Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[C:7]([F:8])=[C:6]([Cl:9])[N:5]=[C:4]([C:10]([O:12][CH:13]([CH3:15])[CH3:14])=[O:11])[CH:3]=1.[Cl:16]N1C(C)(C)C(=O)N(Cl)C1=O.O>C(#N)C>[NH2:1][C:2]1[C:7]([F:8])=[C:6]([Cl:9])[N:5]=[C:4]([C:10]([O:12][CH:13]([CH3:15])[CH3:14])=[O:11])[C:3]=1[Cl:16]
Reactant: CC1(C)C(=O)N(Cl)C(=O)N1Cl
Reactant: CC(C)OC(=O)c1cc(N)c(F)c(Cl)n1
Solvent: O
Solvent: CC#N
Product: CC(C)OC(=O)c1nc(Cl)c(F)c(N)c1Cl
Yield: 163.1 %

Procedure:
Propan-2-yl 4-amino-6-chloro-5-fluoropicolinate (634 milligrams (mg), 2.73 mmol) was slurried in acetonitrile (11 mL). 1,3-Dichloro-5,5-dimethyl-hydantoin (303 mg, 1.54 mmol) was added as a solid, and the reaction mixture was stirred at reflux for 2.5 h. Additional 1,3-dichloro-5,5-dimethylhydantoin (50 mg, 0.25 mmol) was added, and the reaction mixture was stirred at reflux for an additional hour. Water (20 mL) was added. Acetonitrile was then removed by rotary evaporation to give an oily, yellow solid which was extracted with EtOAc (2×20 mL). The combined organic extracts were washed with 10% sodium bisulfite (NaHSO3) solution, satd aq NaHCO3 solution and brine, dried (MgSO4) and concentrated under reduced pressure to provide a pale orange solid (671 mg, 92%): 1H NMR (400 MHz, CDCl3) δ 5.29 (septet, J=6.3 Hz, 1H, CHMe2), 5.19 (br s, 2H, NH2), 1.40 (d, J=6.3 Hz, 6H, CHMe2); 19F NMR (376 MHz, CDCl3) δ −136.5.
Reaction SMILES: CS(O[C@@H:6]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][N:9]=1)[CH3:7])(=O)=O.C(N(CC)C(C)C)(C)C.[N:23]1([C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]1>CS(C)=O.O>[N:9]1[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=1[C@@H:6]([N:26]1[CH2:25][CH2:24][N:23]([C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[CH2:28][CH2:27]1)[CH3:7]
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: C[C@@H](OS(C)(=O)=O)c1ccccn1
Solvent: O
Solvent: CS(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: C[C@@H](c1ccccn1)N1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 80 °C
Yield: 75 %

Procedure:
To a stirred solution of 0.35 g (1.7 mmol) of the title compound from Step A above in 3.5 mL of anhydrous dimethyl sulfoxide was added 0.60 mL (3.5 mmol) of N,N-diisopropylethylamine followed by 0.49 g (2.6 mmol) of tert-butyl piperazine-1-carboxylate. The resulting mixture was heated to 80° C. for 3 h then cooled to ambient temperature. The reaction was diluted with water and the aqueous phase was extracted with ethyl acetate. The combined organic layers were washed with brine, dried over magnesium sulfate, filtered and evaporated to dryness in vacuo. The residue was purified by silica gel chromatography eluting with a 0-100% ethyl acetate in hexanes gradient to afford the title compound as a yellow gum (0.38 g, 75% yield. LC-MS: m/z (ES) 292.4 (MH)+.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[CH:6][C:7]([N:10]2[N:14]=[CH:13][CH:12]=[N:11]2)=[N:8][CH:9]=1)(=[O:3])[CH3:2].[Br:15][Si](C)(C)C.O.BrN1C(=O)CCC1=O>ClCCl.C(N(CC)CC)C>[Br:15][CH2:2][C:1]([C:4]1[CH:5]=[CH:6][C:7]([N:10]2[N:14]=[CH:13][CH:12]=[N:11]2)=[N:8][CH:9]=1)=[O:3]
Reactant: CC(=O)c1ccc(-n2nccn2)nc1
Reactant: C[Si](C)(C)Br
Agent: O=C1CCC(=O)N1Br
Solvent: O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(CBr)c1ccc(-n2nccn2)nc1
Temperature: 25 °C
Yield: 44.7 %

