Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[C:6]([C:7]2[CH:16]=[C:15]3[C:10]([C:11]([NH:18][CH2:19][CH:20]4[CH2:25][CH2:24][O:23][CH2:22][CH2:21]4)=[C:12]([NH2:17])[CH:13]=[N:14]3)=[CH:9][C:8]=2[O:26][CH3:27])=[C:5]([CH3:28])[O:4][N:3]=1.[N:29]#[C:30]Br>C(O)C>[CH3:1][C:2]1[C:6]([C:7]2[C:8]([O:26][CH3:27])=[CH:9][C:10]3[C:11]4[N:18]([CH2:19][CH:20]5[CH2:21][CH2:22][O:23][CH2:24][CH2:25]5)[C:30]([NH2:29])=[N:17][C:12]=4[CH:13]=[N:14][C:15]=3[CH:16]=2)=[C:5]([CH3:28])[O:4][N:3]=1
Reactant: N#CBr
Reactant: COc1cc2c(NCC3CCOCC3)c(N)cnc2cc1-c1c(C)noc1C
Solvent: CCO
Product: COc1cc2c(cc1-c1c(C)noc1C)ncc1nc(N)n(CC3CCOCC3)c12
Temperature: 25 °C
Reaction time: 8 h
Yield: 13.2 %

Procedure:
7-(3,5-Dimethylisoxazol-4-yl)-6-methoxy-N4-((tetrahydro-2H-pyran-4-yl)methyl)quinoline-3,4-diamine (for a preparation see Intermediate 17) (32 mg, 0.084 mmol) was dissolved in ethanol (3 ml) and cyanogen bromide (8.86 mg, 0.084 mmol) was added, then the mixture stirred overnight at room temperature. The reaction mixture was evaporated to dryness, the residue dissolved in DMSO (1 ml) and purified by MDAP (formate) to give 7-(3,5-dimethylisoxazol-4-yl)-8-methoxy-1-((tetrahydro-2H-pyran-4-yl)methyl)-1H-imidazo[4,5-c]quinolin-2-amine (4.5 mg, 0.011 mmol, 13.2% yield) as a yellow glass. LCMS (formate) Rt 0.65 min, MH+ 408
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[C:4]([NH:9][CH3:10])[C:3]=1[N+:11]([O-:13])=[O:12].[NH3:14]>O.C(O)C>[Cl:8][C:6]1[CH:5]=[C:4]([NH:9][CH3:10])[C:3]([N+:11]([O-:13])=[O:12])=[C:2]([NH2:14])[CH:7]=1
Reactant: N
Reactant: CNc1cc(Cl)cc(Cl)c1[N+](=O)[O-]
Solvent: CCO
Solvent: O
Product: CNc1cc(Cl)cc(N)c1[N+](=O)[O-]

Procedure:
0.034 mole (7.5 g) of 2,4-dichloro-6-methylaminonitrobenzene is added to 100 ml of a 28% solution of ammonia in water and 50 ml of ethanol in an autoclave. The reaction medium is heated for 12 hours at 145°-150° C., the pressure being 12 kg/cm2. The product expected precipitates from the reaction medium on cooling. After draining and re-impasting in water, it is dried by heating under vacuum in the presence of phosphorous pentoxide. Recrystallized from isopropanol, it melts at 129° C.
Reaction SMILES: [O:1]=[C:2]([CH2:8][C:9]1[N:13]2[CH:14]=[CH:15][CH:16]=[CH:17][C:12]2=[N:11][CH:10]=1)[C:3]([O:5][CH2:6][CH3:7])=[O:4].[CH3:18][O:19][P:20]([O-:23])[O:21][CH3:22]>>[CH3:18][O:19][P:20]([O:21][CH3:22])([C:2]([OH:1])([CH2:8][C:9]1[N:13]2[CH:14]=[CH:15][CH:16]=[CH:17][C:12]2=[N:11][CH:10]=1)[C:3]([O:5][CH2:6][CH3:7])=[O:4])=[O:23]
Reactant: CCOC(=O)C(=O)Cc1cnc2ccccn12
Reactant: COP([O-])OC
Product: CCOC(=O)C(O)(Cc1cnc2ccccn12)P(=O)(OC)OC
Temperature: 25 °C
Reaction time: 72 h

