Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([NH:5][S:6]([C:9]1[CH:18]=[C:17]([N:19]=[N:20][C:21]2[CH:26]=[C:25]([CH3:27])[C:24]([S:28](O)(=[O:30])=[O:29])=[CH:23][C:22]=2[CH3:32])[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][C:15]=2[NH:33][S:34]([CH3:37])(=[O:36])=[O:35])[C:10]=1[OH:38])(=[O:8])=[O:7])([CH3:4])([CH3:3])[CH3:2].C(#N)C.P(Cl)(Cl)([Cl:44])=O>CN(C)C(=O)C>[C:1]([NH:5][S:6]([C:9]1[CH:18]=[C:17]([N:19]=[N:20][C:21]2[CH:26]=[C:25]([CH3:27])[C:24]([S:28]([Cl:44])(=[O:30])=[O:29])=[CH:23][C:22]=2[CH3:32])[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][C:15]=2[NH:33][S:34]([CH3:37])(=[O:36])=[O:35])[C:10]=1[OH:38])(=[O:8])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: O=P(Cl)(Cl)Cl
Reactant: Cc1cc(S(=O)(=O)O)c(C)cc1N=Nc1cc(S(=O)(=O)NC(C)(C)C)c(O)c2cccc(NS(C)(=O)=O)c12
Solvent: CC(=O)N(C)C
Solvent: CC#N
Product: Cc1cc(S(=O)(=O)Cl)c(C)cc1N=Nc1cc(S(=O)(=O)NC(C)(C)C)c(O)c2cccc(NS(C)(=O)=O)c12
Temperature: 0 °C

Procedure:
To a solution containing 25 g of the naphthol compound obtained in Step (1) above, 180 ml of acetonitrile and 35 ml of phosphorus oxychloride, 15 ml of N,N-dimethylacetamide was added dropwise at a temmperature below 60° C. with stirring. The mixture was stirred at 60° C. for 3 hours and was poured into 800 ml of ice water. The cyrstals thus-precipitated were collected by filtration and washed with 100 ml of acetonitrile.
Reaction SMILES: [C:1]([NH:5][N:6]=[CH:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[Cl:14])(=[O:4])[CH2:2][OH:3].[O:15]1CCOC[CH2:16]1>[H][H].[Pd]>[Cl:14][C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=1[CH2:7][NH:6][NH:5][C:1](=[O:4])[CH2:2][OH:3].[OH:3][CH2:2][C:1]1[O:4][C:16](=[O:15])[N:6]([CH2:7][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[Cl:14])[N:5]=1
Reactant: C1COCCO1
Reactant: [H][H]
Reactant: O=C(CO)NN=Cc1ccccc1Cl
Agent: [Pd]
Product: O=C(CO)NNCc1ccccc1Cl
Product: O=c1oc(CO)nn1Cc1ccccc1Cl

Procedure:
1-(2-Chlorobenzyl)-2-glycolyl-hydrazine is prepared by reducing 2-chlorobenzaldehyde glycolylhydrazone (41.5 g), dissolved in dioxane (415 cc), with hydrogen in the presence of palladium on charcoal in an autoclave, under hydrogen at a pressure of 15 kg/cm2, at a temperature of between 20° and 60° C. After filtration and concentration, 2-hydroxymethyl-4-(2-chlorobenzyl)-1,3,4-oxadiazolin-5-one (38 g) is obtained.
Reaction SMILES: C1([N:4]2[C:9](=[O:10])[C:8]([CH2:11]O)=[C:7](C)[C:6]([C:14]3[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[C:16]([F:22])[CH:15]=3)=[N:5]2)CC1.C(Br)(Br)(Br)[Br:24].N1[CH:33]=[CH:32][CH:31]=[CH:30]C=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>O1CCCC1>[Br:24][CH2:11][C:8]1[C:9](=[O:10])[N:4]([CH2:30][CH:31]2[CH2:33][CH2:32]2)[N:5]=[C:6]([C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[C:16]([F:22])[CH:15]=2)[CH:7]=1
Reactant: BrC(Br)(Br)Br
Reactant: COc1ccc(-c2nn(C3CC3)c(=O)c(CO)c2C)cc1F
Reactant: c1ccncc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COc1ccc(-c2cc(CBr)c(=O)n(CC3CC3)n2)cc1F
Reaction time: 1 h
Yield: 69.2 %