Procedure:
31.9 mg (corresponding to 0.170 mmol) of 5-acetyl-2-(2H-1,2,3-triazole-2-yl)pyridine was dissolved in 1.0 mL of dichloromethane and 71 μL of triethylamine, and then 44.1 μL (corresponding to 0.51 mmol) of bromotrimethylsilane was dropped under ice cooling. The resulting solution was stirred over night at room temperature under argon gas atmosphere, and then, the reaction solution was supplemented with water and extracted 3 times with dichloromethane. The combined dichloromethane layer was washed with water and a saturated saline solution, and dried over anhydrous magnesium sulfate. The solvent was distilled off, the resulting residue was dissolved in 1.0 mL of tetrahydrofuran, and 33.3 mg (corresponding to 0.17 mmol) of N-bromosuccinimide was added thereto under ice cooling. The resulting solution was stirred at room temperature for 30 minutes. After the completion of the reaction, the solvent was distilled off under reduced pressure, and the residue was purified by flash silica gel column chromatography (elution solvent: dichloromethane/ethyl acetate=2/1), to obtain 20.2 mg (corresponding to 0.076 mmol) of 5-(2-bromoacetyl)-2-(2H-1,2,3-triazole-2-yl)pyridine (FIG. 2, step 2).
Reaction SMILES: [Br:1][C:2]1[C:7]([NH2:8])=[CH:6][N:5]=[CH:4][N:3]=1.CC(C)([O-])C.[Na+].I[CH2:16][CH2:17][CH2:18][CH3:19].O>CC(N(C)C)=O>[Br:1][C:2]1[C:7]([NH:8][CH2:16][CH2:17][CH2:18][CH3:19])=[CH:6][N:5]=[CH:4][N:3]=1
Reactant: Nc1cncnc1Br
Reactant: CCCCI
Agent: CC(C)(C)[O-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)N(C)C
Product: CCCCNc1cncnc1Br
Temperature: 60 °C
Yield: 22.7 %

Procedure:
A mixture of 4-bromopyrimidin-5-amine (1 g, 5.75 mmol), sodium tert-butoxide (1.11 g, 11.5 mmol) and 1-iodobutane (1.11 g, 6.03 mmol) in DMA (15 mL) was heated at 60° C. for 15 hours. The mixture was poured into water and extracted with ethyl acetate. The acetate layer was washed with water, brine, dried with MgSO4, filtered, and concentrated under reduced pressure. The residue was purified by chromatography (hexanes-EtOAc 3:1) to afford 300 mg of the title compound. MS (ESI) m/z 230 (M+H)+.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:20]=[CH:19][C:10]([C:11]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[O:12])=[CH:9][CH:8]=1.[CH2:21]([NH:23][CH2:24][CH3:25])[CH3:22].[I-].[K+]>O>[CH2:21]([N:23]([CH2:24][CH3:25])[CH2:2][CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:20]=[CH:19][C:10]([C:11]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[O:12])=[CH:9][CH:8]=1)[CH3:22]
Reactant: CCNCC
Reactant: O=C(c1ccccc1)c1ccc(OCCCCCl)cc1
Agent: [I-]
Agent: [K+]
Solvent: O
Product: CCN(CC)CCCCOc1ccc(C(=O)c2ccccc2)cc1
Reaction time: 19 h