Procedure:
A suspension of ethyl 2-oxo-3-(imidazo[1,2-a]pyridin-3-yl)propanoate (2.32 g; 0.01 mole) in 5.5 g (0.05 mole) of dimethylphosphite is stirred at ambient temperature for 3 days. The excess dimethylphosphite is removed under high vacuum on a rotary evaporator at a bath temperature of about 55° to give the crude product. This is purified by flash chromatography on silica gel to afford ethyl 2-dimethoxyphosphinyl-2-hydroxy-3-(imidazo[1,2-a]pyridin-3-yl)propanoate.
Reaction SMILES: Br[C:2]1[C:7]([CH3:8])=[CH:6][CH:5]=[CH:4][N:3]=1.[C:9]1([CH3:18])[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1B(O)O.C(=O)([O-])[O-].[Na+].[Na+].O>COCCOC.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>[CH3:8][C:7]1[C:2]([C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[CH3:18])=[N:3][CH:4]=[CH:5][CH:6]=1
Reactant: Cc1cccnc1Br
Reactant: Cc1ccccc1B(O)O
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: COCCOC
Solvent: O
Product: Cc1ccccc1-c1ncccc1C
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
A mixture of 2-bromo-3-methylpyridine (1.09 g; 6.34 mmol), o-tolylboronic acid (1.29 g; 9.50 mmol), and Pd(PPh3)4 (147 mg; 2 mol %) in DME (30 ml) is stirred for 10 minutes at room temperature. Sodium carbonate (32 ml of 1M solution in water; 32 mmol) is added to this mixture and the mixture is heated for 16 hours at 80° C. The reaction mixture is treated with water and extracted with dichloromethane. The combined extracts are washed with brine, dried over sodium sulfate, and concentrated in vacuo. The residue is purified by flash chromatography over silica gel (elution with 20% EtOAc/Hexane) to 3-methyl-2-o-tolyl-pyridine as a yellow oil. 1H NMR(300 MHz, CDCl3) δ 8.51(d, 1H), 7.58(d, 1H), 7.27-7.15(m, 5H), 2.14(s, 3H), 2.10(s, 3H).
Reaction SMILES: [H-].[H-].[H-].[H-].[Li+].[Al+3].[C:7]1([C:13]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH2:14][C:15](O)=[O:16])[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1>C1COCC1>[C:24]1([C:13]([C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=2)([C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH2:14][CH2:15][OH:16])[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1
Reactant: O=C(O)CC(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: OCCC(c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 14 h
Yield: 88.3 %

Procedure:
To a magnetically stirred suspension of LAH (8.3 g, 0.219 mol) in dry THF (50 mL) was added a solution of 3,3,3-triphenylpropionic acid (9.5 g, 0.0314 mol) over a period of 30 min at 0° C. The reaction mixture was allowed to stir at RT for 14 h. The reaction mixture was cooled and excess LAH was quenched with 20% NaOH solution (50 mL). The reaction mixture was passed through celite, washed with THF and the filtrate was concentrated under vacuum. The residue was washed with pet ether and dried which gave the title compound (8 g, >85%).
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Cl:20][C:21]1[CH:22]=[CH:23][C:24]2[C:30](=[O:31])[C:29](I)=[C:28]([O:33][CH3:34])[C:27](=[O:35])[NH:26][C:25]=2[CH:36]=1.[C:37]([O:41][CH2:42][CH3:43])(=[O:40])[CH:38]=[CH2:39].C(N(CC)CC)C>C1(C)C=CC=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[Cl:20][C:21]1[CH:22]=[CH:23][C:24]2[C:30](=[O:31])[C:29](/[CH:39]=[CH:38]/[C:37]([O:41][CH2:42][CH3:43])=[O:40])=[C:28]([O:33][CH3:34])[C:27](=[O:35])[NH:26][C:25]=2[CH:36]=1
Reactant: C=CC(=O)OCC
Reactant: COc1c(I)c(=O)c2ccc(Cl)cc2[nH]c1=O
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: CCOC(=O)/C=C/c1c(OC)c(=O)[nH]c2cc(Cl)ccc2c1=O
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 12.8 %