Procedure:
2-Cyclopropyl-methyl-6-(3-fluoro-4-methoxyphenyl)-4-hydroxymethyl-2H-pyridazin-3-one (185 mg, 0.61 mmol), carbon tetrabromide (404 mg, 1.2 mmol) and pyridine (48 mg, 0.61 mmol) were dissolved in tetrahydrofuran (3 mL), and under ice-cold stirring, a solution of triphenylphosphine (319 mg, 1.2 mmol) in tetrahydrofuran (3 mL) was added. Under ice cooling, the mixture was stirred for 1 hour, and further stirred overnight at room temperature. Insoluble materials were filtered off, the solvent was distilled off under reduced pressure, and the residue was isolated and purified by column chromatography on silica gel (hexane/ethyl acetate=2/1) to yield the title compound as a yellow powder (yield: 155 mg, 69.5%).
Reaction SMILES: Br[C:2]1[N:7]=[N:6][C:5]([NH2:8])=[N:4][C:3]=1[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.[C:15]([C:17]1[CH:18]=[C:19](B(O)O)[CH:20]=[CH:21][CH:22]=1)#[N:16]>>[NH2:8][C:5]1[N:6]=[N:7][C:2]([C:21]2[CH:22]=[C:17]([CH:18]=[CH:19][CH:20]=2)[C:15]#[N:16])=[C:3]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[N:4]=1
Reactant: N#Cc1cccc(B(O)O)c1
Reactant: Nc1nnc(Br)c(-c2ccccc2)n1
Product: N#Cc1cccc(-c2nnc(N)nc2-c2ccccc2)c1
Yield: 24.5 %

Procedure:
3-(3-Amino-5-phenyl-1,2,4-triazin-6-yl)benzonitrile (20 mg, 25%) was prepared from 6-bromo-5-phenyl-1,2,4-triazin-3-amine (75 mg, 0.299 mmol) and 3-cyanophenylboronic acid (50.5 mg, 0.344 mmol) according to the general procedure of Example 1.
Reaction SMILES: [CH3:1][C:2]1O[C:4](=[O:12])[C:5]2[CH:11]=[N:10][CH:9]=[CH:8][C:6]=2[N:7]=1.[NH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>N1C=CC=CC=1>[CH3:1][C:2]1[N:13]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:4](=[O:12])[C:5]2[CH:11]=[N:10][CH:9]=[CH:8][C:6]=2[N:7]=1
Reactant: Nc1ccccc1
Reactant: Cc1nc2ccncc2c(=O)o1
Solvent: c1ccncc1
Product: Cc1nc2ccncc2c(=O)n1-c1ccccc1

Procedure:
Compound 17 (350 mg, 21.6 mmol) was mixed with aniline (200 mg, 21.6 mmol) in 3 mL of pyridine. The resulted solution was heated in a microwave for 25 min keeping temperature constant at 250° C. The crude material 18 was concentrated in vacuo, co-evaporated with toluene (3×10 mL), dried under vacuum for 1 h and used in the next step without further purification.
Reaction SMILES: [Br:1][CH2:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[O:9][CH2:8][CH2:7][C:6]2([CH3:14])[CH3:13].[C:15]1([P:21]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>C1(C)C=CC=CC=1>[Br-:1].[CH3:13][C:6]1([CH3:14])[C:5]2[C:10](=[CH:11][CH:12]=[C:3]([CH2:2][P+:21]([C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=3)([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=3)[CH:4]=2)[O:9][CH2:8][CH2:7]1
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Reactant: CC1(C)CCOc2ccc(CBr)cc21
Solvent: Cc1ccccc1
Product: CC1(C)CCOc2ccc(C[P+](c3ccccc3)(c3ccccc3)c3ccccc3)cc21
Product: [Br-]
Yield: 35.4 %

