Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:3]([N:9]2[C:17]3[C:12](=[CH:13][CH:14]=[C:15](I)[CH:16]=3)[CH:11]=[N:10]2)=[N:4][C:5]([NH2:8])=[N:6][CH:7]=1.N1CCCCC1.[S:25]1[CH:29]=[CH:28][N:27]=[C:26]1[C:30]([OH:34])([C:32]#[CH:33])[CH3:31]>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.[Cu]I>[NH2:8][C:5]1[N:4]=[C:3]([N:9]2[C:17]3[C:12](=[CH:13][CH:14]=[C:15]([C:33]#[C:32][C:30]([C:26]4[S:25][CH:29]=[CH:28][N:27]=4)([OH:34])[CH3:31])[CH:16]=3)[CH:11]=[N:10]2)[C:2]([Cl:1])=[CH:7][N:6]=1
Reactant: Nc1ncc(Cl)c(-n2ncc3ccc(I)cc32)n1
Reactant: C#CC(C)(O)c1nccs1
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCNCC1
Product: CC(O)(C#Cc1ccc2cnn(-c3nc(N)ncc3Cl)c2c1)c1nccs1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
To a mixture of 5-chloro-4-(6-iodo-1H-indazol-1-yl)pyrimidin-2-amine (170 mg, 0.46 mmol) and piperidine (1.2 mL) was added tetrakis(triphenylphosphine)palladium (52.9 mg, 0.05 mmol), copper(I) iodide (8.7 mg, 0.05 mmol) and 2-(1,3-thiazol-2-yl)but-3-yn-2-ol (I-1) (140.2 mg, 0.92 mmol). The reaction was purged with N2 and stirred at RT for 20 min. The reaction mixture was concentrated in vacuo and the resultant residue purified by flash chromatography (Isolute column, 1% MeOH in DCM), followed by reverse phase preparative HPLC to give the title compound as a solid: 1H NMR (500 MHz, DMSO) δ 1.91 (3H, s), 7.09 (1H, s), 7.23-7.39 (3H, m), 7.69 (1H, d, J=3.36 Hz), 7.78 (1H, d, J=3.20 Hz), 7.90 (1H, d, J=8.24 Hz), 8.17 (1H, d, J=0.76 Hz), 8.43-8.53 (2H, m); LC-MS: m/z=+397.40 (M+H)+.
Reaction SMILES: C1(C[N:8]2[CH2:12][CH2:11][CH:10]([CH2:13][NH:14][CH2:15][C:16]([F:19])([F:18])[F:17])[CH2:9]2)C=CC=CC=1.[H][H]>[Pd].CO>[F:19][C:16]([F:17])([F:18])[CH2:15][NH:14][CH2:13][CH:10]1[CH2:11][CH2:12][NH:8][CH2:9]1
Reactant: FC(F)(F)CNCC1CCN(Cc2ccccc2)C1
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: FC(F)(F)CNCC1CCNC1
Yield: 53.2 %

Procedure:
A mixture of 7.15 g (26.3 mmole) 1-(phenylmethyl)-N-(2,2,2-trifluoroethyl)-3-pyrrolidinemethanamine 100 ml of methanol and 0.7 g of 20% palladium on carbon was shaken in an atmosphere of hydrogen at about 4.5×105Pa and at room temperature for 24 hours. The catalyst was filtered and the filtrate evaporated under reduced pressure. The residue was distilled under vacuum (63-65° C., 2.8 mm Hg) to give 2.55 g of N-(2,2,2-trifluoroethyl)-3-pyrrolidinemethanamine.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:11])[CH2:5][N:6]1[CH:10]=[N:9][CH:8]=[N:7]1)[CH3:2].C(O[CH:15](OCC)[N:16]([CH3:18])[CH3:17])C>>[CH2:1]([O:3][C:4](=[O:11])[C:5]([N:6]1[CH:10]=[N:9][CH:8]=[N:7]1)=[CH:15][N:16]([CH3:18])[CH3:17])[CH3:2]
Reactant: CCOC(=O)Cn1cncn1
Reactant: CCOC(OCC)N(C)C
Product: CCOC(=O)C(=CN(C)C)n1cncn1