Procedure:
Combine 4-(4-chlorobutoxy)benzophenone (740 g, 1.59 mol), diethylamine (3.7 L), and potassium iodide (50 g) in water (3.7 L). Heat to reflux. After 19 hours, evaporate the reaction mixture in vacuo to give an aqueous residue. Extract two times with ethyl acetate. Extract the combined organic layers with aqueous 10% hydrochloric acid solution and separate the acidic aqueous layer. Combine the acidic aqueous layer and ethyl acetate. Slowly add aqueous 10% sodium hydroxide solution until the pH of the aqueous layer is about 9. Separate the organic layer, extract twice with water and then aqueous saturated sodium chloride solution. Dry the organic layer over MgSO4, filter, and evaporate in vacuo to give 4-(4-diethylaminobutoxy)benzophenone.
Reaction SMILES: [C:1]([CH2:4][N:5]1[C:9]([SH:10])=[N:8][N:7]=[N:6]1)(O)=[O:2].C(N(CC)CC)C.C(Cl)(=O)C(C)(C)C.[CH3:25][N:26]1[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]1>CC(C)=O>[CH3:25][N:26]1[CH2:31][CH2:30][N:29]([C:1]([CH2:4][N:5]2[C:9]([SH:10])=[N:8][N:7]=[N:6]2)=[O:2])[CH2:28][CH2:27]1
Reactant: CN1CCNCC1
Reactant: O=C(O)Cn1nnnc1S
Agent: CC(C)(C)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: CC(C)=O
Product: CN1CCN(C(=O)Cn2nnnc2S)CC1
Temperature: -15 °C
Reaction time: 0.08 h
Yield: 45.4 %

Procedure:
To a solution of 1-carboxymethyl-1H-tetrazole-5-thiol (3.2 g) in dry acetone (60 ml) was added triethyl amine (4.2 g). After the addition of a solution of pivaloyl chloride (4.8 g) in dry acetone (10 ml) with stirring at -15° C. over a period of 5 minutes, the mixture was stirred for one hour and 15 minutes at the same temperature. A solution of 1-methylpiperazine (4.0 g) in dry acetone (10 ml) was dropwise added over a period of 5 minutes and the resulting mixture was stirred at -15° C. for 40 minutes and under ice-cooling for a further 2.5 hours. After the evaporation of the reaction mixture under reduced pressure, water was added to the residue, 4N aqueous solution of sodium hydroxide was added until the crystals were dissolved. The resulting solution was evaporated under reduced pressure and the residue was crystallized from water to give 1-(4-methyl-1-piperazinyl)carbonylmethyl-1H-tetrazole-5-thiol (2.2 g). mp>250° C.
Reaction SMILES: [H-].[H-].[H-].[H-].[Li+].[Al+3].[CH2:7]([O:14][C:15]1[CH:39]=[CH:38][C:18]([O:19][C@@H:20]2[C:28]3[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=3)[CH2:22][C@@H:21]2[N:29]([CH3:37])[C:30](OC(C)(C)C)=O)=[CH:17][CH:16]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.O1CCCC1.C(O)C.C(Cl)(Cl)[Cl:49]>>[ClH:49].[CH2:7]([O:14][C:15]1[CH:39]=[CH:38][C:18]([O:19][C@@H:20]2[C:28]3[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=3)[CH2:22][C@@H:21]2[N:29]([CH3:37])[CH3:30])=[CH:17][CH:16]=1)[C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: CN(C(=O)OC(C)(C)C)[C@H]1Cc2ccccc2[C@H]1Oc1ccc(OCc2ccccc2)cc1
Reactant: ClC(Cl)Cl
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCO
Solvent: C1CCOC1
Product: CN(C)[C@H]1Cc2ccccc2[C@H]1Oc1ccc(OCc2ccccc2)cc1
Product: Cl