Procedure:
A solution of tris(dibenzylideneacetone)dipalladium (O) (0.051 g) in toluene (31 mL) was treated with triphenylphosphine (0.058 g). The solution was stirred under argon at room temperature for 15 minutes and then it was treated with 8-chloro-4-iodo-3-methoxy-2,5-dioxo-2,5-dihydro-1H-benz[b]-azepine (0.97 g) followed by ethyl acrylate (4.3 mL, 4.0 g). The mixture was then treated with triethylamine (0.37 mL, 0.27 g). The mixture was heated to 104° C. for 1.5 hours and then it was cooled to room temperature. Another portion of tris(dibenzylideneacetone)dipalladium (O) (0.025 g) and more triphenyl phosphine (0.029 g) was added to the mixture. The mixture was then treated with more ethyl acrylate (2.8 mL) and it was heated to 105° C. for 1 hour and then it was cooled to room temperature and concentrated to a brown glass. It was dissolved in chloroform and chromatographed on a silica gel column (5.5 cm diameter×20 cm long) using 25% ethyl acetate in hexane to give a pale yellow solid (0.115 g). The solid was recrystallized from ethyl acetate (10 mL) at room temperature to give an off-white solid (0.0712 g); mp 233.8°-234.5° C.; 1H NMR (CDCl3) 7.73 (d, 1, J=16), 6.69 (d, 1, J=16) for trans olefin protons; MS: m/z=336 (M+1). Analysis for C16H14ClNO5 : Calculated: C, 57.24; H, 4.20; N, 4.17; Found C, 57.09; H, 4.16; N, 4.09.
Reaction SMILES: [C:1]([N:4]1[C:12]2[C:7](=[CH:8][C:9]([C:13](=[O:15])[CH3:14])=[CH:10][CH:11]=2)[CH2:6][C:5]1=[O:16])(=[O:3])[CH3:2].[CH3:17][O:18][C:19]1[CH:20]=[C:21]([CH:25]=[CH:26][C:27]=1[O:28][CH3:29])[C:22](O)=[O:23].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.Cl>CN(C)C=O.C(N(CC)CC)C>[C:1]([N:4]1[C:12]2[C:7](=[CH:8][C:9]([C:13](=[O:15])[CH3:14])=[CH:10][CH:11]=2)[C:6](=[C:22]([C:21]2[CH:25]=[CH:26][C:27]([O:28][CH3:29])=[C:19]([O:18][CH3:17])[CH:20]=2)[OH:23])[C:5]1=[O:16])(=[O:3])[CH3:2]
Reactant: CC(=O)c1ccc2c(c1)CC(=O)N2C(C)=O
Reactant: COc1ccc(C(=O)O)cc1OC
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COc1ccc(C(O)=C2C(=O)N(C(C)=O)c3ccc(C(C)=O)cc32)cc1OC
Temperature: 0 °C

