %

Procedure:
A solution of 2 2,2′-bis(diphenylphosphino)-1,1′-binaphthyl (BINAP) (62 mg, 0.1 mmol) and cesium carbonate (329 mg, 1.01 mmol) in dry dioxane (2 ml) were sonicated for 45 min, under argon. To this solution was added 3-phenylsulfonylbromobenzene (D2) (200 mg, 0.67 mmol) and 1-(tert-butyloxycarbonyl)piperazine (314 mg, 1.68 mmol) and the reaction heated at 100° C. for 18 h. The reaction mixture was evaporated in vacuo and the residue partitioned between water (50 ml) and dichloromethane (50 ml). The organic layer was washed with sat. sodium hydrogen carbonate (50 ml), 10% citric acid (50 ml), brine (50 ml) and then dried (MgSO4). Solvents evaporated in vacuo and the residue purified by column chromatography (silica gel; 0-60% ethyl acetate/petroleum ether) to give the product as a colourless oil (192 mg, 71%)
Reaction SMILES: [CH:1]1([CH:7]([C:9]2[C:10]([CH3:24])=[N:11][N:12]([C:14]3[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][CH:15]=3)[CH:13]=2)O)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[NH2:25][C:26]1[CH:31]=[CH:30][C:29]([C:32]([N:34]([CH3:42])[CH2:35][CH2:36][C:37]([O:39]CC)=[O:38])=[O:33])=[CH:28][CH:27]=1>>[CH:1]1([CH:7]([NH:25][C:26]2[CH:27]=[CH:28][C:29]([C:32]([N:34]([CH3:42])[CH2:35][CH2:36][C:37]([OH:39])=[O:38])=[O:33])=[CH:30][CH:31]=2)[C:9]2[C:10]([CH3:24])=[N:11][N:12]([C:14]3[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][CH:15]=3)[CH:13]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: Cc1nn(-c2ccc(C(F)(F)F)cc2)cc1C(O)C1CCCCC1
Reactant: CCOC(=O)CCN(C)C(=O)c1ccc(N)cc1
Product: Cc1nn(-c2ccc(C(F)(F)F)cc2)cc1C(Nc1ccc(C(=O)N(C)CCC(=O)O)cc1)C1CCCCC1
Yield: 34.6 %

Procedure:
Using cyclohexyl{3-methyl-1-[4-(trifluoromethyl)phenyl]-1H-pyrazol-4-yl}methanol (0.36 g) synthesized in Example 27(3) and ethyl 3-{[(4-aminophenyl)carbonyl](methyl)amino}propanoate (0.40 g) synthesized in Example 2(2) and in the same manner as in Example 1(7), the title object compound (0.20 g, 35%) was obtained as a white solid.
Reaction SMILES: [CH2:1](O)[C:2](N)([CH2:5]O)[CH2:3][OH:4].Cl.[Mg+2].[Cl-].[Cl-].[O:13]=[CH:14][C@@H:15]([C@H:17]([C@@H:19]([C@@H:21]([CH2:23][OH:24])[OH:22])[OH:20])[OH:18])[OH:16].P(OC[C@H]1O[C@@H](N2C=CC(=O)NC2=O)[C@H](O)[C@@H]1O)(OP(O)(O)=O)(=O)O.C([O-])(=O)C(C)C>>[C:3]([O:13][C@@H:14]1[O:22][C@H:21]([CH2:23][OH:24])[C@@H:19]([OH:20])[C@H:17]([OH:18])[C@H:15]1[OH:16])(=[O:4])[CH:2]([CH3:5])[CH3:1]
Reactant: O=C[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO
Reactant: NC(CO)(CO)CO
Agent: CC(C)C(=O)[O-]
Agent: Cl
Agent: O=c1ccn([C@@H]2O[C@H](COP(=O)(O)OP(=O)(O)O)[C@@H](O)[C@H]2O)c(=O)[nH]1
Product: CC(C)C(=O)O[C@@H]1O[C@H](CO)[C@@H](O)[C@H](O)[C@H]1O
Reaction time: 2 h