Procedure:
1.9 g (9.8 mmol) [1,2,4]-triazol-1-ylacetic acid ethyl ester [Ainsworth et al., J. Am. Chem. Soc. 1955, 77, 621-623] and 3.6 ml (2.9 g, 19.6 mmol) dimethylformamide diethyl acetal are stirred at a bath temperature of 100° C. for 12 h. For working up, the cooled reaction solution is concentrated on a rotary evaporator and the residue is dried in vacuo.
Reaction SMILES: [C:1]([C:4]1[CH:22]=[CH:21][CH:20]=[CH:19][C:5]=1[CH2:6][O:7][C:8]1[CH:13]=[CH:12][C:11]([CH:14]([CH3:18])C(O)=O)=[CH:10][CH:9]=1)([OH:3])=O.ClCCl.FC(F)(F)[C:28]([O:30]C(=O)C(F)(F)F)=[O:29].Cl>O>[O:3]=[C:1]1[C:4]2[CH:22]=[CH:21][CH:20]=[CH:19][C:5]=2[CH2:6][O:7][C:8]2[CH:9]=[CH:10][C:11]([CH2:14][CH2:18][C:28]([OH:30])=[O:29])=[CH:12][C:13]1=2
Reactant: CC(C(=O)O)c1ccc(OCc2ccccc2C(=O)O)cc1
Reactant: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Agent: Cl
Solvent: O
Solvent: ClCCl
Product: O=C(O)CCc1ccc2c(c1)C(=O)c1ccccc1CO2
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 79.6 %

Procedure:
A stirred suspension of 4-(2-carboxybenzyloxy)phenylpropanoic acid (47.14 g, 0.157 mol) and dichloromethane (500 ml) was treated over 30 seconds with trifluoroacetic anhydride (75.61 g, 0.36 mol). The solid material slowly dissolved. The solution was heated 6 hours under reflux with exclusion of moisture. The cooled solution was treated with water (100 ml) and stirred 20 minutes at ambient temperature (mild exotherm). The mixture was strongly acidified with 5% hydrochloric acid and thoroughly agitated. The organic phase was washed with water (200 ml), dried (Na2SO4) and evaporated to dryness. Recrystallization from 65 ml of isopropanol afforded 35.3 g (79.6%) of 6,11-dihydro-11-oxodibenz[b,e]oxepin-2-propanoic acid, m.p. 138.5°-139.5° C. The compound appeared pure and chromatographically identical with material which had previously been prepared according to procedure 6C below except that it is postulated that the product exists in two polymorphic forms and interconversion by partial melting followed by solidification to afford the higher melting form occurs at 128°-130° C.
Reaction SMILES: Cl[C:2]1[N:11]=[CH:10][C:9]2[N:8]([CH3:12])[C:7](=[O:13])[C@@H:6]([CH2:14][CH3:15])[N:5]([CH:16]([CH3:18])[CH3:17])[C:4]=2[N:3]=1.[C:19]1([C:25]2[NH:26][CH:27]=[CH:28][N:29]=2)[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.CN[C@@H]1CCCC[C@H]1NC.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.CCOC(C)=O>[CH2:14]([C@H:6]1[N:5]([CH:16]([CH3:18])[CH3:17])[C:4]2[N:3]=[C:2]([N:26]3[CH:27]=[CH:28][N:29]=[C:25]3[C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[N:11]=[CH:10][C:9]=2[N:8]([CH3:12])[C:7]1=[O:13])[CH3:15]
Reactant: CC[C@@H]1C(=O)N(C)c2cnc(Cl)nc2N1C(C)C
Reactant: c1ccc(-c2ncc[nH]2)cc1
Agent: CN[C@@H]1CCCC[C@H]1NC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC[C@@H]1C(=O)N(C)c2cnc(-n3ccnc3-c3ccccc3)nc2N1C(C)C
Temperature: 200 °C