Procedure:
4.3 g (20 mmol) 1,5-diacetyl-2-indolinone (Ex. II) are stirred overnight together with 4 g of 3,4-dimethoxybenzoic acid, 7.1 g TBTU (O-benzotriazol-1-yl-N,N,N′,N′-tetramethyluronium tetrafluoroborate) and 14 ml triethylamine in 80 ml DMF (dimethylformamide) at ambient temperature. Then the mixture is poured onto 300 ml ice water with 10 ml of conc. hydrochloric acid and the precipitate formed is suction filtered. The residue is washed with a little methanol and then with ether.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[C:9]([C:17]3[CH:18]=[C:19]([NH:23][C:24](=[O:29])[C:25]([F:28])([F:27])[F:26])[CH:20]=[CH:21][CH:22]=3)=[N:10][N:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=23)[CH:5]=[CH:4][N:3]=1.[O:30]1[C:34]([C:35]2[CH:36]=[C:37]([CH:39]=[CH:40][CH:41]=2)[NH2:38])=[CH:33][N:32]=[CH:31]1.Cl>O1CCOCC1.CC(O)C>[F:26][C:25]([F:28])([F:27])[C:24]([NH:23][C:19]1[CH:20]=[CH:21][CH:22]=[C:17]([C:9]2[C:8]([C:6]3[CH:5]=[CH:4][N:3]=[C:2]([NH:38][C:37]4[CH:39]=[CH:40][CH:41]=[C:35]([C:34]5[O:30][CH:31]=[N:32][CH:33]=5)[CH:36]=4)[N:7]=3)=[C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][N:11]3[N:10]=2)[CH:18]=1)=[O:29]
Reactant: Nc1cccc(-c2cnco2)c1
Reactant: O=C(Nc1cccc(-c2nn3ccccc3c2-c2ccnc(Cl)n2)c1)C(F)(F)F
Agent: Cl
Solvent: CC(C)O
Solvent: C1COCCO1
Product: O=C(Nc1cccc(-c2nn3ccccc3c2-c2ccnc(Nc3cccc(-c4cnco4)c3)n2)c1)C(F)(F)F
Temperature: 90 °C
Yield: 82.2 %

Procedure:
To a solution of N-{3-[3-(2-chloro-4-pyrimidinyl)pyrazolo[1,5-a]pyridin-2-yl]phenyl}-2,2,2-trifluoroacetamide (1.0 g, 0.002 mol) (see Example 1, Step C) in 1,4-dioxane (25 mL) and i-PrOH (5 mL) was added 3-(1,3-oxazol-5-yl)aniline (1.15 g, 0.007 mols) followed by catalytic 12M HCl. After heating overnight at 90° C., the reaction was quenched with saturated NaHCO3 (25 mL), the solvent was removed by rotary evaporation, the aqueous layer extracted with DCM (25 mL), the organic layer concentrated, and purified by column chromatography (5-50% EtOAc in hexanes then 100% EtOAc) to provide the product (0.89 g, 69%) as an off-white solid. ES-LC/MS m/z=542 [M+H]+.
Reaction SMILES: [CH2:1]([CH:3]([CH2:17][CH2:18][CH2:19][CH3:20])[C:4]([NH:6][C:7]1[CH:12]=[C:11]([N+:13]([O-])=O)[CH:10]=[CH:9][C:8]=1[OH:16])=[O:5])[CH3:2]>C(O)C.[H][H].[Ni]>[NH2:13][C:11]1[CH:10]=[CH:9][C:8]([OH:16])=[C:7]([NH:6][C:4](=[O:5])[CH:3]([CH2:1][CH3:2])[CH2:17][CH2:18][CH2:19][CH3:20])[CH:12]=1
Reactant: CCCCC(CC)C(=O)Nc1cc([N+](=O)[O-])ccc1O
Reactant: [H][H]
Agent: [Ni]
Solvent: CCO
Product: CCCCC(CC)C(=O)Nc1cc(N)ccc1O
Reaction time: 2 h

Procedure:
39 g of preliminary product 1 were hydrogenated with H2 /Raney nickel in 200 ml ethanol. The hydrogenation was conducted over a period of 2 hours and within a temperature range from 20 to 40 C. at a pressure of 2. 106Pa. The catalyst was filtered off under suction and 400 ml water were added. The dried, oily product (37 g) which was separated was reacted further without additional purification.
Reaction SMILES: [C:1]1([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH:6]=[CH:5][CH:4]=[C:3]([C:7]2[S:8][C:9]([CH3:15])=[C:10]([CH2:12][CH2:13][OH:14])[N:11]=2)[CH:2]=1.[CH2:22]([O:24][C:25](=[O:37])[C:26]([O:29][C:30]1[CH:35]=[CH:34][C:33](O)=[CH:32][CH:31]=1)([CH3:28])[CH3:27])[CH3:23].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>O1CCCC1.C(OCC)(=O)C>[CH2:22]([O:24][C:25](=[O:37])[C:26]([O:29][C:30]1[CH:35]=[CH:34][C:33]([O:14][CH2:13][CH2:12][C:10]2[N:11]=[C:7]([C:3]3[CH:2]=[C:1]([C:16]4[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=4)[CH:6]=[CH:5][CH:4]=3)[S:8][C:9]=2[CH3:15])=[CH:32][CH:31]=1)([CH3:28])[CH3:27])[CH3:23]
Reactant: Cc1sc(-c2cccc(-c3ccccc3)c2)nc1CCO
Reactant: CCOC(=O)C(C)(C)Oc1ccc(O)cc1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCOC(=O)C(C)(C)Oc1ccc(OCCc2nc(-c3cccc(-c4ccccc4)c3)sc2C)cc1
Reaction time: 24 h
Yield: 10.7 %

