Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:38]=[CH:39][C:40]=1[CH3:41])[CH2:5][NH:6][C:7]([C:9]1[N:10]=[C:11]2[CH:17]([N:18]([C:20](=[O:26])[C:21]([N:23]([CH3:25])[CH3:24])=[O:22])[CH3:19])[CH2:16][N:15]([C:27](OC(C)(C)C)=O)[CH2:14][CH2:13][N:12]2[C:34](=[O:37])[C:35]=1[OH:36])=[O:8].ClCCl.F[C:46](F)(F)[C:47](O)=O>>[Cl:1][C:2]1[CH:3]=[C:4]([CH:38]=[CH:39][C:40]=1[CH3:41])[CH2:5][NH:6][C:7]([C:9]1[N:10]=[C:11]2[CH:17]([N:18]([CH3:19])[C:20](=[O:26])[C:21]([N:23]([CH3:25])[CH3:24])=[O:22])[CH2:16][N:15]([CH:27]3[CH2:47][CH2:46]3)[CH2:14][CH2:13][N:12]2[C:34](=[O:37])[C:35]=1[OH:36])=[O:8]
Reactant: Cc1ccc(CNC(=O)c2nc3n(c(=O)c2O)CCN(C(=O)OC(C)(C)C)CC3N(C)C(=O)C(=O)N(C)C)cc1Cl
Reactant: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1ccc(CNC(=O)c2nc3n(c(=O)c2O)CCN(C2CC2)CC3N(C)C(=O)C(=O)N(C)C)cc1Cl

Procedure:
The compound of Step 2 was stirred in dichloromethane/trifluoroacetic acid (8/2 v/v) for 1 hour, then concentrated under reduced pressure and triturated with diethyl ether. A portion of this material was purified by prep RP HPLC (C18, 5 μM, H2O/MeCN with 1% of TFA as eluant) affording title compound as a white solid. 1H NMR (400 MHz, CD3CN) δ 12.40 (bs, 1H), 9.78 (bs, 1H), 7.43 (s, 1H), 7.28-7.21 (m, 2H), 5.37-5.29 (m, 2H), 4.58 (dd, J=14.6 Hz, J=6.86 Hz, 1H), 4.47 (dd, J=14.6 Hz, J=6.41 Hz, 1H), 4.01-3.3.92 (m, 3H), 3.78-3.69 (m, 1H), 3.22-3.12 (m, 1H), 3.08 (s, 3H), 2.93 (s, 3H), 2.91 (s, 3H), 2.28 (s, 3H); MS (ES) C22H27ClN6O5 requires 490. Found: 491 (M+H+). N-(2-{[(3-chloro-4-methylbenzyl)amino]carbonyl}-3-hydroxy-4-oxo-4,6,7,8,9,10-hexahydropyrimido[1,2-d][1,4]diazepin-10-yl)-N,N′,N′-trimethylethanediamide has been resolved into its enantiomers by semipreparative chiral SFC using the following conditions:
Reaction SMILES: [O:1]=[C:2]1[NH:6][C:5](=[S:7])[CH2:4][S:3]1.[NH:8]=[C:9]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11](=N)[NH:10]1>CO>[NH:8]=[C:9]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11](=[C:4]2[S:3][C:2](=[O:1])[NH:6][C:5]2=[S:7])[NH:10]1
Reactant: N=C1NC(=N)c2ccccc21
Reactant: O=C1NC(=S)CS1
Solvent: CO
Product: N=C1NC(=C2SC(=O)NC2=S)c2ccccc21
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a stirred solution of 49.7 parts of 2-oxo-4-thioxothiazolidine in 990 parts of methanol there was added at 40°C and under an atmosphere of nitrogen 54.3 parts of powdered 1,3-diiminoisoindoline. Initially, a thick slurry resulted. The reaction mixture was stirred at room temperature for 2 hours during which time the mixture gradually thinned. The mixture was then heated at reflux for approximately two hours and after cooling to 25°C, was filtered. The collected solid was washed with fresh methanol and dried in vacuo at 50°C to obtain 1-imino-3-(2-oxo-4-thioxo-5-thiazolidinylidene)isoindoline as an orange powder melting at 267°-8°C (dec.).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([I:8])=[CH:4][N:3]=1.Cl[C:10]([C:12]([CH3:19])([CH3:18])[CH2:13][O:14][C:15](=[O:17])[CH3:16])=[O:11]>>[I:8][C:5]1[CH:6]=[CH:7][C:2]([NH:1][C:10]([C:12]([CH3:19])([CH3:18])[CH2:13][O:14][C:15](=[O:17])[CH3:16])=[O:11])=[N:3][CH:4]=1
Reactant: Nc1ccc(I)cn1
Reactant: CC(=O)OCC(C)(C)C(=O)Cl
Product: CC(=O)OCC(C)(C)C(=O)Nc1ccc(I)cn1