Procedure:
The title compound was prepared in a similar manner to Example 12 from LiAlH4 (769 mg, 20.2 mmol), cis-1-(4-benzyloxyphenoxy)-2-(N-methyl-N-tert-butoxycarbonylamino)indane (900 mg, 2.02 mmol) and tetrahydrofuran (50 ml). After a reaction time of 3 hours the reaction was worked up as previously described and subjected to column chromatography on silica gel eluting with 5% ethanol in chloroform to afford a pale green oil (640 mg) which was converted to the HCl salt and crystallised to afford the title compound as a white solid. m.p. 215°-216° C. dec. (from methanol-diethyl ether).
Reaction SMILES: [NH2:1][C:2]1[N:14]=[C:13]([C:15]2[C:20]([O:21][CH2:22][C:23]3[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][CH:24]=3)=[CH:19][CH:18]=[CH:17][C:16]=2[O:31][CH2:32][CH:33]2[CH2:35][CH2:34]2)[CH:12]=[C:11]([NH:36][CH2:37][CH2:38][NH:39][C:40]([O:42][C:43]([CH3:46])([CH3:45])[CH3:44])=[O:41])[C:3]=1[C:4](OC(C)(C)C)=[O:5].COCCO[AlH2-]OCCOC.[Na+]>C1COCC1>[NH2:1][C:2]1[C:3]([CH2:4][OH:5])=[C:11]([NH:36][CH2:37][CH2:38][NH:39][C:40](=[O:41])[O:42][C:43]([CH3:45])([CH3:46])[CH3:44])[CH:12]=[C:13]([C:15]2[C:20]([O:21][CH2:22][C:23]3[CH:24]=[CH:25][C:26]([O:29][CH3:30])=[CH:27][CH:28]=3)=[CH:19][CH:18]=[CH:17][C:16]=2[O:31][CH2:32][CH:33]2[CH2:34][CH2:35]2)[N:14]=1
Reactant: COc1ccc(COc2cccc(OCC3CC3)c2-c2cc(NCCNC(=O)OC(C)(C)C)c(C(=O)OC(C)(C)C)c(N)n2)cc1
Agent: COCCO[AlH2-]OCCOC
Agent: [Na+]
Solvent: C1CCOC1
Product: COc1ccc(COc2cccc(OCC3CC3)c2-c2cc(NCCNC(=O)OC(C)(C)C)c(CO)c(N)n2)cc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 77.6 %

Procedure:
To a cold (0° C.) solution of tert-butyl 2-amino-4-({2-[(tert-butoxycarbonyl)amino]ethyl}amino)-6-{2-(cyclopropylmethoxy)-6-[(4-methoxybenzyl)oxy]phenyl}-nicotinate (0.113 g, 0.178 mmol) in THF (5 mL) was added a solution of Vitride® (3.4 M, 1.0 mL, 3.4 mmol). The mixture was stirred at 0° C. for 0.5 hrs, quenched with saturated aqueous potassium sodium tartaric acid solution, and then partitioned between ethyl acetate and water. The organic phase was washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure to give a solid, which was triturated with ethyl acetate and diisopropyl ether to give tert-butyl 2-{[2-amino-6-{2-(cyclopropylmethoxy)-6-[(4-methoxybenzyl)oxy]-phenyl}-3-(hydroxymethyl)-4-pyridinyl]amino}ethylcarbamate as a pink solid (0.078 g, yield; 78%).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:14]([NH:16][CH2:17][C:18]2[C:19](=[O:26])[NH:20][C:21]([CH3:25])=[CH:22][C:23]=2[CH3:24])=[O:15])[C:5]2[CH:10]=[N:9][N:8]([CH:11]([CH3:13])[CH3:12])[C:6]=2[N:7]=1.[OH:27][CH2:28][C:29]1[CH:30]=[C:31](B(O)O)[CH:32]=[CH:33][CH:34]=1.C([O-])([O-])=O.[Na+].[Na+].CCOC(C)=O>O1CCOCC1.O.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>[CH3:24][C:23]1[CH:22]=[C:21]([CH3:25])[NH:20][C:19](=[O:26])[C:18]=1[CH2:17][NH:16][C:14]([C:4]1[C:5]2[CH:10]=[N:9][N:8]([CH:11]([CH3:13])[CH3:12])[C:6]=2[N:7]=[C:2]([C:33]2[CH:32]=[CH:31][CH:30]=[C:29]([CH2:28][OH:27])[CH:34]=2)[CH:3]=1)=[O:15]
Reactant: OCc1cccc(B(O)O)c1
Reactant: Cc1cc(C)c(CNC(=O)c2cc(Br)nc3c2cnn3C(C)C)c(=O)[nH]1
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
Solvent: O
Solvent: CCOC(C)=O
Product: Cc1cc(C)c(CNC(=O)c2cc(-c3cccc(CO)c3)nc3c2cnn3C(C)C)c(=O)[nH]1
Temperature: 100 °C
Reaction time: 2 h
Yield: 78.8 %