Procedure:
To a solution of 2-(2-biphenyl-3-yl-5-methyl-thiazol-4-yl)-ethanol (2.58 g, 8.73 mmol), 2-(4-hydroxy-phenoxy)-2-methyl-propionic acid ethyl ester (1.9 6 g, 8.73 mmol), and triphenylphosphine (2.2 9 g, 8.73 mmol) in 90 mL tetrahydrofuran was added diisopropylazodicarboxylate (1.76 g, 8.73 mmol) dropwise over 30 min. After stirring 24 h, the solution was diluted with ethyl acetate, washed with water and brine, dried over magnesium sulfate, filtered and concentrated to an orange oil. Silica gel chromatography (100 g silica gel, 15% ethyl acetate/hexanes) afforded 470 mg (11% yield) of 2-{4-[2-(2-biphenyl-3-yl-5-methyl-thiazol-4-yl)-ethoxy]-phenoxy}-2-methyl-propionic acid ethyl ester as a colorless oil. 1H NMR (400MHz, CDCl3) δ8.06 (s, 1H), 7.81 (d, 1H), 7.62 (d, 2H), 7.57 (d, 1H), 7.46-7.42 (m, 3H), 7.37-7.34 (m, 1H), 6.80-6.74 (m, 4H), 4.235 (t, 2H), 4.20 (q, 2H), 3.15 (t, 2H), 2.44 (s, 3H), 1.49 (s, 6H), 1.24 (t, 3H). MS EI+(m/e) 502.1
Reaction SMILES: [CH3:1][CH:2]1[CH2:11][C:10](=[O:12])[NH:9][C:8]2[N:7]=[C:6](Br)[C:5]3[N:14]=[CH:15][CH:16]=[CH:17][C:4]=3[C:3]1=2>C(O)C.C(O)(=O)C.[Pd]>[CH3:1][CH:2]1[CH2:11][C:10](=[O:12])[NH:9][C:8]2[N:7]=[CH:6][C:5]3[NH:14][CH2:15][CH2:16][CH2:17][C:4]=3[C:3]1=2
Reactant: CC1CC(=O)Nc2nc(Br)c3ncccc3c21
Agent: [Pd]
Solvent: CC(=O)O
Solvent: CCO
Product: CC1CC(=O)Nc2ncc3c(c21)CCCN3
Yield: 64.4 %