Procedure:
A mixture of Intermediate C (100 mg, 0.37 mmol), 2-phenyl-1H-imidazole (533 mg, 3.7 mmol), Cut (35 mg, 0.18 mmol), trans-1,2-bis(methylamino)cyclo-hexane (52.5 mg, 0.07 mL, 0.37 mmol) and solid K2CO3 (511 mg, 3.7 mmol) in 2 mL of DMF was heated in a microwave reaction apparatus for 2 h at 200° C. After this time the reaction was transferred to a round bottom flask with the aid of EtOAc, then evaporated. The residue was purified by reverse-phase HPLC (PLRPS C-18 column, eluting with a gradient of 20-25% acetonitrile in water over 30 min) to give the title compound. LCMS: 377.2 m/z (M+H)+; ret. Time: 2.56 min (Analytical Method A); 1H NMR (400 MHz, CDCl3) δ: 7.9-7.8 (dd, 2H), 7.6-7.3 (m, 6H), 4.3 (dd, 1H), 3.8 (m, 1H), 3.4 (s, 3H), 1.9 (dd, 1H), 1.7 (dd, 1H), 1.05 (d, 3H), 0.9 (d, 3H) and 0.8 (d, 3H) ppm.
Reaction SMILES: Br[C:2]1[C:3]([N:9](CC2C=C(OC)C=C(OC)C=2)[CH2:10][CH2:11][C:12]([NH:14][CH3:15])=[O:13])=[N:4][C:5]([Cl:8])=[N:6][CH:7]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[Cl:8][C:5]1[N:4]=[C:3]2[C:2]([N:14]([CH3:15])[C:12](=[O:13])[CH2:11][CH2:10][NH:9]2)=[CH:7][N:6]=1
Reactant: CNC(=O)CCN(Cc1cc(OC)cc(OC)c1)c1nc(Cl)ncc1Br
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CN1C(=O)CCNc2nc(Cl)ncc21
Reaction time: 8 h

Procedure:
3-[(5-bromo-2-chloro-pyrimidin-4-yl)-[(3,5-dimethoxyphenyl)methyl]amino]-N-methyl-propanamide (Intermediate 97; 83 mg, 0.23 mmol) was taken up in DCM (1 mL) and TFA (1 mL) and stirred for 30 minutes. A further addition of TFA (1 mL) was made and stirring continued overnight. The reaction mixture was diluted with DCM (25 mL) and poured directly onto a SCX-3 cartridge (2 g). The cartridge was washed through with methanol (50 mL). Products were eluted with 2M ammonia in methanol and ammoniacal eluant evaporated to dryness to afford the title compound as an off white solid (34 mg, 70%)
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([C:13]([OH:15])=[O:14])[CH:7]=[C:8]([CH:12]=1)[C:9]([OH:11])=[O:10])([O-])=O.C(O)(=O)C.[C:20]1(=O)[O:25][C:23](=[O:24])[CH:22]=[CH:21]1>[OH-].[Na+].[Pd].O1CCOCC1>[C:20]1(=[O:25])[N:1]([C:4]2[CH:5]=[C:6]([C:13]([OH:15])=[O:14])[CH:7]=[C:8]([CH:12]=2)[C:9]([OH:11])=[O:10])[C:23](=[O:24])[CH:22]=[CH:21]1
Reactant: O=C1C=CC(=O)O1
Reactant: O=C(O)c1cc(C(=O)O)cc([N+](=O)[O-])c1
Agent: [Pd]
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: C1COCCO1
Product: O=C(O)c1cc(C(=O)O)cc(N2C(=O)C=CC2=O)c1