Procedure:
A solution of 6-bromo-N-((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-1-isopropyl-1H-pyrazolo[3,4-b]pyridine-4-carboxamide (2.5 g, 5.98 mmol), (3-(hydroxymethyl)phenyl)boronic acid (1 g, 6.57 mmol) and Pd(PPh3)4 (0.69 g, 0.598 mmol.) in 1,4-dioxane (30 mL) was purged with argon for 10 min. Then, 2 M Na2CO3 (2.3 g, 21.69 mmol) in water was added to it and again argon was purged through it for 10 min. The reaction mixture was stirred at 100° C. for 2 h. After completion of the reaction, water was added to it and extraction was carried out using EtOAc. The combined organic layers were washed with water, dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to afford crude material which was purified by column chromatography to give the desired compound (2.1 g, 80.7%).
Reaction SMILES: C([O:8][C:9]1[CH:30]=[C:29]([Cl:31])[C:12]([CH2:13][C@@H:14]2[CH2:18][CH2:17][N:16]([C@H:19]3[CH2:27][CH2:26][C:25]4[C:21](=[CH:22][NH:23][N:24]=4)[CH2:20]3)[C:15]2=[O:28])=[C:11]([Cl:32])[CH:10]=1)C1C=CC=CC=1.[H][H]>C(O)C.[OH-].[OH-].[Pd+2]>[OH:8][C:9]1[CH:30]=[C:29]([Cl:31])[C:12]([CH2:13][C@@H:14]2[CH2:18][CH2:17][N:16]([C@H:19]3[CH2:27][CH2:26][C:25]4[C:21](=[CH:22][NH:23][N:24]=4)[CH2:20]3)[C:15]2=[O:28])=[C:11]([Cl:32])[CH:10]=1
Reactant: [H][H]
Reactant: O=C1[C@H](Cc2c(Cl)cc(OCc3ccccc3)cc2Cl)CCN1[C@H]1CCc2n[nH]cc2C1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CCO
Product: O=C1[C@H](Cc2c(Cl)cc(O)cc2Cl)CCN1[C@H]1CCc2n[nH]cc2C1
Reaction time: 6 h

Procedure:
Dissolve (3R,5S)-3-(4-Benzyloxy-2,6-dichloro-benzyl)-1-(4,5,6,7-tetrahydro-2H-indazol-5-yl)-pyrrolidin-2-one (Example 35) (8.79 g, 18.7 mmol) in absolute ethanol (60 mL), treat with 20% Pd(OH)2 (6.0 g) and stir at 30 psi hydrogen pressure. After 6 h, ESMS shows starting material consumed and product formed. Remove the catalyst by filtration, rinse with ethanol and evaporate to a dark foam. Filtration through 50 g SCX mega-bond elut using 95:5 CH2Cl2/MeOH followed by 95:5 CH2Cl2/7.0 M NH3/MeOH yields 5.6 g (79%) as an amorphous solid MS (m/z): 380 (M+1)
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7](Cl)[CH:8]=2)[N:3]=1.[CH3:13][O:14][C:15]1[CH:22]=[CH:21][CH:20]=[CH:19][C:16]=1[CH2:17][NH2:18].[CH3:23][N:24]1[CH:28]=[C:27]([CH2:29][NH2:30])[N:26]=[CH:25]1>>[CH3:13][O:14][C:15]1[CH:22]=[CH:21][CH:20]=[CH:19][C:16]=1[CH2:17][NH:18][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([NH:30][CH2:29][C:27]3[N:26]=[CH:25][N:24]([CH3:23])[CH:28]=3)[CH:8]=2)[N:3]=1
Reactant: COc1ccccc1CN
Reactant: Cn1cnc(CN)c1
Reactant: Clc1ccc2nc(Cl)ccc2c1
Product: COc1ccccc1CNc1ccc2cc(NCc3cn(C)cn3)ccc2n1