Procedure:
1.5 g (0.005 mol) of 1-methyl-6-bromo-1,2-dihydropyrido[2,3-c][1,8]naphthyridin-3(4H)-one are hydrogenated for 24 hours at room temperature and atmospheric pressure in a mixture of 100 ml of ethanol and 100 ml of glacial acetic acid with Pd/C (0.3 g/10%) with addition of 0.4 g (0.005 mol) of Na-acetate. The catalyst is removed by filtration under suction, the filtrate is concentrated, and the residue is recrystallized from ethanol. 0.7 g (64.4% of theory) of 1-methyl-1,2,7,8,9,10-hexahydropyrido[2,3-c][1,8]naphthyridin-3(4H)one is obtained.
Reaction SMILES: [NH2:1][C:2]1[N:6]([C:7]2[C:12]([Cl:13])=[CH:11][C:10]([C:14]([F:17])([F:16])[F:15])=[CH:9][C:8]=2[Cl:18])[N:5]=[C:4]([C:19]#[N:20])[C:3]=1I.CN(C)C=O.[CH2:27]([O:30][CH3:31])[C:28]#[CH:29]>C(N(CC)CC)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[NH2:1][C:2]1[N:6]([C:7]2[C:12]([Cl:13])=[CH:11][C:10]([C:14]([F:17])([F:16])[F:15])=[CH:9][C:8]=2[Cl:18])[N:5]=[C:4]([C:19]#[N:20])[C:3]=1[C:29]#[C:28][CH2:27][O:30][CH3:31]
Reactant: N#Cc1nn(-c2c(Cl)cc(C(F)(F)F)cc2Cl)c(N)c1I
Reactant: C#CCOC
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COCC#Cc1c(C#N)nn(-c2c(Cl)cc(C(F)(F)F)cc2Cl)c1N
Temperature: 70 °C

Procedure:
To a stirred solution of 5-amino-3-cyano-1-(2,6-dichloro-4-trifluoromethylphenyl)4-iodopyrazole (200 mg, the compound of Example A1) in triethylamine (2 ml) and dimethylformamide (1 ml) at room temperature was added methyl propargyl ether (0.5 ml), cuprous iodide (15 mg) and bis(triphenylphosphine)palladium(II) chloride (30 mg). The reaction mixture was heated at 70° C. for two hours. The reaction mixture was partitioned between ether (50 ml) and aqueous citric acid solution (50 ml, 20%). The organic layer was separated, washed with water, dried (MgSO4) and evaporated. The residue was purified by column chromatography on silica gel eluted with dichloromethane to provide the title compound as a pale yellow solid m.p. 210° C. decomp.
Reaction SMILES: [C:1]1([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH:6]=[CH:5][C:4]([S:7]([N:10]2[CH2:14][CH2:13][S:12][CH:11]2[C:15](O)=[O:16])(=[O:9])=[O:8])=[CH:3][CH:2]=1.[NH2:24][C@H:25]([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[CH2:26][OH:27]>>[C:1]1([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH:2]=[CH:3][C:4]([S:7]([N:10]2[CH2:14][CH2:13][S:12][CH:11]2[C:15]([NH:24][C@H:25]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH2:26][OH:27])=[O:16])(=[O:9])=[O:8])=[CH:5][CH:6]=1
Reactant: O=C(O)C1SCCN1S(=O)(=O)c1ccc(-c2ccccc2)cc1
Reactant: N[C@@H](CO)c1ccccc1
Product: O=C(N[C@@H](CO)c1ccccc1)C1SCCN1S(=O)(=O)c1ccc(-c2ccccc2)cc1

Procedure:
Following the general strategies and protocols outlined in Example 1, starting from 3-([1,1′-biphenyl]-4-ylsulfonyl)-1,3-thiazolidine-2-carboxylic acid (Intermediate 8) and commercial (2R)-2-amino-2-phenylethanol, the title compound was obtained in 98% purity by HPLC.
Reaction SMILES: [CH3:1][CH:2]([C:4]1[S:20][C:7]2[N:8]=[C:9]3[CH:16]=[CH:15][C:14]([C:17]([NH2:19])=O)=[CH:13][N:10]3[C:11](=[O:12])[C:6]=2[CH:5]=1)[CH3:3].C(Cl)(Cl)Cl>P(Cl)(Cl)(Cl)=O>[CH3:3][CH:2]([C:4]1[S:20][C:7]2[N:8]=[C:9]3[CH:16]=[CH:15][C:14]([C:17]#[N:19])=[CH:13][N:10]3[C:11](=[O:12])[C:6]=2[CH:5]=1)[CH3:1]
Reactant: CC(C)c1cc2c(=O)n3cc(C(N)=O)ccc3nc2s1
Solvent: ClC(Cl)Cl
Solvent: O=P(Cl)(Cl)Cl
Product: CC(C)c1cc2c(=O)n3cc(C#N)ccc3nc2s1