Procedure:
The title compound, a white solid, MS: m/e=363.2 (M+H+), can be prepared in accordance with the general method of example 39, step 1 from 2-amino-5-iodopyridine and acetic acid 2-chlorocarbonyl-2-methyl-propyl ester (example 40, step 2).
Reaction SMILES: [CH:1](NC(C)C)(C)C.C([Li])CCC.[CH3:13][O:14][C:15]1[CH:20]=[CH:19][C:18]([N:21]2[C:25]([C:26]3[CH:31]=[CH:30][N:29]=[CH:28][CH:27]=3)=[CH:24][N:23]=[CH:22]2)=[CH:17][CH:16]=1.CI>O1CCCC1>[CH3:13][O:14][C:15]1[CH:16]=[CH:17][C:18]([N:21]2[C:25]([C:26]3[CH:31]=[CH:30][N:29]=[CH:28][CH:27]=3)=[CH:24][N:23]=[C:22]2[CH3:1])=[CH:19][CH:20]=1
Reactant: CC(C)NC(C)C
Reactant: COc1ccc(-n2cncc2-c2ccncc2)cc1
Agent: [Li]CCCC
Solvent: CI
Solvent: C1CCOC1
Product: COc1ccc(-n2c(-c3ccncc3)cnc2C)cc1
Temperature: -20 °C
Reaction time: 0.17 h
Yield: 72 %

Procedure:
A solution of diisopropyl amine (0.51 mL, 3.6 mmol) in tetrahydrofuran (12 mL) at −20° C., was treated with n-butyl lithium (2.5 M in hexanes, 1.45 mL, 3.6 mmol) and the solution was stirred for 10 minutes. A solution of Preparation 80 (4-(1-(4-methoxyphenyl)-1H-imidazol-5-yl)pyridine, 730 mg, 2.9 mmol) in tetrahydrofuran was added and the solution became dark orange. The solution was stirred for 30 minutes as the temperature was allowed to rise to 0° C. After cooling to −20° C., methyl iodide (0.54 mL, 8.7 mmol) in tetrahydrofuran (12 mL) was added and the solution was stirred for 30 min at −20° C. and for 2 hr at 23° C. The solvent was removed in vacuo, the residue was diluted with brine and was extracted with ethyl acetate. The organic layer was then dried (MgSO4), was filtered, and was concentrated in vacuo. The residue was purified by silica gel chromatography using ethyl acetate-hexanes-methanol (63:32:5 to 72:18:10) to afford 555 mg (72% yield) of the title compound; diagnostic 13C NMR signals (100 MHz, CDCl3) δ 160.144, 150.034, 149.197, 137.749, 131.265, 129.463, 128.985, 128.828, 120.849, 115.233, 55.78, 14.203; MS (AP/CI) 266.4 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]([F:11])[CH:8]=[CH:7][C:3]=1[C:4]([NH2:6])=[O:5].F[B-](F)(F)F.[CH2:17]([O+](CC)CC)[CH3:18]>>[Cl:1][C:2]1[CH:10]=[C:9]([F:11])[CH:8]=[CH:7][C:3]=1[C:4](=[NH:6])[O:5][CH2:17][CH3:18]
Reactant: CC[O+](CC)CC
Reactant: NC(=O)c1ccc(F)cc1Cl
Agent: F[B-](F)(F)F
Product: CCOC(=N)c1ccc(F)cc1Cl

Procedure:
starting from 2-chloro-4-fluorobenzamide and triethyloxonium tetrafluoroborate there is obtained ethyl 2-chloro-4-fluorobenzimidate as an oil; 1H-NMR(CDCl3): 1.43 (t, CH3), 4.40 (q, CH2), 6.9-7.8 (3 aromatic H+NH).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[CH:4][C:3]=1[S:12]([NH:15][C:16]1[C:17](Cl)=[CH:18][CH:19]=[C:20]2[C:25]=1[N:24]=[CH:23][CH:22]=[C:21]2[O:26][CH3:27])(=[O:14])=[O:13].C([O-])=O.[NH4+]>[Pd].C(O)(=O)C.CCOC(C)=O>[NH2:1][C:2]1[CH:7]=[C:6]([C:8]([F:10])([F:9])[F:11])[CH:5]=[CH:4][C:3]=1[S:12]([NH:15][C:16]1[CH:17]=[CH:18][CH:19]=[C:20]2[C:25]=1[N:24]=[CH:23][CH:22]=[C:21]2[O:26][CH3:27])(=[O:13])=[O:14]
Reactant: COc1ccnc2c(NS(=O)(=O)c3ccc(C(F)(F)F)cc3N)c(Cl)ccc12
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: COc1ccnc2c(NS(=O)(=O)c3ccc(C(F)(F)F)cc3N)cccc12
Yield: 101.3 %