Procedure:
The title compound, MS: m/e=374.4 (M+H+), was prepared in accordance with the general method of example 1 from 2,6-dichloroquinoline, 2-methoxybenzylamine and (1-methyl-1H-imidazol-4-yl)methylamine.
Reaction SMILES: [N:1]1[C:9]2[CH2:8][CH2:7][NH:6][CH2:5][C:4]=2[S:3][C:2]=1[NH:10][C:11](=[O:13])[CH3:12].Cl[C:15]1[CH:20]=[N:19][CH:18]=[CH:17][N:16]=1.O>CN1C(=O)CCC1>[N:16]1[CH:17]=[CH:18][N:19]=[CH:20][C:15]=1[N:6]1[CH2:7][CH2:8][C:9]2[N:1]=[C:2]([NH:10][C:11](=[O:13])[CH3:12])[S:3][C:4]=2[CH2:5]1
Reactant: Clc1cnccn1
Reactant: CC(=O)Nc1nc2c(s1)CNCC2
Solvent: CN1CCCC1=O
Solvent: O
Product: CC(=O)Nc1nc2c(s1)CN(c1cnccn1)CC2
Temperature: 250 °C
Yield: 9.7 %

Procedure:
As shown in step 10-iv of Scheme 10, to a solution of 50 mg of Compound 1035 in 3 mL of NMP was added 100 mg of 2-chloro pyrazine. The reaction mixture was warmed to 250° C. for 10 minutes under microwave irradiation. The reaction was poured into water (10 mL) and the crude product collected by filtration. The crude solid was purified by silica gel chromatography (CH2Cl2 to EtOH) to provide N-(5-(pyrazin-2-yl)-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)acetamide (Compound 1, 6.8 mg): ESMS (M+H) 276.16.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:18]=[C:17]2[C:12]([C:13]([Cl:19])=[N:14][CH:15]=[N:16]2)=[CH:11][C:10]=1[O:20][CH3:21])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:22][C:23]1[CH:29]=[CH:28][C:26]([NH2:27])=[C:25]([F:30])[CH:24]=1>CC(O)C>[ClH:19].[CH2:1]([O:8][C:9]1[CH:18]=[C:17]2[C:12]([C:13]([NH:27][C:26]3[CH:28]=[CH:29][C:23]([Cl:22])=[CH:24][C:25]=3[F:30])=[N:14][CH:15]=[N:16]2)=[CH:11][C:10]=1[O:20][CH3:21])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Nc1ccc(Cl)cc1F
Reactant: COc1cc2c(Cl)ncnc2cc1OCc1ccccc1
Solvent: CC(C)O
Product: COc1cc2c(Nc3ccc(Cl)cc3F)ncnc2cc1OCc1ccccc1
Product: Cl
Yield: 63.3 %

Procedure:
A solution of 7-benzyloxy-4chloro-6-methoxyquinazoline (1.2 g, 4 mmol), (prepared as described for the starting material in Example 1), and 4-chloro-2-fluoroaniline (4441 μl, 4 mmol) in 2-propanol (40 ml) was refluxed for 1.5 hours. After cooling, the precipitate was collected by filtration, washed with 2-propanol then ether and dried under vacuum to give 7-benzyloxy-4-(4-chloro-2-fluoroanilino)-6-methoxyquinazoline hydrochloride (1.13 g, 64%). m.p. 239-242° C.
Reaction SMILES: [C:1]([O:5][C:6](=[O:17])[CH2:7]/[N:8]=[CH:9]/[CH2:10][C:11]([CH3:16])([CH3:15])[CH:12]([CH3:14])[CH3:13])([CH3:4])([CH3:3])[CH3:2].[Cl:18][C:19]1[C:20]([F:37])=[C:21](/[CH:25]=[C:26](/[C:29]2[CH:34]=[CH:33][C:32]([Cl:35])=[CH:31][C:30]=2[F:36])\[C:27]#[N:28])[CH:22]=[CH:23][CH:24]=1.C(N(CC)CC)C>ClCCl>[C:1]([O:5][C:6]([CH:7]1[CH:25]([C:21]2[CH:22]=[CH:23][CH:24]=[C:19]([Cl:18])[C:20]=2[F:37])[C:26]([C:29]2[CH:34]=[CH:33][C:32]([Cl:35])=[CH:31][C:30]=2[F:36])([C:27]#[N:28])[CH:9]([CH2:10][C:11]([CH3:15])([CH3:16])[CH:12]([CH3:13])[CH3:14])[NH:8]1)=[O:17])([CH3:4])([CH3:3])[CH3:2]
Reactant: N#C/C(=C\c1cccc(Cl)c1F)c1ccc(Cl)cc1F
Reactant: CC(C)C(C)(C)C/C=N/CC(=O)OC(C)(C)C
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)C(C)(C)CC1NC(C(=O)OC(C)(C)C)C(c2cccc(Cl)c2F)C1(C#N)c1ccc(Cl)cc1F
Yield: 57 %