Procedure:
A mixture of 7.25 g (28.4 mmole) of 6-bromomethyl-4,4-dimethylchroman, 14.8 g (56.8 mmole) of triphenylphosphine and 100 ml of toluene were heated under reflux for 12 hours, and then the solvent was removed by evaporation in vacuo. The residue (an oil) was dissolved in dichloromethane and decolorized with activated carbon. The solvent was removed by evaporation in vacuo and the residue was triturated under hexane to remove starting materials. The product so obtained was recrystallized from toluene-chloroform and the solid was discarded. The recrystallization mother liquors were evaporated in vacuo and the oily residue was triturated under 1N hydrochloric acid and then dissolved in dichloromethane. This latter solution was dried (MgSO4) and evaporated in vacuo to give 5.2 g of the title compound as a light brown solid.
Reaction SMILES: Cl.[C:2]([O:6][C:7](=[O:13])[C@H:8]([CH:10]([CH3:12])[CH3:11])[NH2:9])([CH3:5])([CH3:4])[CH3:3].C(N(CC)CC)C.Br[CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24]>CN(C)C=O>[CH2:26]([O:25][C:23](=[O:24])[CH2:22][NH:9][C@@H:8]([CH:10]([CH3:11])[CH3:12])[C:7]([O:6][C:2]([CH3:5])([CH3:4])[CH3:3])=[O:13])[CH3:27]
Reactant: CC(C)[C@H](N)C(=O)OC(C)(C)C
Reactant: CCOC(=O)CBr
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCOC(=O)CN[C@H](C(=O)OC(C)(C)C)C(C)C
Reaction time: 1 h
Yield: 78 %

Procedure:
To a solution of (L)-valine tert-butyl ester hydrochloride (4.94 g, 23.6 mmol) in N,N-dimethylformamide (55 mL) was added triethylamine (3.28 mL, 1 equivalent), and the mixture was stirred for 1 h. The reaction was filtered to remove solid salts, and the filtrate was treated with triethylamine (9.85 mL, 3 equivalents) and ethyl bromoacetate (7.84 mL, 3 equivalents), and the reaction was stirred for 3 h at 25° C. The reaction was partitioned between ethyl acetate and water, and the organic was washed with brine and dried over MgSO4, filtered and evaporated to give 4.48 g (78%) of the product which was used without further purification.
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[C:7]([C:9]2[N:13]=[C:12]([C:14]3[CH:19]=[C:18]([CH3:20])[CH:17]=[C:16]([CH2:21][N:22]([CH2:24][CH3:25])[CH3:23])[CH:15]=3)[O:11][N:10]=2)[CH:6]=[C:5]([CH3:26])[C:4]=1[OH:27])[CH3:2].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CC1(C)[O:52][C@H:51]([CH2:53]O)[CH2:50][O:49]1.CCOC(/N=N/C(OCC)=O)=O>C1COCC1.C1(C)C=CC=CC=1>[CH2:1]([C:3]1[CH:8]=[C:7]([C:9]2[N:13]=[C:12]([C:14]3[CH:19]=[C:18]([CH3:20])[CH:17]=[C:16]([CH2:21][N:22]([CH2:24][CH3:25])[CH3:23])[CH:15]=3)[O:11][N:10]=2)[CH:6]=[C:5]([CH3:26])[C:4]=1[O:27][CH2:53][C@@H:51]([OH:52])[CH2:50][OH:49])[CH3:2]
Reactant: CCc1cc(-c2noc(-c3cc(C)cc(CN(C)CC)c3)n2)cc(C)c1O
Reactant: CC1(C)OC[C@@H](CO)O1
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: CCc1cc(-c2noc(-c3cc(C)cc(CN(C)CC)c3)n2)cc(C)c1OC[C@@H](O)CO
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
To a solution of 2-ethyl-4-(5-{3-[(ethyl-methyl-amino)-methyl]-5-methyl-phenyl}-[1,2,4]oxadiazol-3-yl)-6-methyl-phenol (99 mg, 271 μmol) in THF (2 mL), PPh3 (107 mg, 406 μmol) and (R)-2,2-dimethyl-1,3-dioxolane-4-methanol (36 mg, 271 μmol) were added. The mixture was cooled to 0° C. and DEAD (177 mg, 406 μmol, 186 μL of a 40% solution in toluene) was added. Stirring was continued at 0° C. for 10 min, then at rt for 1 h before another portion of PPh3 (107 mg, 406 μmol) and (R)-2,2-dimethyl-1,3-dioxolane-4-methanol (36 mg, 271 μmol) was added. Stirring was continued for 1 h and the reaction mixture was separated by prep. HPLC. The product containing fraction were combined, evaporated and dissolved in MeCN (1.5 mL) and 1N aq. HCl (0.4 mL). The mixture was stirred at rt for 10 min before it was again separated by prep. HPLC to give the title compound as a colourless resin (27 mg). LC-MS**: tR=0.56 min; [M+1]+=440.21; 1H NMR (D6-DMSO): δ 1.06 (t, J=7.0 Hz, 3H), 1.23 (t, J=7.0 Hz, 3H), 2.15 (s, 3H), 2.36 (s, 3H), 2.42-2.47 (m, 5H), 2.75 (q, J=7.3 Hz, 2H), 3.50 (d, J=4.8 Hz, 2H), 3.56 (s, 2H), 3.72-3.78 (m, 1H), 3.83-3.89 (m, 2H), 7.47 (s, 1H), 7.79 (s, 2H), 7.91 (s, 1H), 8.18 (s, 1H).
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([OH:14])=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][N:3]=1.[C:15]([N:18]1[CH2:23][CH2:22][N:21]([CH2:24][CH2:25][CH2:26]O)[CH2:20][CH2:19]1)(=[O:17])[CH3:16].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>ClCCl>[CH3:8][CH2:7][CH2:6][CH:11]([CH3:2])[CH3:10].[C:15]([N:18]1[CH2:23][CH2:22][N:21]([CH2:24][CH2:25][CH2:26][O:14][C:8]2[CH:7]=[C:6]3[C:11]([C:2]([Cl:1])=[N:3][CH:4]=[N:5]3)=[CH:10][C:9]=2[O:12][CH3:13])[CH2:20][CH2:19]1)(=[O:17])[CH3:16]
Reactant: COc1cc2c(Cl)ncnc2cc1O
Reactant: CC(=O)N1CCN(CCCO)CC1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: CCCC(C)C
Product: COc1cc2c(Cl)ncnc2cc1OCCCN1CCN(C(C)=O)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 147.2 %