Procedure:
211.2 g (1.0 mol) of 5-nitroisophthalic acid are dissolved in 1,590 g of aqueous sodium hydroxide (90.0 g of sodium hydroxide in 1,500 ml of water) and the solution is rendered neutral with 15 ml of anhydrous acetic acid and hydrogenated in the presence of 10 g of a palladium-on-charcoal catalyst (5% by weight of Pd). The catalyst is filtered off and a solution of 118.0 g (1.2 mols) of maleic anhydride in 150 ml of dioxane is added to the filtrate in the course of 2 hours, whilst stirring vigorously. A white suspension is formed and is stirred overnight at 20°-25° C., 250 ml of acetic acid are then added and the mixture is stirred for a further 2 hours. The amide-acid which has precipitated is filtered off, washed with water and methanol and dried at 30° C. in vacuo for 24 hours. The reaction product (315 g) is then heated, in 2,500 ml of acetic anhydride, whilst stirring, to 80°-85° C. for 30 minutes. About 1.8 liters of liquid (acetic acid + acetic anhydride) are distilled off under a waterpump vacuum. The residual suspension is poured onto 2,000 g of ice and the mixture is stirred overnight. The reaction product which has precipitated is filtered off, washed with water and methanol and dried at 60° C. in vacuo for 12 hours. 210 g of white, crystalline 5-maleimidylisophthalic acid are obtained; melting point > 300° C. (= 80% of theory, based on the nitroisophthalic acid).
Reaction SMILES: [OH-].[K+].[C:3]([CH2:5][C:6]([NH2:8])=[O:7])#[N:4].[O:9]([C:16]1[CH:17]=[C:18]([N:22]=[C:23]=[S:24])[CH:19]=[CH:20][CH:21]=1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.Cl>CN(C=O)C.O>[C:3]([CH:5]([C:23](=[S:24])[NH:22][C:18]1[CH:19]=[CH:20][CH:21]=[C:16]([O:9][C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH:17]=1)[C:6]([NH2:8])=[O:7])#[N:4]
Reactant: S=C=Nc1cccc(Oc2ccccc2)c1
Reactant: N#CCC(N)=O
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CN(C)C=O
Product: N#CC(C(N)=O)C(=S)Nc1cccc(Oc2ccccc2)c1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 72.4 %

Procedure:
To a suspension of 85% powdered KOH in 20 ml DMF was added 1.74 g of cyanoacetamide at room temperature. The solution was stirred at room temperature for 15 minutes and then cooled in a water bath at room temperature. To this solution 4.7 g of 3-phenoxy-phenyl isothiocyanate was added dropwise. The solution exothermed slightly with the internal temperature rising to 28° C. during the addition. The solution was stirred at room temperature for 16 h, then diluted with 150 ml water and extracted with ethyl acetate to remove small amounts of starting material and by-products. The aqueous layer was isolated and acidified with 1N HCl to pH 1 with vigorous stirring. The resulting tan precipitate was filtered, washed with water, and dried for 16 hours in a vacuum oven to afford 4.66 g of 2-cyano-2-(3-phenoxy-phenylthiocarbamoyl)-acetamide.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([Mg]Br)[CH:6]=[CH:7][CH:8]=1.[N:11]12[CH2:18][CH2:17][C:14]([C:19]([O:21]CC)=O)([CH2:15][CH2:16]1)[CH2:13][CH2:12]2>C1COCC1>[N:11]12[CH2:12][CH2:13][C:14]([C:19]([C:7]3[CH:6]=[CH:5][CH:4]=[C:3]([O:2][CH3:1])[CH:8]=3)([C:5]3[CH:6]=[CH:7][CH:8]=[C:3]([O:2][CH3:1])[CH:4]=3)[OH:21])([CH2:15][CH2:16]1)[CH2:17][CH2:18]2
Reactant: CCOC(=O)C12CCN(CC1)CC2
Reactant: COc1cccc([Mg]Br)c1
Solvent: C1CCOC1
Product: COc1cccc(C(O)(c2cccc(OC)c2)C23CCN(CC2)CC3)c1
Temperature: 25 °C
Yield: 92.9 %

Procedure:
A solution of 3-(methyloxy)phenylmagnesiumbromide (1.0 M in THF, 3.3 mL, 3.3 mmol) was chilled down to 0° C. under Ar. Ethyl 1-azabicyclo[2.2.2]octane-4-carboxylate (0.1608 g, 0.877 mmol) in THF (4 mL) was slowly added to the reaction mixture at 0° C. over 20 min. The reaction was allowed to warm up to room temperature and then heated at 60° C. for 16 h. The reaction was chilled in an ice bath, quenched with saturated NH4Cl, and concentrated under vacuum. The resulting residue was treated with H2O and extracted with EtOAc. The combined organic layers were dried with MgSO4, filtered, and concentrated under vacuum to yield the desired product (0.2881 g, 92.9%). EI-MS m/z 354(M+H+) Rt (1.46 min).
Reaction SMILES: [F:1][C:2]1[CH:19]=[CH:18][CH:17]=[CH:16][C:3]=1[CH2:4][N:5]1[C:9]([OH:10])=[CH:8][C:7]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[N:6]1.IC.[C:22](=O)([O-])[O-].[K+].[K+]>CC(C)=O>[F:1][C:2]1[CH:19]=[CH:18][CH:17]=[CH:16][C:3]=1[CH2:4][N:5]1[C:9]([O:10][CH3:22])=[CH:8][C:7]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[N:6]1
Reactant: CCOC(=O)c1cc(O)n(Cc2ccccc2F)n1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: CC(C)=O
Product: CCOC(=O)c1cc(OC)n(Cc2ccccc2F)n1