Procedure:
2-(1-Methylethyl)-4-oxo-4H-pyrido[1,2-a]thieno[2,3-d]pyrimidine-7-carboxamide (Example 15), 8.7 g (0.0303 mol), in 250 ml of phosphorus oxychloride and 250 ml of chloroform is refluxed on a steam bath for four hours under nitrogen. The chloroform and excess phosphorus oxychloride are evaporated in vacuo and the residue is treated with 2 L of ice water. The resulting precipitate is filtered to give 5.3 g of 2-(1-methylethyl)-4-oxo-4H-pyrido[1,2-a]thieno[2,3-d]pyrimidine-7-carbonitrile; mp 225°-226° C. after recrystallization from pyridine.
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[C:8]([C:10]([F:13])([F:12])[F:11])[CH:7]=[CH:6][C:3]=1[C:4]#[N:5].[S:14](Cl)(=[O:17])(=[O:16])[NH2:15]>>[C:4]([C:3]1[CH:6]=[CH:7][C:8]([C:10]([F:11])([F:12])[F:13])=[CH:9][C:2]=1[NH:1][S:14]([NH2:15])(=[O:17])=[O:16])#[N:5]
Reactant: N#Cc1ccc(C(F)(F)F)cc1N
Reactant: NS(=O)(=O)Cl
Product: N#Cc1ccc(C(F)(F)F)cc1NS(N)(=O)=O

Procedure:
Prepared as in Example 77a from 2-amino-4-trifluoromethylbenzonitrile and sulfamoyl chloride. 1H NMR (400 MHz, DMSO-d6) δ 7.53 (s, 1H), 7.74-7.76 (d, J=8.4 Hz, 1H), 8.01-8.03 (dd, J=8.4 Hz, 1.6 Hz, 1H), 8.23 (s, 1H), 10.16 (b, 1H).
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:23])[C@@H:10]([NH:15][C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:11][CH2:12][CH2:13]I)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH:24]1[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]1.C(Cl)(Cl)Cl>CN(C)C=O>[CH2:1]([O:8][C:9](=[O:23])[C@@H:10]([NH:15][C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:11][CH2:12][CH2:13][N:24]1[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C1CCNCC1
Reactant: CC(C)(C)OC(=O)N[C@@H](CCCI)C(=O)OCc1ccccc1
Solvent: ClC(Cl)Cl
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N[C@@H](CCCN1CCCCC1)C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 93.3 %

Procedure:
To a solution of N-t-butoxycarbonyl-(S)-2-amino-5-iodopentanoic acid benzyl ester(J.Org. Chem. 1998, 7875-7884)(100.8 mg, 0.23 mmol) in N,N-dimethylformamide (0.25 mL) was added piperidine (41.5 mg, 0.49 mmol) and the mixture was stirred for 3 hours at room temperature. To the reaction mixture was added chloroform (30 mL) and the mixture was washed with saturated aqueous sodium hydrogencarbonate solution (3×3 mL). The organic phase was dried over anhydrous sodium sulfate and concentrated under vacuum to obtain crude N-t-butoxycarbonyl-(S)-2-amino-5-(1-piperidinyl)pentanoic acid benzyl ester(83.8 mg) as a colorless oily material.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:13]2[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=2)([OH:12])[C:9]([OH:11])=O)=[CH:4][CH:3]=1.[NH2:20][CH2:21][CH2:22][CH2:23][N:24]1[CH2:29][CH2:28][CH:27]([C:30]2[CH:31]=[C:32]([NH:37][C:38](=[O:42])[CH:39]([CH3:41])[CH3:40])[CH:33]=[CH:34][C:35]=2[CH3:36])[CH2:26][CH2:25]1>>[F:19][C:16]1[CH:17]=[CH:18][C:13]([C:8]([C:5]2[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=2)([OH:12])[C:9]([NH:20][CH2:21][CH2:22][CH2:23][N:24]2[CH2:29][CH2:28][CH:27]([C:30]3[CH:31]=[C:32]([NH:37][C:38](=[O:42])[CH:39]([CH3:40])[CH3:41])[CH:33]=[CH:34][C:35]=3[CH3:36])[CH2:26][CH2:25]2)=[O:11])=[CH:14][CH:15]=1
Reactant: O=C(O)C(O)(c1ccc(F)cc1)c1ccc(F)cc1
Reactant: Cc1ccc(NC(=O)C(C)C)cc1C1CCN(CCCN)CC1
Product: Cc1ccc(NC(=O)C(C)C)cc1C1CCN(CCCNC(=O)C(O)(c2ccc(F)cc2)c2ccc(F)cc2)CC1