Procedure:
In a manner similar to the method described in Example 1c, [3,3,4-trimethyl-pent-(E)-ylideneamino]-acetic acid tert-butyl ester prepared in Example 78a (1.5 g, 6.2 mmol) was reacted with (Z)-3-(3-chloro-2-fluoro-phenyl)-2-(4-chloro-2-fluoro-phenyl)-acrylonitrile (1.1 g, 3.5 mmol) prepared in Example 52a, AgF (1.2 g, 9.5 mmol), and triethylamine (2 g, 20 mmol) in dichloromethane (150 mL) at room temperature for 18 h to give rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2,3-trimethyl-butyl)-pyrrolidine-2-carboxylic acid tert-butyl ester as a white foam (1.1 g, 56%).
Reaction SMILES: [CH2:1]([O:8][N:9]([CH2:20][CH2:21]Br)[S:10]([C:13]1[CH:18]=[CH:17][C:16]([CH3:19])=[CH:15][CH:14]=1)(=[O:12])=[O:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[P:23]([O:30]CC)([O:27][CH2:28][CH3:29])[O:24][CH2:25][CH3:26].C(OCC)(=O)C.C(OC(C)C)(C)C>O>[CH2:1]([O:8][N:9]([CH2:20][CH2:21][P:23](=[O:30])([O:27][CH2:28][CH3:29])[O:24][CH2:25][CH3:26])[S:10]([C:13]1[CH:18]=[CH:17][C:16]([CH3:19])=[CH:15][CH:14]=1)(=[O:12])=[O:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cc1ccc(S(=O)(=O)N(CCBr)OCc2ccccc2)cc1
Reactant: CCOP(OCC)OCC
Solvent: O
Solvent: CC(C)OC(C)C
Solvent: CCOC(C)=O
Product: CCOP(=O)(CCN(OCc1ccccc1)S(=O)(=O)c1ccc(C)cc1)OCC
Temperature: 160 °C
Reaction time: 10 h
Yield: 57 %

Procedure:
A mixture of N-benzyloxy-N-(2-bromoethyl)-p-toluenesulfonamide (16.2 g.) and triethyl phosphite (21.0 g.) was stirred at 160° C. for 10 hours and then cooled to ambient temperature. To the reaction mixture was added ethyl acetate and water. The ethyl acetate layer was separated, washed with water, dried over magnesium sulfate and concentrated under reduced pressure to give an oily residue (20.5 g.). A small volume of isopropyl ether was added to the residue to give crystals, which was separated by filtration and dried to give crystalline diethyl 2-(N-benzyloxy-N-tosylamino)ethylphosphonate (10.6 g.). The object compound (2.1 g.) was also recovered from the mother liquor by subjecting to a column chromatography on silicagel (developing solvent: chloroform)
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[C:9]([CH3:11])[CH:8]=[C:7]([CH3:12])[C:3]=1[CH2:4][C:5]#[N:6].[NH2:13][C:14]1[N:19]=[C:18]([NH2:20])[C:17]([CH:21]=O)=[CH:16][N:15]=1.N>C>[CH3:1][C:2]1[CH:10]=[C:9]([CH3:11])[CH:8]=[C:7]([CH3:12])[C:3]=1[C:4]1[C:5]([NH2:6])=[N:20][C:18]2[N:19]=[C:14]([NH2:13])[N:15]=[CH:16][C:17]=2[CH:21]=1
Reactant: Nc1ncc(C=O)c(N)n1
Reactant: Cc1cc(C)c(CC#N)c(C)c1
Agent: C
Agent: N
Product: Cc1cc(C)c(-c2cc3cnc(N)nc3nc2N)c(C)c1