Procedure:
10% palladium on carbon (82 mg) was added to a solution of 2-amino-N-(7-chloro-4-methoxy-quinolin-8-yl)-4-trifluoromethyl-benzenesulfonamide (Intermediate 195) (670 mg, 1.5 mmol) and ammonium formate (481 mg, 7.5 mmol) in 50% acetic acid (5 ml) and the reaction was heated under reflux for 30 min. After cooling the mixture was diluted with EtOAc (100 ml), washed sat sodium bicarbonate solution, dried (MgSO4) concentrated in vacuo. The crude residue was purified by column chromatography with DCM/MeOH (98:2) as the eluent to give the title compound (604 mg, 100%).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:8])[CH:5](Br)[CH3:6])[CH3:2].[Br:9][C:10]1[CH:15]=[CH:14][C:13]([NH2:16])=[CH:12][C:11]=1[CH3:17].CN(C)C1C=CC=CC=1>>[CH2:1]([O:3][C:4](=[O:8])[CH:5]([NH:16][C:13]1[CH:14]=[CH:15][C:10]([Br:9])=[C:11]([CH3:17])[CH:12]=1)[CH3:6])[CH3:2]
Reactant: Cc1cc(N)ccc1Br
Reactant: CCOC(=O)C(C)Br
Solvent: CN(C)c1ccccc1
Product: CCOC(=O)C(C)Nc1ccc(Br)c(C)c1
Temperature: 60 °C
Reaction time: 15 h

Procedure:
2-Bromo-propionic acid ethyl ester (973 mg, 5.22 mmol) was added to 4-bromo-3-methyl-phenylamine (1.00 g, 5.37 mmol) and dimethylphenylamine (682 μL, 5.37 mmol) at room temperature, and the mixture was stirred at 60° C. for 15 hours. The reaction solution was then cooled and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane-ethyl acetate) to give 2-(4-bromo-3-methyl-phenylamino)-propionic acid ethyl ester as a yellow form (1.38 g, 90%).
Reaction SMILES: [CH:1]1([C:7]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[C:10](=O)[NH:9][N:8]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.P(Cl)(Cl)([Cl:20])=O>ClC(Cl)C>[Cl:20][C:10]1[C:11]2[C:16](=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:7]([CH:1]2[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]2)=[N:8][N:9]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: O=c1[nH]nc(C2CCCCC2)c2ccccc12
Solvent: CC(Cl)Cl
Product: Clc1nnc(C2CCCCC2)c2ccccc12
Temperature: 100 °C
Reaction time: 4 h

Procedure:
1.0 g of 4-cyclohexyl-1-phthalazinone and 5 ml of phosphorus oxychloride were dissolved in 10 ml of dichloroethane, and the solution was stirred at 100° C. for 4 hours. The reaction solution was distilled off, and a 1-N aqueous NaOH solution was added thereto under cooling with ice. The solution was extracted with chloroform and dried over magnesium sulfide. The solvent was then distilled off, thereby obtaining 1.1 g of 1-chloro-4-cyclo-hexylphthalazine.
Reaction SMILES: [C:1](#[N:3])[CH3:2].C[Si]([N-][Si](C)(C)C)(C)C.[Li+].[CH3:14][C:15]1[O:19][C:18]([C:20](OC)=[O:21])=[CH:17][CH:16]=1.Cl>C1COCC1>[CH3:14][C:15]1[O:19][C:18]([C:20](=[O:21])[CH2:2][C:1]#[N:3])=[CH:17][CH:16]=1
Reactant: CC#N
Reactant: COC(=O)c1ccc(C)o1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: Cl
Agent: [Li+]
Solvent: C1CCOC1
Product: Cc1ccc(C(=O)CC#N)o1
Temperature: -20 °C
Reaction time: 0.5 h
Yield: 55.5 %