Procedure:
A reaction mixture of 50 mM Tris-HCl (pH 7.0), 10 mM MgCl2, 10 mM dithiotheritol 10 mM uridine 5'-diphosphate glucose, 1 mM isobutyrate, 2 units of GTI activity is made up. Reaction is carried out for 2 hrs. at 37° C. 1-O-isobutyryl-β-D-glucose is formed.
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]([CH2:11][NH:12][CH3:13])=[C:3]1[CH3:14].[NH2:15][C:16]1[N:21]=[CH:20][C:19](/[CH:22]=[CH:23]/[C:24]([OH:26])=O)=[CH:18][CH:17]=1.CCN(CC)CC.C1C=CC2N(O)N=NC=2C=1.O.C(Cl)CCl>CN(C=O)C.C(C1CCCCC1)C1CCCCC1>[NH2:15][C:16]1[N:21]=[CH:20][C:19](/[CH:22]=[CH:23]/[C:24]([N:12]([CH2:11][C:4]2[C:5]3[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=3)[N:2]([CH3:1])[C:3]=2[CH3:14])[CH3:13])=[O:26])=[CH:18][CH:17]=1
Reactant: Nc1ccc(/C=C/C(=O)O)cn1
Reactant: CNCc1c(C)n(C)c2ccccc12
Agent: C1CCC(CC2CCCCC2)CC1
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: Cc1c(CN(C)C(=O)/C=C/c2ccc(N)nc2)c2ccccc2n1C
Yield: 96.8 %

Procedure:
To a stirred solution of 1,2-dimethyl-3-(methylaminomethyl)-1H-indol e (0.8 g, 4.2 mmole) in 1:1 DMF/CH2Cy2 (30 mL) at RT was added (E)-3-(6-aminopyridin-3-yl)acrylic acid (0.7 g, 4.3 mmole), Et3N (0.61 ml, 4.3 mmole), HOBt H2O (0.58 g, 4.3 mmole) and EDC (0.83 g, 4.3 mmole). After 16 h the reaction was concentrated under vacuum and the residue was taken up in EtOAc (100 mL). The solution was washed with 1.0 N Na2CO3 (100 mL) then with brine, dried (Na2SO4), and concentrated. Purification by flas h chromatography on silica gel (4% MeOv.CHCl3) followed by trituration with 1:1 Et2O/petroleum ether and drying under vacuum gave (he title compound (1.36 g, 97%) as an off-white solid: MS (ES) H+e 335.2 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:22])=[C:6]([C:8]2[NH:9][C:10]([C:15](=O)/[CH:16]=[CH:17]/[N:18](C)[CH3:19])=[CH:11][C:12]=2[C:13]#[N:14])[CH:7]=1.C(O)(=O)C.C(N)=[NH:28].O>CN(C=O)C>[N:18]1[CH:17]=[CH:16][C:15]([C:10]2[NH:9][C:8]([C:6]3[CH:7]=[C:2]([Cl:1])[CH:3]=[CH:4][C:5]=3[CH3:22])=[C:12]([C:13]#[N:14])[CH:11]=2)=[N:28][CH:19]=1
Reactant: Cc1ccc(Cl)cc1-c1[nH]c(C(=O)/C=C/N(C)C)cc1C#N
Reactant: N=CN
Solvent: CN(C)C=O
Solvent: O
Solvent: CC(=O)O
Product: Cc1ccc(Cl)cc1-c1[nH]c(-c2ccncn2)cc1C#N
Temperature: 150 °C