Procedure:
The title compound was prepared according to Example 1, starting from 0.915 g of 2,4,6-trimethyl-benzyl cyanide and 0.76 g of 2,4-diamino-5-pyrimidine-carboxaldehyde; mp 276°-282° C.; CIMS (1% ammonia in methane): m/z (relative intensity) 279 (MH+, 54), 280 (MH+ +1, 100).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:12]=[C:11]([NH:13]/[C:14](/[NH:26][CH2:27][CH:28]([CH3:30])[CH3:29])=[N:15]\[C:16](=[O:25])[C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([S:23][CH3:24])[CH:18]=3)[NH:10][N:9]=2)=[CH:4][CH:3]=1.I(O)(=O)(=O)=[O:32]>CC(C)=O.C(#N)C>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:12]=[C:11]([NH:13]/[C:14](/[NH:26][CH2:27][CH:28]([CH3:30])[CH3:29])=[N:15]\[C:16](=[O:25])[C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([S:23]([CH3:24])=[O:32])[CH:18]=3)[NH:10][N:9]=2)=[CH:4][CH:3]=1
Reactant: [O-][I+3]([O-])([O-])O
Reactant: CSc1cccc(C(=O)/N=C(/NCC(C)C)Nc2cc(-c3ccc(F)cc3)n[nH]2)c1
Solvent: CC#N
Solvent: CC(C)=O
Product: CC(C)CN/C(=N/C(=O)c1cccc(S(C)=O)c1)Nc1cc(-c2ccc(F)cc2)n[nH]1
Temperature: 25 °C
Reaction time: 21 h
Yield: 77 %

Procedure:
To an orange solution of (Z)—N-[[[3-(4-fluorophenyl)-1H-pyrazol-5-yl]amino]-(isobutylamino)methylene]-3-methylsulfanyl-benzamide (500 mg, 1.175 mmol) and ferric chloride trihydrate (9.5 mg, 0.035 mmol) in acetone:acetonitrile (1:1) was added periodic acid (295 mg, 1.3 mmol) in one portion. After stirring the resulting mixture at room temperature for ca. 21 hr, the reaction was quenched by adding aqueous sodium thiosulfate. The product was extracted with DCM, and the organic layer was washed with brine and dried over MgSO4. The drying reagent was removed by filtration, and the filtrate was concentrated onto silica gel and purified by silica chromatography (50-90% EtOAc in hexanes) to provide the title compound (77% yield). MS (EI+) m/z: 442.17.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH2:9][CH:10]([N:19]=[C:20]=[S:21])[C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([CH3:17])[C:12]=2[CH3:18])[CH:5]=[C:6]([CH3:8])[CH:7]=1.[CH2:22]([CH2:24][NH2:25])[OH:23]>C(Cl)(Cl)Cl>[CH3:1][C:2]1[CH:3]=[C:4]([CH2:9][CH:10]([NH:19][C:20]([NH:25][CH2:24][CH2:22][OH:23])=[S:21])[C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([CH3:17])[C:12]=2[CH3:18])[CH:5]=[C:6]([CH3:8])[CH:7]=1
Reactant: NCCO
Reactant: Cc1cc(C)cc(CC(N=C=S)c2cccc(C)c2C)c1
Solvent: ClC(Cl)Cl
Product: Cc1cc(C)cc(CC(NC(=S)NCCO)c2cccc(C)c2C)c1
Reaction time: 3 h
Yield: 95.9 %

Procedure:
To a solution of [2-(3,5-dimethyl-phenyl)-1-(2,3-dimethyl-phenyl)-ethyl]-isothiocyanate (81.9 g) in chloroform (1 l) was added ethanolamine (25.4 g) dropwise at room temperature. The mixture was stirred for 3 hours and the solvent evaporated, the remainder dissolved in ethyl acetate and washed 6 times with water. The solution was dried over sodium sulphate. Removal of the solvent in vacuo yielded the 1-[2-(3,5-Dimethylphenyl)-1-(2,3-dimethyl-phenyl)-ethyl]-3-(2-hydroxy-ethyl)-thiourea (94.8 g) as an off-white powder.