Procedure:
Following the method of Turner and Jacks (J. Org. Chem. 1989, 54, 4229), to a stirred solution of 5.6 ml (107 mmol) acetonitrile in 20 ml dry THF under argon at −78° C. was added dropwise 47.0 ml (47.09 mmol) lithium bis(trimethylsilyl)amide solution (1M in THF) and stirring continued for 30 minutes, after which a solution of 3.0 g (21.4 mmol) methyl 5-methyl-2-furoate in 20 ml THF was added dropwise and stirring continued while the reaction mixture was allowed to warm slowly to −20° C. The reaction mixture was then cannulated into a rapidly stirred solution of 1M hydrochloric acid at 0° C. The mixtured was extracted twice with ether and the combined organic phases dried over sodium sulfate and concentrated in vacuo. Chromatography (ethyl acetatephexane 1/1) afforded 1.77 g (55%) 3-(5-methyl-furan-2-yl)-3-oxo-propionitrile as a yellow crystalline solid. EI-MS m/e (%): 149 (M+, 24), 109 ([M—CH2CN]+, 100), 53 (30).
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[C:3]1[C:11]2[CH:10]=[CH:9][CH:8]=[C:7]([OH:12])[C:6]=2[CH2:5][CH:4]=1.[H][H]>CO.CCOC(C)=O.[Pd]>[F:1][C:2]([F:13])([F:14])[CH:3]1[C:11]2[CH:10]=[CH:9][CH:8]=[C:7]([OH:12])[C:6]=2[CH2:5][CH2:4]1
Reactant: Oc1cccc2c1CC=C2C(F)(F)F
Reactant: [H][H]
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CO
Product: Oc1cccc2c1CCC2C(F)(F)F
Yield: 96.2 %

Procedure:
A mixture of 1-trifluoromethyl-3H-inden-4-ol (70 mg, 0.349) and 10% Pd/C (20 mg) in methanol (2 ml) was hydrogenated under 50 psi hydrogen atmosphere for 3 hours. The mixture was dissolved in EtOAc, filtered through a celite pad. The filtrate was concentrated tinder reduced pressure, and dried to give 1-trifluoromethyl-indan-4-ol (68 mg, 97%).
Reaction SMILES: [CH2:1]1[CH2:13][O:12][C:11]2[CH:10]=[CH:9][C:5]([CH2:6][CH2:7][NH2:8])=[CH:4][C:3]=2[O:2]1.Cl[C:15]1[C:16]2[C:29]([Cl:30])=[C:28]([CH3:31])[S:27][C:17]=2[N:18]=[C:19]([C:21]2[CH:22]=[N:23][CH:24]=[CH:25][CH:26]=2)[N:20]=1>>[N:23]1[CH:24]=[CH:25][CH:26]=[C:21]([C:19]2[N:20]=[C:15]([NH:8][CH2:7][CH2:6][C:5]3[CH:9]=[CH:10][C:11]4[O:12][CH2:13][CH2:1][O:2][C:3]=4[CH:4]=3)[C:16]3[C:29]([Cl:30])=[C:28]([CH3:31])[S:27][C:17]=3[N:18]=2)[CH:22]=1
Reactant: NCCc1ccc2c(c1)OCCO2
Reactant: Cc1sc2nc(-c3cccnc3)nc(Cl)c2c1Cl
Product: Cc1sc2nc(-c3cccnc3)nc(NCCc3ccc4c(c3)OCCO4)c2c1Cl

Procedure:
With the procedure of Example 1, the reaction of 3,4-ethylenedioxyphenethylamine with 4-chloro-2-(pyridin-3-yl)-5-chloro-6-methyl-thieno-[2,3-d]-pyrimidine yields 2-(pyridin-3-yl)-4-(3,4-ethylenedioxyphenethylamino)-5-chloro-6-methyl-thieno-[2,3-d]-pyrimidine.
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([N:23]2[CH2:28][CH2:27][O:26][CH2:25][CH2:24]2)[C:5]2[N:11]=[C:10]([CH2:12][N:13]3[CH2:18][CH2:17][CH:16]([C:19]([OH:22])([CH3:21])[CH3:20])[CH2:15][CH2:14]3)[CH:9]=[CH:8][C:6]=2[N:7]=1.[NH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=1[NH2:36]>>[NH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=1[NH:36][C:2]1[N:3]=[C:4]([N:23]2[CH2:28][CH2:27][O:26][CH2:25][CH2:24]2)[C:5]2[N:11]=[C:10]([CH2:12][N:13]3[CH2:14][CH2:15][CH:16]([C:19]([OH:22])([CH3:21])[CH3:20])[CH2:17][CH2:18]3)[CH:9]=[CH:8][C:6]=2[N:7]=1
Reactant: Nc1ccccc1N
Reactant: CC(C)(O)C1CCN(Cc2ccc3nc(Cl)nc(N4CCOCC4)c3n2)CC1
Product: CC(C)(O)C1CCN(Cc2ccc3nc(Nc4ccccc4N)nc(N4CCOCC4)c3n2)CC1