Procedure:
To a suspension of 2-(5-chloro-2-methyl-phenyl)-5-((E)-3-dimethylamino-acryloyl)-1H-pyrrole-3-carbonitrile (313 mg, 1.0 mmol) in DMF (5 mL) was added formamidine acetate (208 mg, 2.0 mmol). The mixture was heated to 150° C. for 5 h under efficient stirring. The resulting mixture was diluted by dropwise addition of water and extracted with EtOAc.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[CH:9]([CH3:20])[C:10]([C:14]1[CH:15]=[N:16][CH:17]=[CH:18][CH:19]=1)([OH:13])[CH2:11][OH:12].[H-].[Na+].[CH2:23](I)[CH3:24].C(=O)(O)[O-].[Na+]>CN(C)C=O>[CH2:23]([O:12][CH2:11][C:10]([CH:9]([CH3:20])[C:3]1[CH:4]=[CH:5][C:6]([Cl:8])=[CH:7][C:2]=1[Cl:1])([C:14]1[CH:15]=[N:16][CH:17]=[CH:18][CH:19]=1)[OH:13])[CH3:24]
Reactant: CCI
Reactant: CC(c1ccc(Cl)cc1Cl)C(O)(CO)c1cccnc1
Agent: O=C([O-])O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOCC(O)(c1cccnc1)C(C)c1ccc(Cl)cc1Cl
Reaction time: 6 h

Procedure:
1.2 g of 3-(2,4-dichlorophenyl)-2-(3-pyridyl)-1,2-butanediol are dissolved under argon in 19 ml of N,N-dimethylformamide and treated at -15° C. with 0.12 g of sodium hydride (99%). The mixture is left to come to 0° C. and stirred at this temperature for 6 hours and 0.4 ml of ethyl iodide is added thereto. There thereby results a red-orange colored suspension which, after stirring at 0° C. for 1 hour, is treated with 20 ml of saturated aqueous sodium bicarbonate solution and subsequently evaporated under a pressure of 0.1 mmHg in order to remove the solvent. The residue is taken up in water and the aqueous solution extracted with ethyl acetate, and the organic phase is washed with saturated aqueous sodium chloride solution and then evaporated to dryness under reduced pressure. The oily residue is purified by chromatography on silica gel with diethyl ether/n-hexane (17:3) and it is recrystallized from methylene chloride/n-hexane. In this manner there is obtained 0.7 g of α-ethoxymethyl-α-(2,4-dichloro-α-methylbenzyl)-3-pyridinemethanol as colorless crystals, m.p. 86° C.
Reaction SMILES: [Br:1][C:2]1[CH:21]=[CH:20][C:5]([O:6][C:7]2[CH:19]=[CH:18][C:10]([C:11]([CH:13]=[CH:14][C:15]([OH:17])=[O:16])=[O:12])=[CH:9][CH:8]=2)=[CH:4][CH:3]=1.[CH3:22][C:23]1C=CC(OC2C=CC(C(C=CC(O)=O)=O)=CC=2)=CC=1>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([O:6][C:7]2[CH:8]=[CH:9][C:10]([C:11]([CH:13]=[CH:14][C:15]([O:17][CH2:22][CH3:23])=[O:16])=[O:12])=[CH:18][CH:19]=2)=[CH:20][CH:21]=1
Reactant: Cc1ccc(Oc2ccc(C(=O)C=CC(=O)O)cc2)cc1
Reactant: O=C(O)C=CC(=O)c1ccc(Oc2ccc(Br)cc2)cc1
Product: CCOC(=O)C=CC(=O)c1ccc(Oc2ccc(Br)cc2)cc1