Procedure:
21.58 g of ethyl 1-(2-fluorobenzyl)-5-hydroxy-1H-pyrazole-3-carboxylate 1-1-2 (81.66 mmol, 1.0 eq) were dissolved in dry acetone. Then 10.17 mL of iodomethane (163.3 mmol, 2.0 eq) and 40.63 g of potassium carbonate (294 mmol, 3.6 eq) were added. The precipitate was filtered off and the filtrate was concentrated in vacuo. The residue was partitioned between DCM and water, the aqueous layer was separated and extracted with DCM twice. The combined organic layers were dried over magnesium sulfate, filtered off and concentrated in vacuo to give 14.74 g (52.96 mmol, 65%) of the crude target compound that was used for the next transformation without further purification.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[N:17]([CH2:18][C:19]2[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=2)[C:8]2=[N:9][CH:10]=[C:11]([S:13]([CH3:16])(=[O:15])=[O:14])[CH:12]=[C:7]2[CH:6]=1)=O.O.[NH2:27][NH2:28]>C(O)C>[F:25][C:22]1[CH:21]=[CH:20][C:19]([CH2:18][N:17]2[C:8]3=[N:9][CH:10]=[C:11]([S:13]([CH3:16])(=[O:14])=[O:15])[CH:12]=[C:7]3[CH:6]=[C:5]2[C:3]2[O:2][CH:1]=[N:27][N:28]=2)=[CH:24][CH:23]=1
Reactant: COC(=O)c1cc2cc(S(C)(=O)=O)cnc2n1Cc1ccc(F)cc1
Reactant: NN
Solvent: O
Solvent: CCO
Product: CS(=O)(=O)c1cnc2c(c1)cc(-c1nnco1)n2Cc1ccc(F)cc1
Yield: 71.4 %

Procedure:
To a solution of 1-(4-fluorobenzyl)-5-methanesulfonyl-1H-pyrrolo[2,3-b]pyridine-2-carboxylic acid methyl ester obtained in Example 33 (5) (0.3 g) in ethanol (9 ml), hydrazine monohydrate (0.22 g) was added at 15 to 30° C. and the mixture was heated under reflux for 6 hours, followed by further addition of hydrazine monohydrate (0.11 g), and the mixture was heated under reflux for 4 hours. Furthermore, hydrazine monohydrate (0.11 g) was added to the mixture, followed by heating under reflux for 16 hours. The reaction solution was concentrated under reduced pressure. To the resulting crude product was added orthoformic acid triethyl ester (25 ml) and the mixture was heated under reflux for 18 hours. The reaction solution was separated using silica gel column chromatography (ethyl acetate:hexane=1:1) to obtain 220 mg of the desired product.
Reaction SMILES: [Cl:1][C:2]1[C:7]2[O:8][CH2:9][CH2:10][CH2:11][O:12][C:6]=2[CH:5]=[C:4]([CH2:13][NH:14][CH2:15][CH:16]([CH3:18])[CH3:17])[CH:3]=1.C(OC([N:26]1[CH2:31][CH2:30][N:29]([CH2:32][C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[CH2:28][CH:27]1[C:39](O)=[O:40])=O)(C)(C)C.Cl.C(N=C=NCCCN(C)C)C.CC1C=CN=C(N)C=1C>ClCCl.O>[CH2:32]([N:29]1[CH2:30][CH2:31][NH:26][CH:27]([C:39]([N:14]([CH2:13][C:4]2[CH:3]=[C:2]([Cl:1])[C:7]3[O:8][CH2:9][CH2:10][CH2:11][O:12][C:6]=3[CH:5]=2)[CH2:15][CH:16]([CH3:18])[CH3:17])=[O:40])[CH2:28]1)[C:33]1[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=1
Reactant: CC(C)CNCc1cc(Cl)c2c(c1)OCCCO2
Reactant: CC(C)(C)OC(=O)N1CCN(Cc2ccccc2)CC1C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cc1ccnc(N)c1C
Agent: Cl
Solvent: ClCCl
Solvent: O
Product: CC(C)CN(Cc1cc(Cl)c2c(c1)OCCCO2)C(=O)C1CN(Cc2ccccc2)CCN1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
The mixture of N-(9-chloro-3,4-dihydro-2H-1,5-benzodioxepin-7-ylmethyl)-2-methylpropan-1-amine (84 mg), 4-benzyl-piperazine-1,2-dicarboxylic acid 1-tert-butyl ester (100 mg), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (90 mg), and dimethyl aminopyridine (53 mg) in dichloromethane (8 ml) was stirred at room temperature overnight. After addition of water (8 ml) the reaction mixture was extracted with ethyl acetate (8 ml×3). The organic layers were combined, washed with saturated sodium bicarbonate, water and brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude product was purified by column chromatography on silica (20% ethyl acetate in hexane) to give a resin: MS (m+1)=572.4.
Reaction SMILES: CON(C)[C:4]([C:6]1[CH:11]=[C:10]([CH3:12])[N:9]=[C:8]([NH:13][CH:14]([CH3:16])[CH3:15])[N:7]=1)=[O:5].[CH2:18]1COCC1>C[Mg]Br.CCOCC>[CH:14]([NH:13][C:8]1[N:7]=[C:6]([C:4](=[O:5])[CH3:18])[CH:11]=[C:10]([CH3:12])[N:9]=1)([CH3:15])[CH3:16]
Reactant: CON(C)C(=O)c1cc(C)nc(NC(C)C)n1
Reactant: C1CCOC1
Agent: C[Mg]Br
Solvent: CCOCC
Product: CC(=O)c1cc(C)nc(NC(C)C)n1
Temperature: 5 °C
Reaction time: 1.5 h