Procedure:
2-(1-((2-chloro-4-morpholinopyrido[3,2-d]pyrimidin-6-yl)methyl)piperidin-4-yl)propan-2-ol from Example 8 (0.12 g) was reacted with diaminobenzene via General Procedure C to afford crude 2-(1-((2-(2-aminophenylamino)-4-morpholinopyrido[3,2-d]pyrimidin-6-yl)methyl)piperidin-4-yl)propan-2-ol after elution thru a Biotage isolute scx-2 cartridge.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]([CH2:12][CH2:13][CH2:14][Cl:15])[C:9]([OH:11])=O)=[N:6][CH:7]=1.CCN(CC)CC.C1CN([P+](Br)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.[Br:47][C:48]1[CH:53]=[CH:52][C:51]([NH2:54])=[CH:50][CH:49]=1>C(Cl)Cl>[Br:47][C:48]1[CH:53]=[CH:52][C:51]([NH:54][C:9](=[O:11])[CH:8]([C:5]2[CH:4]=[CH:3][C:2]([Br:1])=[CH:7][N:6]=2)[CH2:12][CH2:13][CH2:14][Cl:15])=[CH:50][CH:49]=1
Reactant: O=C(O)C(CCCCl)c1ccc(Br)cn1
Reactant: Nc1ccc(Br)cc1
Agent: Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(Nc1ccc(Br)cc1)C(CCCCl)c1ccc(Br)cn1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 2-(5-Bromo-pyridin-2-yl)-5-chloro-pentanoic acid (1.9 g, 6.5 mmol), Et3N (3.6 mL, 26 mmol), and Pybrop (6 g, 13 mmol) in CH2Cl2 (30 mL) was added 4-bromo-phenylamine (1.45 g, 8.45 mmol). This mixture was stirred overnight at room temperature and then evaporated. The mixture was redissolved in EtOAc (40 mL) and washed with 2N HCl (20 mL×3), brine, 5% NaHCO3 (20 mL×3), brine, dried with Na2SO4, filtered and evaporated. The residue was purified by column chromatography on silica gel using hexane/EtOAc to give a white solid (1.63 g, 56% for two steps). MS: calc'd 444 (MH+), exp 444 (MH+). 1H NMR (400 MHz, CDCl3-d) 9.65 (broad s, 1H), 8.72 (d, 1H, J=2.0 Hz), 8.06 (d, 1H, J=8.4 Hz), 7.53-7.41 (m, 4H), 4.18-4.08 (m, 1H), 3.66-3.54 (m, 2H), 2.45-2.35 (m, 1H), 2.21-2.11 (m, 1H), 1.98-1.87 (m, 1H), 1.83-1.72 (m, 1H).
Reaction SMILES: [NH2:1][CH2:2][C:3]1[N:8]=[C:7]([OH:9])[C:6]([O:10][CH3:11])=[CH:5][N:4]=1.[I:12][C:13]1[CH:14]=[C:15]2[C:20](=[CH:21][CH:22]=1)[C:19](=[O:23])[NH:18][C:17](=[O:24])[C:16]2=[CH:25]OC>CN(C)C=O>[OH:9][C:7]1[C:6]([O:10][CH3:11])=[CH:5][N:4]=[C:3]([CH2:2][NH:1][CH:25]=[C:16]2[C:15]3[C:20](=[CH:21][CH:22]=[C:13]([I:12])[CH:14]=3)[C:19](=[O:23])[NH:18][C:17]2=[O:24])[N:8]=1
Reactant: COC=C1C(=O)NC(=O)c2ccc(I)cc21
Reactant: COc1cnc(CN)nc1O
Solvent: CN(C)C=O
Product: COc1cnc(CNC=C2C(=O)NC(=O)c3ccc(I)cc32)nc1O
Yield: 34.6 %