Procedure:
The procedure in Example 17(1) was followed, except that 6.92 g 3-[4-(4-bromophenoxy)benzoyl]acrylic acid were used in place of 3-[4-(4-methylphenoxy)benzoyl]acrylic acid, to give 6.00 g of ethyl 3-[4-(4-bromophenoxy)benzoyl]acrylate in the form of an oil.
Reaction SMILES: S1C=CN=C1.[NH2:6][C:7]1[N:12]=[CH:11][N:10]=[C:9]2[N:13]([C@H:30]3[CH2:35][CH2:34][C@@H:33]([N:36]4[CH2:41][CH2:40][N:39]([CH3:42])[CH2:38][CH2:37]4)[CH2:32][CH2:31]3)[N:14]=[C:15]([C:16]3[CH:21]=[CH:20][C:19]([NH:22][C:23]4[S:24][CH:25]=[C:26]([CH2:28][CH3:29])[N:27]=4)=[CH:18][CH:17]=3)[C:8]=12.Br[CH2:44][C:45]([C:47]1C=CC=C[CH:48]=1)=O>>[NH2:6][C:7]1[N:12]=[CH:11][N:10]=[C:9]2[N:13]([C@H:30]3[CH2:35][CH2:34][C@@H:33]([N:36]4[CH2:41][CH2:40][N:39]([CH3:42])[CH2:38][CH2:37]4)[CH2:32][CH2:31]3)[N:14]=[C:15]([C:16]3[CH:17]=[CH:18][C:19]([NH:22][C:23]4[S:24][CH:25]=[C:26]([C:28]5[CH:48]=[CH:47][CH:45]=[CH:44][CH:29]=5)[N:27]=4)=[CH:20][CH:21]=3)[C:8]=12
Reactant: CCc1csc(Nc2ccc(-c3nn([C@H]4CC[C@@H](N5CCN(C)CC5)CC4)c4ncnc(N)c34)cc2)n1
Reactant: O=C(CBr)c1ccccc1
Agent: c1cscn1
Product: CN1CCN([C@H]2CC[C@@H](n3nc(-c4ccc(Nc5nc(-c6ccccc6)cs5)cc4)c4c(N)ncnc43)CC2)CC1

Procedure:
The procedure for thiazole synthesis, described in the preparation of cis-N2-(4-{4-amino-1-[4-(4-methylpiperazino)cyclohexyl]-1H-pyrazolo[3,4-d]pyrimidin-3-yl}phenyl)-4-ethyl-1,3-thiazol-2-amine, was employed with the exception that 2-bromoacetophenone (0.131 g, 0.66 mmol) was used as the alkylating agent. Purification of the product by preparative HPLC (25 to 100% acetonitrile in 0.1 M aqueous ammonium acetate over 20 min at 21 mL/min using an 8μ Hypersil HS C18, 250×21 mm column, Rt 8.7-9.8 min) afforded cis-N2-(4-{4-amino-1-[4-(4-methylpiperazino)cyclohexyl]-1H-pyrazolo[3,4-d]pyrimidin-3-yl}phenyl)-4-phenyl-1,3-thiazol-2-amine as a yellow powder (0.036 g, 0.064 mmol); RP-HPLC (25 to 100% acetonitrile in 0.1 M aqueous ammonium acetate over 10 min at 1 mL/min using a 5μ Hypersil HS C18, 250×4.6 mm column) Rt 8.22 min; MS (MH)+ 566.
Reaction SMILES: [OH:1][CH2:2][C:3]([CH2:7][OH:8])([CH2:5][OH:6])[CH3:4].CO[C:11](OC)([CH3:13])[CH3:12].S(=O)(=O)(O)O>CC(C)=O>[CH3:4][C:3]1([CH2:7][OH:8])[CH2:5][O:6][C:11]([CH3:13])([CH3:12])[O:1][CH2:2]1
Reactant: COC(C)(C)OC
Reactant: CC(CO)(CO)CO
Agent: O=S(=O)(O)O
Solvent: CC(C)=O
Product: CC1(CO)COC(C)(C)OC1
Temperature: 0 °C
Reaction time: 2 h
Yield: 72 %

Procedure:
In a three-necked flaks, 1,1,1-tris(hydroxymethyl)ethane (200 g) and 2,2-dimethoxypropane (260 g) were suspended in acetone (150 g), one droplet of concentrated sulfuric acid was added thereto at 0° C., and then the mixture was stirred for 2 hours. The temperature was changed back to a room temperature, and the mixture was stirred for 2 hours. After acetone was distilled off, a fraction obtained at 70° C. under reduced pressure (1.7 mmHg) was collected to obtain (1,4,4-trimethyl-3,5-dioxanyl)methane-1-ol (192 g).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15]2[N:20]=[C:19]([O:21][CH3:22])[N:18]=[C:17]([O:23][CH3:24])[N:16]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.[ClH:25]>O1CCOCC1>[ClH:25].[ClH:25].[CH3:22][O:21][C:19]1[N:18]=[C:17]([O:23][CH3:24])[N:16]=[C:15]([NH:14][CH:11]2[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]2)[N:20]=1
Reactant: COc1nc(NC2CCN(C(=O)OC(C)(C)C)CC2)nc(OC)n1
Agent: Cl
Solvent: C1COCCO1
Product: COc1nc(NC2CCNCC2)nc(OC)n1