Procedure:
4-Chloro-7-hydroxy-6-methoxyquinazoline (3 g, 14.2 mmol), (prepared as described for the starting material in Example 4), 3-(4-acetylpiperazin-1-yl)propan-1-ol (3.2 g, 17.1 mmol), (prepared as described for the starting material in this example hereinbefore), and triphenylphosphine (4.5 g, 17.1 mmol) were stirred together in dichloromethane (140 ml). Diisopropyl azodicarboxylate (3.4 ml, 17.1 mmol) was added dropwise and an ice/water bath used to keep the temperature of the reaction mixture below 10° C. After the addition, the reaction mixture was allowed to warm to ambient temperature and stirred overnight. The mixture was concentrated under reduced pressure. Column chromatography of the residue (2:1 iso-hexane:ethyl acetate then 3%-5% methanol/dichloromethane) gave 7-[3-(4-acetylpiperazin-1-yl)propoxy]-4-chloro-6-methoxyquinazoline (3.96 g, 74%) as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([F:21])[CH2:13][CH2:12][N:11](C(OC(C)(C)C)=O)[CH2:10]2)[CH:5]=[C:6]([Cl:8])[CH:7]=1.FC(F)(F)C(O)=O>ClCCl>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([F:21])[CH2:13][CH2:12][NH:11][CH2:10]2)[CH:5]=[C:6]([Cl:8])[CH:7]=1
Reactant: CC(C)(C)OC(=O)N1CCC(F)(c2cc(Cl)cc(Cl)c2)C1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: FC1(c2cc(Cl)cc(Cl)c2)CCNC1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
Preparation according to Preparation 2: tert-Butyl 3-(3,5-dichlorophenyl)-3-fluoro-pyrrolidin-1-carboxylate (0.45 g, 1.34 mmol), dichloromethane (2 mL), trifluoroacetic acid (2 mL). Stirred for 4 h at ambient temperature. Purification on a Biotage Isolute SCX-3 SPE column (washed with methanol and eluted with methanol/triethylamine, 4:1) followed by HPLC on Waters OBD C18, 5 μm (MeOH/33 mM NH3, 20:80 to 60:40) and flash chromatography on silica gel (ethyl acetate/methanol, 1:0 to 1:1). Yield: 0.15 g. The amine was converted to the hydrochloric acid salt and recrystallized from ethanol/diethyl ether: M.p. 201-202° C.; MS m/z (relative intensity, 70 eV) 235 (M+, 64), 233 (M+, bp), 213 (28), 133 (49), 120 (32).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[CH:9]1[C:13]2[N:14]=[C:15]([NH:20][C:21]3[CH:26]=[CH:25][C:24]([N:27]4[CH:31]=[N:30][C:29]([CH3:32])=[N:28]4)=[C:23]([O:33][CH3:34])[CH:22]=3)[N:16]=[C:17]([NH:18][CH3:19])[C:12]=2[CH2:11][CH2:10]1.O.C(O)(C(F)(F)F)=O>C(=O)=O.CO>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C@@H:9]1[C:13]2[N:14]=[C:15]([NH:20][C:21]3[CH:26]=[CH:25][C:24]([N:27]4[CH:31]=[N:30][C:29]([CH3:32])=[N:28]4)=[C:23]([O:33][CH3:34])[CH:22]=3)[N:16]=[C:17]([NH:18][CH3:19])[C:12]=2[CH2:11][CH2:10]1
Reactant: CNc1nc(Nc2ccc(-n3cnc(C)n3)c(OC)c2)nc2c1CCC2c1ccc(F)cc1F
Agent: O=C=O
Solvent: CO
Solvent: O=C(O)C(F)(F)F
Solvent: O
Product: CNc1nc(Nc2ccc(-n3cnc(C)n3)c(OC)c2)nc2c1CC[C@@H]2c1ccc(F)cc1F
Reaction time: 0.25 h