Procedure:
2-Aminomethyl-5-methoxy-pyrimidin-4-ol (10 mg, 0.064 mmol) and 6-iodo-4-methoxymethylene-4H-isoquinoline-1,3-dione (50 mg, 0.15 mmol) in N,N-dimethylformamide (3 mL) is stirred at room temperature for 1 hour. The N,N-dimethylformamide is then removed and residue purified to provide the title compound (10 mg, 34%). MS (ESI): 453 (M+1)+1.
Reaction SMILES: [C:1]1([N:7]=[C:8]=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH2:10][CH:11]1[C:17](=[O:18])[N:16]([CH2:19][C:20]([N:22]([CH:31]([CH3:33])[CH3:32])[C:23]2[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][CH:24]=2)=[O:21])[C:15]2[CH:34]=[CH:35][CH:36]=[CH:37][C:14]=2[N:13]([C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][N:39]=2)[C:12]1=[O:44]>C(Cl)Cl>[O:18]=[C:17]1[N:16]([CH2:19][C:20]([N:22]([CH:31]([CH3:33])[CH3:32])[C:23]2[CH:24]=[CH:25][C:26]([O:29][CH3:30])=[CH:27][CH:28]=2)=[O:21])[C:15]2[CH:34]=[CH:35][CH:36]=[CH:37][C:14]=2[N:13]([C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][N:39]=2)[C:12](=[O:44])[CH:11]1[NH:10][C:8]([NH:7][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)=[O:9]
Reactant: O=C=Nc1ccccc1
Reactant: COc1ccc(N(C(=O)CN2C(=O)C(N)C(=O)N(c3ccccn3)c3ccccc32)C(C)C)cc1
Solvent: ClCCl
Product: COc1ccc(N(C(=O)CN2C(=O)C(NC(=O)Nc3ccccc3)C(=O)N(c3ccccn3)c3ccccc32)C(C)C)cc1
Yield: 35.2 %

Procedure:
A solution of phenyl isocyanate (25.6 mg) in methylene chloride (1 ml) was added to a solution of 2-(3-Amino-2,4-dioxo-5-pyrdin-2-yl-2,3,4,5-tetrahydrobenzo[b][1,4]diazepin-1-yl)-N-isopropyl-N-(4-methoxy-phenyl)-acetamide (100 mg) in methylene chloride (1 ml) and the resultant mixture was stirred at rt for 4 h. The solvents were removed in vacuo and the residue was recrystalised from ethyl acetate to afford the title product (44 mg) as an off-white solid. 1H NMR (300 MHz, CDCl3); 1.03 (2×d, J=7 Hz, 6H), 3.81 (s, 3H), 4.17 (d J=16 Hz, 1H), 4.37 (d, J=16 Hz, 1H), 5.0 (sept, J=7.1 Hz, 1H), 5.40 (d, J=6.3 Hz, 1H), 6.40 (d, J=5.3 Hz, 1H), 6.8-7.3 (m, 17H), 7.80 (br, 1H), 8.42 (d, J=3.9 Hz, 1H).Tlc (10% MeOH, CH2Cl2) Rf=0.53. m/z [MH]+ =593.
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[CH2:5]([C:10]1[CH:15]=[CH:14][C:13]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[CH:12][CH:11]=1)[CH2:6][CH2:7][CH2:8][CH3:9].[C:22](Cl)(=[O:24])[CH3:23].Cl>[N+](C1C=CC=CC=1)([O-])=O.O>[CH2:5]([C:10]1[CH:15]=[CH:14][C:13]([C:16]2[CH:17]=[CH:18][C:19]([C:22](=[O:24])[CH3:23])=[CH:20][CH:21]=2)=[CH:12][CH:11]=1)[CH2:6][CH2:7][CH2:8][CH3:9]
Reactant: CC(=O)Cl
Reactant: CCCCCc1ccc(-c2ccccc2)cc1
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: O
Solvent: O=[N+]([O-])c1ccccc1
Product: CCCCCc1ccc(-c2ccc(C(C)=O)cc2)cc1
Temperature: 25 °C
Yield: 83.8 %