Procedure:
A solution of 4-(4,6-dimethoxy-[1,3,5]triazin-2-ylamino)-piperidine-1-carboxylic acid tert-butyl ester (2.60 g, 7.66 mmol) in 4 M HCl in dioxane (100 mL) was stirred at 0° C. for 1 h. The solvent was removed under reduced pressure and the crude product used in the consecutive step without further purification assuming quantitative deprotection and formation of the dihydrochloride salt. MS (ISP): 240.4 [M+H]+.
Reaction SMILES: [F:1][C:2]1[C:7]([S:8]([CH3:11])(=[O:10])=[O:9])=[CH:6][CH:5]=[CH:4][C:3]=1[N:12]1[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]1.C(=O)([O-])[O-].[K+].[K+].I[CH2:25][CH2:26][CH3:27].Cl>C(#N)C>[F:1][C:2]1[C:7]([S:8]([CH3:11])(=[O:9])=[O:10])=[CH:6][CH:5]=[CH:4][C:3]=1[N:12]1[CH2:17][CH2:16][N:15]([CH2:25][CH2:26][CH3:27])[CH2:14][CH2:13]1
Reactant: CCCI
Reactant: CS(=O)(=O)c1cccc(N2CCNCC2)c1F
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCCN1CCN(c2cccc(S(C)(=O)=O)c2F)CC1

Procedure:
Preparation according to Example 1: 1-[2-fluoro-3-(methylsulfonyl)phenyl]piperazine (0.13 g, 0.52 mmol), acetonitrile (4 ml), potassium carbonate (014 g, 1.1 mmol) and 1-iodopropane (0.05 ml, 0.55 mmol). Yield: 0.1 g (64%). The amine was converted to the hydrochloric acid salt and recrystallized from ethanol/diethyl ether: M.p. 241-243° C. MS m/z (relative intensity, 70 eV) 300 (M+, 18), 272 (14), 271 (bp), 228 (11), 70 (49).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[O:16][C:15]3([CH2:21][CH2:20][CH:19]([O:22][CH3:23])[CH2:18][CH2:17]3)[C:8]3([NH:12][C:11](=S)[C:10]([CH3:14])=[N:9]3)[C:6]=2[CH:7]=1.[NH3:24].CO>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[O:16][C:15]3([CH2:21][CH2:20][CH:19]([O:22][CH3:23])[CH2:18][CH2:17]3)[C:8]3([N:12]=[C:11]([NH2:24])[C:10]([CH3:14])=[N:9]3)[C:6]=2[CH:7]=1
Reactant: N
Reactant: COC1CCC2(CC1)Oc1ccc(Br)cc1C21N=C(C)C(=S)N1
Solvent: CO
Product: COC1CCC2(CC1)Oc1ccc(Br)cc1C21N=C(C)C(N)=N1
Temperature: 120 °C
Yield: 27 %