Procedure:
To a solution of 2-isopropylamino-6-methyl-pyrimidine-4-carboxylic acid methoxy-methyl-amide (2.39 g, 10.0 mmol) in THF (50 mL), methyl magnesium bromide (7.0 mL of a 3 M solution in ether, 20.1 mmol) is added dropwise at 5° C. The mixture is stirred at 5° C. for 1.5 h. The reaction is quenched by adding NH4Cl. The mixture is diluted with EtOAc (75 mL), washed with sat. aq. NaHCO3, dried over Na2SO4, filtered and concentrated to give 1-(2-isopropylamino-6-methyl-pyrimidin-4-yl)-ethanone (1.71 g) as a yellow solid. LC-MS: tR=0.75 min, [M+H]+=194.01; 1H NMR (CDCl3): δ 1.29 (d, J=6.5 Hz, 6H), 2.41 (s, 3H), 2.62 (s, 3H), 4.22 (m, 1H), 5.02 (m, 1H), 6.97 (s, 1H).
Reaction SMILES: [Cl:1][C:2]1[C:11]([OH:12])=[C:10]2[C:5]([CH:6]=[N:7][CH:8]=[N:9]2)=[CH:4][CH:3]=1.C([O-])(=O)C.[K+].[I:18]I>CO.O>[Cl:1][C:2]1[C:11]([OH:12])=[C:10]2[C:5]([CH:6]=[N:7][CH:8]=[N:9]2)=[C:4]([I:18])[CH:3]=1
Reactant: II
Reactant: Oc1c(Cl)ccc2cncnc12
Agent: CC(=O)[O-]
Agent: [K+]
Solvent: O
Solvent: CO
Product: Oc1c(Cl)cc(I)c2cncnc12