Procedure:
Example 156 was prepared from bis(4-fluorophenyl)(hydroxy)acetic acid and N-{3-[1-(3-aminopropyl)-4-piperidinyl]-4-methylphenyl}-2-methylpropanamide according to the procedures described in Scheme 12: 1H NMR (400 MHz, CDCl3) δ 9.44 (s, br, 1 H), 8.18 (s, 1 H), 7.62–7.48 (m, 4 H), 7.32 (s, 1 H), 7.07–7.00 (m, 1 H), 7.00–6.89 (m, 4 H), 6.72–6.53 (m, 1 H), 5.96–5.71 (br, 1 H), 3.55–3.44 (m, 2 H), 3.14–3.02 (m, 2 H), 2.83–2.66 (m, 1 H), 2.63–2.49 (m, 2 H), 2.39–2.22 (m, 1 H), 2.29 (s, 3 H), 2.17–1.98 (m, 4 H), 1.78–1.59 (m, 4 H), 0.92 (d, 6 H, J=6.8 Hz); ESMS m/e: 564.4 (M+H)+.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]3[O:15][CH2:16][CH2:17][O:18][C:11]=3[CH:10]=2)[C:5]([F:19])=[CH:4][N:3]=1.[OH:20][C:21]1[CH:22]=[C:23]([CH:25]=[CH:26][CH:27]=1)[NH2:24].Cl>CO.O>[CH2:17]1[CH2:16][O:15][C:12]2[CH:13]=[CH:14][C:9]([NH:8][C:6]3[C:5]([F:19])=[CH:4][N:3]=[C:2]([NH:24][C:23]4[CH:25]=[CH:26][CH:27]=[C:21]([OH:20])[CH:22]=4)[N:7]=3)=[CH:10][C:11]=2[O:18]1
Reactant: Nc1cccc(O)c1
Reactant: Fc1cnc(Cl)nc1Nc1ccc2c(c1)OCCO2
Agent: Cl
Solvent: CO
Solvent: O
Product: Oc1cccc(Nc2ncc(F)c(Nc3ccc4c(c3)OCCO4)n2)c1
Temperature: 100 °C

Procedure:
To a solution of 2-chloro-N4-(3,4-ethylenedioxyphenyl)-5-fluoro-4-pyrimidineamine (0.028 g, 0.1 mmol) in MeOH:H2O (1.8:0.2 mL) was added 3-hydroxyaniline (0.033 g, 0.3 mmol) and heated in a sealed tube at 100° C. for 24 h. The resulting reaction was diluted with H2O (10 mL), acidified with 2N HCl (pH>2), saturated and the resulting solid was filtered to give the desired product, N4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl))-2,4-pyrimidinediamine (R926210). Purification can be done by filtration through a pad of silica gel using 1-5% MeOH in CH2Cl2 or by crystallization using an appropriate solvent system. 1H NMR (CDCl3+CD3OD): δ 7.76 (bs, 1H), 7.30 (d, 1H, J=2.4 Hz), 7.10 (m, 1H), 7.03 (t, 1H, J=8.1 Hz), 6.89 (dd, 2H, J=2.4 and 9 Hz), 6.78 (d, 1H, J=8.7 Hz), 6.42 (dd, 1H, J=2.4 and 9 Hz), 4.22 (m, 4H); 19F NMR (CDCl3+CD3OD): −47196; LCMS: ret. time: 19.55 min.; purity: 95%; MS (m/e): 355 (MH+).