Procedure:
A racemic mixture of 7-(2,4-difluorophenyl)-N2-(3-methoxy-4-(3-methyl-1H-1,2,4-triazol-1-yl)phenyl)-N4-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidine-2,4-diamine (Example 193) was purified using chiral supercritical fluid chromatography (SFC) to afford peak A (Example 193A) and peak B (Example 193B). SFC Method: Chiralpak OJ-H (30×150 mm), 30% methanol (0.1% diethylamine) in CO2, 100 bar, flow rate 50 mL/min for 12 min, absorbance 268 nm, injection 2.0 mL of 10 mg/mL solution in methanol, tR (peak A)=4.7 min, tR (peak B) 9.6 min. The absolute stereochemistry of individual enantiomers (Examples 193A and 193B) was not determined 193A: LC-MS (M+H)+=446.2. LC Rt 13.03 min (Waters Sunfire 4.6×150 mm 10 to 100% B in A over 15 min, 1.5 mL/min. (A is 90:10:0.1 water:MeOH:TFA; B is 90:10:0.1 MeOH:water:TFA)). 1H NMR (500 MHz, CHLOROFORM-d) δ ppm 8.46 (1H, s), 8.04 (1H, s), 7.51 (1H, d, J=8.55 Hz), 7.04-7.13 (2H, m), 6.78-6.87 (3H, m), 4.42-4.50 (1H, m), 3.68 (3H, s), 3.13 (3H, s), 2.62-2.79 (3H, m), 2.49 (3H, s), 1.96-2.08 (1H, m).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([CH:7]=[CH:8][C:9](=O)[NH:10]2)=[CH:5][C:4]=1[N+:14]([O-:16])=[O:15].P(Cl)(Cl)([Cl:19])=O>>[Cl:19][C:9]1[CH:8]=[CH:7][C:6]2[C:11](=[CH:12][C:3]([O:2][CH3:1])=[C:4]([N+:14]([O-:16])=[O:15])[CH:5]=2)[N:10]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: COc1cc2[nH]c(=O)ccc2cc1[N+](=O)[O-]
Product: COc1cc2nc(Cl)ccc2cc1[N+](=O)[O-]
Temperature: 110 °C