Procedure:
392 Gram of granular anhydrous aluminum chloride and 700 ml of nitrobenzene were introduced into 5 l three neck flask, and dissolved with stirring. A solution of 600 g of 4-n-pentylbiphenyl and 220 g of acetyl chloride dissolved in 500 ml of nitrobenzene (prepared in advance) was dropwise added to said three neck flask over 1 hour, followed by stirring for one hour, further stirring at 40°-45° C for 2 hours, cooling to room temperature, pouring cautiously into a mixed liquid of 250 ml of conc. hydrochloric acid and 1.25 l of water, distilling off nitrobenzene from nitrobenzene layer by distillation under a reduced pressure, separating the resulting solid by filtration, and recrystallizing it from ethanol, to give 597 g of 4'-n-pentyl-4-acetylbiphenyl (m.p. 81°-82°) (Yield 84%).
Reaction SMILES: [I:1][C:2]1[CH:3]=[CH:4][C:5]([O:9][CH:10]([CH3:12])[CH3:11])=[C:6]([OH:8])[CH:7]=1.C([O-])([O-])=O.[K+].[K+].[CH2:19](I)[CH3:20]>CN(C=O)C.C(OCC)C>[CH2:19]([O:8][C:6]1[CH:7]=[C:2]([I:1])[CH:3]=[CH:4][C:5]=1[O:9][CH:10]([CH3:12])[CH3:11])[CH3:20]
Reactant: CC(C)Oc1ccc(I)cc1O
Reactant: CCI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOCC
Product: CCOc1cc(I)ccc1OC(C)C
Temperature: 40 °C
Reaction time: 2 h
Yield: 98.4 %

Procedure:
To a solution of 5-iodo-2-isopropoxyphenol (2.3 g, 8.3 mmol) in DMF (20 mL), K2CO3 (2.3 g, 16.5 mmol) and ethyl iodide (0.86 mL, 10.8 mmol) were added. The mixture was stirred at 40° C. for 2.0 h. It was diluted with diethyl ether, washed with brine, dried over MgSO4. The crude was purified by chromatography (5:1 EtOAc/hexanes) to give 2-ethoxy-4-iodo-1-isopropoxybenzene (2.5 g, 96% yield) as an oil.
Reaction SMILES: [CH3:1][C:2]([CH3:21])([CH3:20])[CH2:3][N:4]([CH2:17][CH2:18][OH:19])[C:5]1[CH:12]=[CH:11][C:8]([C:9]#[N:10])=[C:7]([C:13]([F:16])([F:15])[F:14])[CH:6]=1.[CH3:22][C:23]([C:25]1[CH:26]=[CH:27][C:28](O)=[CH:29][CH:30]=1)=[O:24]>>[C:23]([C:25]1[CH:26]=[CH:27][C:28]([O:19][CH2:18][CH2:17][N:4]([CH2:3][C:2]([CH3:21])([CH3:20])[CH3:1])[C:5]2[CH:12]=[CH:11][C:8]([C:9]#[N:10])=[C:7]([C:13]([F:14])([F:15])[F:16])[CH:6]=2)=[CH:29][CH:30]=1)(=[O:24])[CH3:22]
Reactant: CC(=O)c1ccc(O)cc1
Reactant: CC(C)(C)CN(CCO)c1ccc(C#N)c(C(F)(F)F)c1
Product: CC(=O)c1ccc(OCCN(CC(C)(C)C)c2ccc(C#N)c(C(F)(F)F)c2)cc1

Procedure:
Synthesized as described in Example 1C from 4-[(2,2-dimethylpropyl)(2-hydroxyethyl)amino]-2-(trifluoromethyl)benzonitrile and 4-hydroxyacetophenone: 1H NMR (400 MHz, CDCl3) δ 7.91 (d, J=8.5 Hz, 2H), 7.57 (d, J=8.8 Hz, 1H), 7.11 (app. s, 1H), 6.92 (app. bd, J=8.9 Hz, 1H), 6.86 (d, J=8.5 Hz, 2H), 4.18 (t, J=5.6 Hz, 2H), 3.96 (t, J=5.6 Hz, 2H), 3.41 (s, 2H), 2.55 (s, 3H), 1.02 (s, 9H).
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]#[N:9])=[C:6]([C:10]2[O:11][CH:12]=[CH:13][CH:14]=2)[C:5]([C:15]#[N:16])=[C:4]([S:17][CH3:18])[N:3]=1.C1(C2[O:27]N2S(C2C=CC=CC=2)(=O)=O)C=CC=CC=1>ClCCl>[NH2:1][C:2]1[C:7]([C:8]#[N:9])=[C:6]([C:10]2[O:11][CH:12]=[CH:13][CH:14]=2)[C:5]([C:15]#[N:16])=[C:4]([S:17]([CH3:18])=[O:27])[N:3]=1
Reactant: CSc1nc(N)c(C#N)c(-c2ccco2)c1C#N
Reactant: O=S(=O)(c1ccccc1)N1OC1c1ccccc1
Solvent: ClCCl
Product: CS(=O)c1nc(N)c(C#N)c(-c2ccco2)c1C#N
Reaction time: 48 h
Yield: 93 %