Procedure:
To a solution of 7-chloro-8-hydroxy-quinazoline (A69) (0.1 mol) and potassium acetate (0.15 mol) in MeOH and H2O (19:1, 250 mL) was added, over 30 min, a solution of iodine (0.095 mol) in MeOH and H2O (19:1, 350 mL). The mixture was then heated under reflux for 15 min, cooled and H2O (400 mL) was added. The precipitate was isolated by filtration, washed with saturated sodium thiosulfate and H2O, and dried. This provided 7-chloro-8-hydroxy-5-iodo-quinazoline (A70) as a solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:13][CH2:12][NH:11][CH2:10][C:9]2([CH3:15])[CH3:14])=[CH:4][CH:3]=1.[NH:16]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[C@@H:17]([C:21](O)=[O:22])[CH:18]([CH3:20])[CH3:19]>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:13][CH2:12][N:11]([C:21](=[O:22])[C@H:17]([NH:16][C:24](=[O:25])[O:26][C:27]([CH3:30])([CH3:29])[CH3:28])[CH:18]([CH3:20])[CH3:19])[CH2:10][C:9]2([CH3:15])[CH3:14])=[CH:4][CH:3]=1
Reactant: CC1(C)CNCCC1c1ccc(F)cc1
Reactant: CC(C)[C@@H](NC(=O)OC(C)(C)C)C(=O)O
Product: CC(C)[C@@H](NC(=O)OC(C)(C)C)C(=O)N1CCC(c2ccc(F)cc2)C(C)(C)C1

Procedure:
The title compound was prepared from 4-(4-fluorophenyl)-3,3-dimethylpiperidine and Boc-D-Val-OH using the procedure described in Example 581, Step 5. MS (ESI+)=351.40, (M-tert-Bu)+.
Reaction SMILES: Cl[CH2:2][CH2:3][O:4][C:5]1[C:13]2[C:8](=[N:9][CH:10]=[N:11][C:12]=2[NH:14][C:15]2[CH:20]=[CH:19][C:18]([O:21][CH2:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][N:24]=3)=[C:17]([Cl:29])[CH:16]=2)[NH:7][N:6]=1.[F:30][CH:31]1[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]1>>[Cl:29][C:17]1[CH:16]=[C:15]([NH:14][C:12]2[N:11]=[CH:10][N:9]=[C:8]3[NH:7][N:6]=[C:5]([O:4][CH2:3][CH2:2][N:34]4[CH2:35][CH2:36][CH:31]([F:30])[CH2:32][CH2:33]4)[C:13]=23)[CH:20]=[CH:19][C:18]=1[O:21][CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][N:24]=1
Reactant: FC1CCNCC1
Reactant: ClCCOc1n[nH]c2ncnc(Nc3ccc(OCc4ccccn4)c(Cl)c3)c12
Product: FC1CCN(CCOc2n[nH]c3ncnc(Nc4ccc(OCc5ccccn5)c(Cl)c4)c23)CC1
Yield: 38 %

Procedure:
The procedure described in Example 23 was repeated using 3-(2-chloroethoxy)-N-[3-chloro-4-(pyridin-2-ylmethoxy)phenyl]-1H-pyrazolo[3,4-d]pyrimidin-4-amine (prepared as described in Example 13) and 4-fluoropiperidine to give the title compound in 38% yield; NMR Spectrum: 1.68-1.72 (m, 2H), 1.78-1.87 (m, 2H), 2.41-2.44 (m, 2H), 2.62-2.66 (m, 2H), 2.81 (t, 2H), 4.42 (t, 2H), 4.65 (dm, 1H), 5.29 (s, 2H), 7.24 (d, 1H), 7.36-7.38 (m, 1H), 7.55-7.58 (m, 2H), 7.85-7.91 (m, 2H), 8.29 (s, 1H), 8.51 (s, 1H), 8.59 (d, 1H); Mass Spectrum: 498 (MH+).
Reaction SMILES: [H-].[Na+].[CH3:3][C:4]([OH:8])([C:6]#[CH:7])[CH3:5].Br[CH2:10][C:11]([O:13][CH3:14])=[O:12]>C1COCC1>[CH3:14][O:13][C:11](=[O:12])[CH2:10][O:8][C:4]([CH3:5])([CH3:3])[C:6]#[CH:7]
Reactant: C#CC(C)(C)O
Reactant: COC(=O)CBr
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: C#CC(C)(C)OCC(=O)OC
Temperature: 0 °C
Reaction time: 1 h
Yield: 21.3 %