Procedure:
A mixture of 5′-bromo-4-methoxy-5″-methyldispiro[cyclohexane-1,2′-[1]benzofuran-3′,2″-imidazole]-4″(3″H)-thione (Example 29 Step 3, 365 mg, 0.92 mmol) and 7M ammonia in MeOH (10 mL, 70.00 mmol) was prepared in a microwave vial. The vial was sealed and the reaction was heated at 120° C. for 30 min in a microwave reactor. The mixture was concentrated and the residue was dissolved in 7M ammonia in MeOH (4 mL) and heated once more at 120° C. for 30 min using MW. Again, the mixture was concentrated, 7M ammonia in MeOH (10 mL, 70.00 mmol) was added and the mixture was heated at 120° C. The mixture was concentrated and the crude product was dissolved in 20% MeOH in DCM and filtered through a silica pad and eluted is with 20% MeOH in DCM. After concentration of the organic layer, DCM was added to the residue. A solid was formed which was filtered off and washed with DCM, yielding 94 mg of the title compound (27% yield). The mother liquor was concentrated, Et2O was added and the solid was filtered off and dried, yielding a second crop of the title compound (85 mg, 24% yield). 1H NMR (500 MHz, DMSO-d6) δ ppm 1.19 (d, 1 H), 1.43 (m, 3 H), 1.80 (d, 2 H), 1.95 (m, 2 H), 2.20 (s, 3 H), 3.07 (d, 1 H), 3.21 (s, 3 H), 6.68 (d, 1 H), 6.74 (br. s., 2 H), 6.87 (d, 1 H), 7.31 (dd, 1 H); MS (ES+) m/z 379 [M+H]+.
Reaction SMILES: [OH:1][CH:2]1[CH2:7][CH2:6][N:5]([C:8]2[N:13]=[CH:12][C:11]([C:14]3[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][C:15]=3[Cl:21])=[CH:10][N:9]=2)[CH2:4][CH2:3]1.[C:22](OC(=O)C)(=[O:24])[CH3:23]>>[C:22]([O:1][CH:2]1[CH2:3][CH2:4][N:5]([C:8]2[N:9]=[CH:10][C:11]([C:14]3[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][C:15]=3[Cl:21])=[CH:12][N:13]=2)[CH2:6][CH2:7]1)(=[O:24])[CH3:23]
Reactant: CC(=O)OC(C)=O
Reactant: OC1CCN(c2ncc(-c3ccc(Cl)cc3Cl)cn2)CC1
Product: CC(=O)OC1CCN(c2ncc(-c3ccc(Cl)cc3Cl)cn2)CC1

Procedure:
6 g of 2-(4-hydroxypiperidino)-5-(2,4-dichlorophenyl)pyrimidine (Example 5) and 60 ml of acetic anhydride are heated under reflux for 4 hours.
Reaction SMILES: [CH:1]1([C:7]2[C:8]3[CH:9]=[CH:10][C:11]([C:27]([O:29]C)=[O:28])=[CH:12][C:13]=3[N:14]3[C:21]=2[C:20]2[CH:22]=[CH:23][CH:24]=[CH:25][C:19]=2[O:18][CH2:17][C@@H:16]([OH:26])[CH2:15]3)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[OH-].[Na+].[Cl-].[CH2:34]([NH+:41]([CH3:45])[CH2:42][CH2:43][Cl:44])[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1>C1(C)C=CC=CC=1>[Cl-:44].[CH2:34]([NH+:41]([CH3:45])[CH2:42][CH2:43][O:26][C@H:16]1[CH2:15][N:14]2[C:13]3[CH:12]=[C:11]([C:27]([OH:29])=[O:28])[CH:10]=[CH:9][C:8]=3[C:7]([CH:1]3[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]3)=[C:21]2[C:20]2[CH:22]=[CH:23][CH:24]=[CH:25][C:19]=2[O:18][CH2:17]1)[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1
Reactant: COC(=O)c1ccc2c(C3CCCCC3)c3n(c2c1)C[C@H](O)COc1ccccc1-3
Reactant: C[NH+](CCCl)Cc1ccccc1
Agent: [Cl-]
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1
Product: C[NH+](CCO[C@@H]1COc2ccccc2-c2c(C3CCCCC3)c3ccc(C(=O)O)cc3n2C1)Cc1ccccc1
Reaction time: 0.5 h
Yield: 25 %