Procedure:
A mixture of 7-methoxy-6-nitro-1H-quinolin-2-one (0.13 g) and phosphorus oxychloride (1 mL) was heated at 110° C. for 2 hours. The resulting mixture was then cooled and poured into ice. The solid which formed was collected by filtration and dried under vacuum to afford 0.119 g of 2-chloro-7-methoxy-6-nitro-quinoline as a brown solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[NH:9][C:10]1[NH:11][C:12]2[C:18]3[CH2:19][C:20]([CH3:23])([CH3:22])[O:21][C:17]=3[C:16]([C:24](O)=[O:25])=[CH:15][C:13]=2[N:14]=1.S(Cl)(Cl)=O.[F:31][C:32]([F:41])([F:40])[C:33]1[CH:34]=[C:35]([NH2:39])[CH:36]=[CH:37][CH:38]=1.CCN(C(C)C)C(C)C>C1COCC1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[NH:9][C:10]1[NH:11][C:12]2[C:18]3[CH2:19][C:20]([CH3:23])([CH3:22])[O:21][C:17]=3[C:16]([C:24]([NH:39][C:35]3[CH:36]=[CH:37][CH:38]=[C:33]([C:32]([F:31])([F:40])[F:41])[CH:34]=3)=[O:25])=[CH:15][C:13]=2[N:14]=1
Reactant: Nc1cccc(C(F)(F)F)c1
Reactant: Cc1ccc(Cl)c(Nc2nc3cc(C(=O)O)c4c(c3[nH]2)CC(C)(C)O4)c1
Solvent: O=S(Cl)Cl
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccc(Cl)c(Nc2nc3cc(C(=O)Nc4cccc(C(F)(F)F)c4)c4c(c3[nH]2)CC(C)(C)O4)c1
Yield: 16.5 %

Procedure:
The title compound was prepared by following the procedure described for Example-108 using 2-[(2-chloro-5-methylphenyl)amino]-7,7-dimethyl-7,8-dihydro-1H-furo[3,2-e]benzimidazole-5-carboxylic acid (Intermediate-27, 0.175 g, 0.471 mmol), thionyl chloride (2.0 mL), 3-trifluoromethyl phenyl amine (0.114 g, 0.707 mmol), THF (5.0 mL) and DIPEA (2 mL). The obtained crude product was purified by column chromatography on neutral alumina eluting with 0.9% MeOH:DCM to afford 0.040 g of the desired product. 1HNMR (DMSO-d6): δ 1.61 (s, 6H), 2.33 (s, 3H), 3.16 (d, J=5.4 Hz, 2H), 6.87-6.88 (m, 1H), 7.35 (d, J=8.4 Hz, 1H), 7.44 (d, J=7.2 Hz, 1H), 7.60 (t, J=7.8 Hz, 1H), 7.73 (s, 1H), 7.78 (d, J=7.8 Hz, 1H), 8.34 (s, 2H), 9.00 (s, 1H), 10.01 (s, 1H), 10.05 (s, 1H); MS [M+H]+: 515.22.
Reaction SMILES: [H-].[Na+].[CH3:3][N:4]1[C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=2[S:7][CH:6]([C:14]2[CH:19]=[CH:18][C:17]([O:20][CH:21]3[CH2:26][CH2:25][CH2:24][CH2:23][O:22]3)=[CH:16][CH:15]=2)[C:5]1=[O:27].[CH3:28][N:29]([CH3:34])[CH2:30][CH2:31][CH2:32]Cl.O>CN(C)C=O>[CH3:28][N:29]([CH3:34])[CH2:30][CH2:31][CH2:32][C:6]1([C:14]2[CH:15]=[CH:16][C:17]([O:20][CH:21]3[CH2:26][CH2:25][CH2:24][CH2:23][O:22]3)=[CH:18][CH:19]=2)[C:5](=[O:27])[N:4]([CH3:3])[C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=2[S:7]1
Reactant: CN(C)CCCCl
Reactant: CN1C(=O)C(c2ccc(OC3CCCCO3)cc2)Sc2ccccc21
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CN(C)CCCC1(c2ccc(OC3CCCCO3)cc2)Sc2ccccc2N(C)C1=O
Reaction time: 0.5 h
Yield: 81 %