Procedure:
A mechanically stirred suspension of sodium hydride (10.0 g, 0.25 mol) in THF (170 mL) at 0° C. under N2 gas was treated dropwise with a solution of 2-methyl-3-butyn-2-ol (29.1 mL, 0.30 mol) in THF (70 mL). After stirring at 0° C. for 1 hour, the reaction mixture was treated at 0° C. with a solution of methyl bromoacetate (35.5 mL, 0.38 mol) in THF (100 mL). After stirring at ambient temperature overnight, the reaction mixture was quenched into 1M HCl (300 mL) and extracted with ethyl acetate (3×300 mL). The organic layers were combined, dried over Na2SO4, and concentrated to half the volume. The residue was distilled by vacuum distillation (bp. 118-120° C./20 mmHg) to provide the title compound (10.0 g).
Reaction SMILES: C(OC([N:8]1[C@@H:12]([CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:11](=[O:20])OC1)=O)(C)(C)C.Br[CH2:22][Cl:23].C([Li])CCC.Cl>CCCCCC.O1CCCC1>[ClH:23].[NH2:8][C@@H:12]([CH2:13][C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1)[C:11](=[O:20])[CH2:22][Cl:23]
Reactant: ClCBr
Reactant: CC(C)(C)OC(=O)N1COC(=O)[C@@H]1Cc1ccccc1
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: N[C@@H](Cc1ccccc1)C(=O)CCl
Temperature: -78 °C
Reaction time: 0.67 h
Yield: 77 %

Procedure:
(4S)-N-tert-butoxycarbonyl-4-phenylmethyloxazolidin-5-one (1.00 g) and bromochloromethane (0.31 ml) were added to dehydrated tetrahydrofuran (36 ml). After cooling to −78° C., 1.53 M solution (3.07 ml) of n-butyllithium in hexane was added to the obtained mixture, and they were stirred for 40 minutes. 6 N Hydrochloric acid was added to the reaction mixture to terminate the reaction. The temperature of the reaction mixture was elevated to room temperature. The reaction mixture was concentrated to a half volume, stirred at 50° C. for 1 hour and cooled to room temperature. After the addition of isopropyl acetate followed by the extraction with water twice, the obtained aqueous solution was analyzed by HPLC to find that intended (S)-3-amino-1-chloro-4-phenyl-2-butanone hydrochloride (0.65 g) was obtained in a yield of 77%. According to HPLC analysis with an optically active column, the optical purity of (S)-3-amino-1-chloro-4-phenyl-2-butanone hydrochloride thus obtained was confirmed to be >99% e.e.
Reaction SMILES: Cl.Cl.Cl.[O:4]1[C:8]2=[C:9]([N:13]3[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][C@H:21]4[CH2:26][CH2:25][C@H:24]([NH2:27])[CH2:23][CH2:22]4)[CH2:15][CH2:14]3)[N:10]=[CH:11][CH:12]=[C:7]2[CH2:6][CH2:5]1.[CH3:28][N:29]1[CH2:34][CH2:33][N:32]([C:35]2[CH:43]=[CH:42][C:38]([C:39](O)=[O:40])=[CH:37][CH:36]=2)[CH2:31][CH2:30]1>>[O:4]1[C:8]2=[C:9]([N:13]3[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][C@H:21]4[CH2:26][CH2:25][C@H:24]([NH:27][C:39](=[O:40])[C:38]5[CH:37]=[CH:36][C:35]([N:32]6[CH2:31][CH2:30][N:29]([CH3:28])[CH2:34][CH2:33]6)=[CH:43][CH:42]=5)[CH2:23][CH2:22]4)[CH2:15][CH2:14]3)[N:10]=[CH:11][CH:12]=[C:7]2[CH2:6][CH2:5]1
Reactant: N[C@H]1CC[C@H](CCN2CCN(c3nccc4c3OCC4)CC2)CC1
Reactant: CN1CCN(c2ccc(C(=O)O)cc2)CC1
Agent: Cl
Product: CN1CCN(c2ccc(C(=O)N[C@H]3CC[C@H](CCN4CCN(c5nccc6c5OCC6)CC4)CC3)cc2)CC1

Procedure:
The title compound, white solid (116 mg, 87%), MS (ISP) m/z=533.4 [(M+H)+], mp 235.5° C., was prepared in accordance with the general method of example 6 from trans-4-{2-[4-(2,3-dihydro-furo[2,3-c]pyridin-7-yl)-piperazin-1-yl]-ethyl}-cyclohexylamine trihydrochloride (intermediate B) (110 mg, 0.25 mmol) and 4-(4-methyl-piperazin-1-yl)-benzoic acid.