Procedure:
To a stirred suspension of 680 mg (2.66 mmol) 2-amino-4-furan-2-yl-6-methylsulfanyl-pyridine-3,5-dicarbonitrile in 25 ml dichloromethane was added 1,39 g (5.32 mmol) 3!phenyl-2-(phenylsulfonyl)oxaziridine and stirring continued for 48 hours at room temperature. The resulting crystals were collected by filtration and washed with cold dichloromethane to afford 670 mg (93%) 2-amino-4-furan-2-yl-6-methanesulfinyl-pyridine-3,5-dicarbonitrile as a light brown crystalline solid. ES-MS m/e (%): 295 (M+Na+, 70), 273 (M+H+, 100).
Reaction SMILES: [NH:1]([C:8]([N:10]1[CH2:15][CH2:14][C:13]2[N:16]=[C:17]([C:19]([O:21][CH2:22][CH3:23])=[O:20])[S:18][C:12]=2[CH2:11]1)=[S:9])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:24]([O-])([O-])=O.[K+].[K+].IC>CC(C)=O>[CH3:24][S:9]/[C:8](=[N:1]\[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)/[N:10]1[CH2:15][CH2:14][C:13]2[N:16]=[C:17]([C:19]([O:21][CH2:22][CH3:23])=[O:20])[S:18][C:12]=2[CH2:11]1
Reactant: O=C([O-])[O-]
Reactant: CCOC(=O)c1nc2c(s1)CN(C(=S)Nc1ccccc1)CC2
Agent: [K+]
Solvent: CC(C)=O
Solvent: CI
Product: CCOC(=O)c1nc2c(s1)CN(/C(=N/c1ccccc1)SC)CC2
Reaction time: 0.25 h

Procedure:
To a solution of ethyl 5-(anilinocarbonothioyl)-4,5,6,7-tetrahydro[1,3]thiazolo[5,4-c]pyridine-2-carboxylate obtained in step I (1 eq) in acetone, K2CO3 (1.2 eq) was added and the reaction mixture was stirred for 15 min. To this, iodomethane (1.2 eq) was added and the reaction was continued at room temperature for 5 h. Solvent was evaporated and the residue was diluted dichloromethane. It was then washed with water and the organic layer was separated, dried over anhydrous Na2SO4 and concentrated under reduced pressure to afford crude product, which, on purification by column chromatography afforded the ethyl 5-[(Z)(methylthio)(phenylimino)methyl]-4,5,6,7-tetrahydro[1,3]thiazolo[5,4-c]pyridine-2-carboxylate.
Reaction SMILES: [OH:1][C:2]1[N:6]([C:7]2[CH:12]=[C:11]([C:13]#[N:14])[CH:10]=[CH:9][N:8]=2)[N:5]=[CH:4][CH:3]=1.[F:15][C:16]1[CH:17]=[C:18]2[C:23](=[CH:24][CH:25]=1)[CH:22](O)[CH2:21][CH2:20][CH2:19]2>>[F:15][C:16]1[CH:17]=[C:18]2[C:23](=[CH:24][CH:25]=1)[CH:22]([O:1][C:2]1[N:6]([C:7]3[CH:12]=[C:11]([C:13]#[N:14])[CH:10]=[CH:9][N:8]=3)[N:5]=[CH:4][CH:3]=1)[CH2:21][CH2:20][CH2:19]2
Reactant: N#Cc1ccnc(-n2nccc2O)c1
Reactant: OC1CCCc2cc(F)ccc21
Product: N#Cc1ccnc(-n2nccc2OC2CCCc3cc(F)ccc32)c1

Procedure:
The title compound was prepared from 2-(5-hydroxy-1H-pyrazol-1-yl)pyridine-4-carbonitrile and 6-fluoro-1,2,3,4-tetrahydronaphthalen-1-ol according to the procedure for the preparation of Example 39, part C. 1H NMR (400 MHz, CDCl3): δ 1.82-1.88 (1H, m), 1.99-2.10 (2H, m), 2.28-2.34 (1H, m), 2.74-2.94 (2H, m), 5.35 (1H, t, J=4.0 Hz), 5.85 (1H, d, J=1.6 Hz), 6.84-6.89 (2H, m), 7.29 (1H, dd, J=5.6 Hz, 8.4 Hz), 7.36 (1H, dd, J=0.8 Hz, 4.8 Hz), 7.63 (1H, d, J=2.0 Hz), 7.86 (1H, s), 8.65 (1H, d, J=4.8 Hz). [M+H] Calc'd for C19H15FN4O, 335. Found, 335.