Procedure:
To a stirred suspension of 60% sodium hydride (3.1 g) in dimethylformamide (30 ml), 3,4-dihydro-4-methyl-3-oxo-2-[4-(tetrahydropyran-2-yloxy)phenyl]-2H-1,4-benzothiazine (25.0 g) dissolved in dimethylformamide (60 ml) is added under nitrogen atmosphere, and the mixture is stirred for 30 minutes. A solution of 3-dimethylaminopropyl chloride in dimethylformamide [prepared by mixing of 3-dimethylaminopropyl chloride hydrochloride (13.3 g) and triethylamine (11.8 ml) in dimethylformamide (50 ml) and followed by filtration to remove precipitate] is added to the reaction mixture, and the mixture is stirred for 1 hour at 65°-75° C. The mixture is poured into water and extracted with ethyl acetate. The organic layer is washed with saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated in vacuo to give 25.1 g (81.0%) of the titled compound.
Reaction SMILES: C1CCN(C(N=NC(N2CCCCC2)=O)=O)CC1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[OH:38][C:39]1[CH:40]=[C:41]2[C:45](=[CH:46][CH:47]=1)[C@H:44]([CH2:48][C:49]([O:51][CH2:52][CH3:53])=[O:50])[CH2:43][CH2:42]2.[CH3:54][C:55]1[N:56]=[C:57]([C:63]2[CH:68]=[CH:67][CH:66]=[CH:65][CH:64]=2)[O:58][C:59]=1[CH2:60][CH2:61]O>C1COCC1.C(Cl)Cl>[CH3:54][C:55]1[N:56]=[C:57]([C:63]2[CH:68]=[CH:67][CH:66]=[CH:65][CH:64]=2)[O:58][C:59]=1[CH2:60][CH2:61][O:38][C:39]1[CH:40]=[C:41]2[C:45](=[CH:46][CH:47]=1)[C@H:44]([CH2:48][C:49]([O:51][CH2:52][CH3:53])=[O:50])[CH2:43][CH2:42]2
Reactant: CCOC(=O)C[C@@H]1CCc2cc(O)ccc21
Reactant: Cc1nc(-c2ccccc2)oc1CCO
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Solvent: C1CCOC1
Product: CCOC(=O)C[C@@H]1CCc2cc(OCCc3oc(-c4ccccc4)nc3C)ccc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 73 %

Procedure:
ADDP (0.205 g, 0.81 mmol) was added to a mixture of PPh3 (0.212 g, 0.81 mmol), ethyl [(1S)-5-hydroxy-2,3-dihydro-1H-inden-1-yl]acetate (0.107 g, 0.49 mmol), and 2-(4-methyl-2-phenyl-1,3-oxazol-5-yl)ethanol (0.110 g, 0.54 mmol) in THF (5 mL). The reaction was stirred overnight at rt, and additional ADDP (0.136 g, 0.54 mmol) and PPh3 (0.141 g 0.54 mmol) were added with CH2Cl2(5 mL). The solution was stirred for 24h at rt and filtered. The filtrate was evaporated and the resulting mixture was purified by Biotage using a gradient 0 to 50% EtOAc/hexane. Gave ethyl {(1S)-5-[2-(4-methyl-2-phenyl-1,3-oxazol-5-yl)ethoxy]-2,3-dihydro-1H-inden-1-yl}acetate (0.145g, 66% yield) as yellowish oil. ES-MS m/z 406.2 ((MH)+); HPLC RT (min) 3.89; 1H NMR (Acetone-d6) δ 7.85-7.82 (m, 2H), 7.36-7.30 (m, 3H), 6.94 (d, 1H), 6.65 (s, 1H), 6.60-6.55 (m, 1H), 4.10 (t, 2H), 3.98 (q, 2H), 3.31-3.27 (m, 1H), 3.03 (t, 2H), 3.27-2.51 (m, 3H), 2.24-2.14 (m, 2H), 2.18 (s, 3H), 1.58-1.53 (m, 1H), 1.08 (t, 3H).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[C:13]3[N:14]=[C:15]([Cl:19])[N:16]=[C:17](Cl)[C:12]=3[CH2:11][O:10][CH2:9]2)=[CH:4][CH:3]=1.Cl.[CH3:21][NH2:22]>>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[C:13]3[N:14]=[C:15]([Cl:19])[N:16]=[C:17]([NH:22][CH3:21])[C:12]=3[CH2:11][O:10][CH2:9]2)=[CH:4][CH:3]=1
Reactant: Clc1nc(Cl)c2c(n1)C(c1ccc(Br)cc1)COC2
Reactant: CN
Agent: Cl
Product: CNc1nc(Cl)nc2c1COCC2c1ccc(Br)cc1
Yield: 42.6 %