Procedure:
To a suspension of methyl (7S)-14-cyclohexyl-7-hydroxy-7,8-dihydro-6H-indolo[1,2-e][1,5]benzoxazocine-11-carboxylate (prepared as described in International patent application WO2006/046030) in toluene (0.05 M), were added 10 eq of 30% w/w aq. NaOH followed by 0.25 eq of NBu4Br. After stirring for 30 min, 2.5 eq of N-benzyl-2-chloro-N-methylethanaminium chloride were added and the reaction mixture was stirred at 60° C. for 16 h. The reaction mixture was concentrated in vacuo, and the residue purified by RP-HPLC (Waters Xterra prep. C18 column, 5 um, 19×100 mm. Mobile phase: MeCN/H2O buffered with 0.1% TFA). Fractions containing the pure compound were combined and freeze dried in the presence of HCl to afford the title compound (25%) as a white powder. (ES+) m/z 539 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:18]2[C:19]([NH2:24])=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH:5]=[C:6]([F:17])[C:7]=1[N:8]1[CH:12]=[CH:11][C:10]([C:13]([F:16])([F:15])[F:14])=[N:9]1.[Cl:25][C:26]1[C:31]([C:32](Cl)=[O:33])=[CH:30][CH:29]=[CH:28][N:27]=1.C(N(CC)CC)C>ClCCl>[Cl:25][C:26]1[C:31]([C:32]([NH:24][C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=2[C:4]2[CH:5]=[C:6]([F:17])[C:7]([N:8]3[CH:12]=[CH:11][C:10]([C:13]([F:16])([F:15])[F:14])=[N:9]3)=[C:2]([F:1])[CH:3]=2)=[O:33])=[CH:30][CH:29]=[CH:28][N:27]=1
Reactant: Nc1ccccc1-c1cc(F)c(-n2ccc(C(F)(F)F)n2)c(F)c1
Reactant: O=C(Cl)c1cccnc1Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(Nc1ccccc1-c1cc(F)c(-n2ccc(C(F)(F)F)n2)c(F)c1)c1cccnc1Cl

Procedure:
A mixture of 3′,5′-difluoro-4′-[3-(trifluoromethyl)-1H-pyrazol-1-yl][1,1′-biphenyl]-2-amine (i.e. the product of Step D; 0.17 g, 0.52 mmol), 2-chloro-3-pyridinecarbonyl chloride (0.092 g, 0.52 mmol) and triethylamine (0.050 g, 0.52 mmol) in dichloromethane (5 mL) was stirred for 16 h at room temperature. The reaction mixture was then concentrated under reduced pressure, and the residue was purified by medium pressure liquid chromatography on silica gel eluted with 0 to 100% ethyl acetate in hexanes. The resulting solid was triturated with 1-chlorobutane and hexanes to yield the title compound (0.090 g), a compound of the present invention.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH2:14][CH2:15][CH2:16]Cl)[N:9]=[CH:8][NH:7][C:6]2=[O:18].[NH:19]1[CH2:24][CH2:23][S:22][CH2:21][CH2:20]1.C(O)(CC)C>CO>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH2:14][CH2:15][CH2:16][N:19]1[CH2:24][CH2:23][S:22][CH2:21][CH2:20]1)[N:9]=[CH:8][NH:7][C:6]2=[O:18]
Reactant: COc1cc2c(=O)[nH]cnc2cc1OCCCCl
Reactant: C1CSCCN1
Solvent: CO
Solvent: CCC(C)O
Product: COc1cc2c(=O)[nH]cnc2cc1OCCCN1CCSCC1
Temperature: 105 °C
Reaction time: 7.5 h
Yield: 87.6 %

Procedure:
In a 100 mL volume glass vessel equipped with a stirrer and a thermometer were placed 4.0 g (14.9 mmol) of 6-methoxy-7-(3-chloropropoxy)quinazolin-4-one prepared by procedures similar to those of Reference Example V-1, 5.0 g (48.5 mmol) of thiomorpholine, and 16 mL of sec-butyl alcohol. The resulting mixture was stirred at 105° C. for 7.5 hours. After the reaction was complete, 16 mL of methanol was added to the reaction mixture. The reaction mixture was refluxed for one hour and cooled to room temperature. Thus precipitated crystalline product was collected by filtration and dried at 60° C. under reduced pressure, to give 4.38 g (isolated yield: 81%) of 6-methoxy-7-(3-thiomorpholinopropoxy)quinazolin-4-one.