Procedure:
8-(4-bromophenyl)-2,4-dichloro-7,8-dihydro-5H-pyrano[4,3-d]pyrimidine (Preparation L) (500 mg, 1.389 mmol) and methanamine hydrochloride (141 mg, 2.083 mmol) were combined and purified as per Preparation Ha to give 8-(4-bromophenyl)-2-chloro-N-methyl-7,8-dihydro-5H-pyrano[4,3-d]pyrimidin-4-amine (210 mg, 0.592 mmol, 42.6% yield). LC-MS (M+H)+=356.0. 1H NMR (500 MHz, MeOD) δ ppm 7.46 (2H, d, J=8.24 Hz), 7.13 (2H, d, J=8.55 Hz), 4.43-4.71 (2H, m), 4.09 (1H, dd, J=11.44, 4.12 Hz), 3.92-4.03 (1H, m), 3.86 (1H, d, J=3.05 Hz), 3.00 (3H, s).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[NH:9][C:10](=[NH:17])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.C([Li])CCC.Cl[P:24]([C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.P>C(OCC)C>[CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[NH:9][C:10](=[N:17][P:24]([C:31]1[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=1)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1
Reactant: ClP(c1ccccc1)c1ccccc1
Reactant: Cc1cccc(C)c1NC(=N)c1ccccc1
Agent: P
Agent: [Li]CCCC
Solvent: CCOCC
Product: Cc1cccc(C)c1NC(=NP(c1ccccc1)c1ccccc1)c1ccccc1
Temperature: 0 °C
Reaction time: 2 h
Yield: 56.5 %

Procedure:
N1-(2,6-dimethylphenyl)benzamidine (3.36 g, 15.0 mmol) was dissolved in 50 mL of diethylether and cooled to 0° C. Butyllithium (7.50 mL of 2.0 M solution in diethylether, 15.0 mmol) was added dropwise, producing a fluffy white suspended solid. The slurry was warmed to room temperature and stirred for 2 hours. Chlorodiphenylphosphine (2.69 mL, 15.0 mmol) was added slowly at room temperature. The suspended solid became finer and denser and the solution became slightly yellow upon complete addition of the phosphine. Stirring was continued for 1 hour. The solution was filtered to remove a small amount of white solid, presumably lithium chloride, and the solvent was removed in vacuo. The yellow foamy residue was suspended in 50 mL of pentane and stirred for 3 hours. Filtration and drying afforded 3.46 g (56%) of off-white solid.
Reaction SMILES: [CH3:1][C:2]1([CH3:29])[C:24]2=[CH:25][CH:26]=[N:27][CH:28]=[C:23]2[C:5]2[C:6]([OH:22])=[CH:7][C:8]([CH:10]([CH2:12][CH2:13][CH2:14][C:15]3[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=3)[CH3:11])=[CH:9][C:4]=2[O:3]1.[CH2:30](Br)[CH:31]=[CH2:32]>>[CH3:29][C:2]1([CH3:1])[C:24]2=[CH:25][CH:26]=[N:27][CH:28]=[C:23]2[C:5]2[C:6]([O:22][CH2:32][CH:31]=[CH2:30])=[CH:7][C:8]([CH:10]([CH2:12][CH2:13][CH2:14][C:15]3[CH:16]=[CH:17][C:18]([F:21])=[CH:19][CH:20]=3)[CH3:11])=[CH:9][C:4]=2[O:3]1
Reactant: C=CCBr
Reactant: CC(CCCc1ccc(F)cc1)c1cc(O)c2c(c1)OC(C)(C)c1ccncc1-2
Product: C=CCOc1cc(C(C)CCCc2ccc(F)cc2)cc2c1-c1cnccc1C(C)(C)O2

Procedure:
5,5-Dimethyl-8-[5-(4-fluorophenyl)-2-pentyl]-10-(2-propenyloxy)-5H-[1]benzopyrano[3,4-d]pyridine was prepared by reacting 5,5-dimethyl-8-[5-(4-fluorophenyl)-2-pentyl]-10-hydroxy-5H-[1]benzopyrano[3,4-d]pyridine with 2-propenyl bromide following the procedure of Example 51.