Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:3]1([C:6]2[CH:7]=[C:8]([CH:12]=[CH:13][CH:14]=2)[C:9]([OH:11])=O)[CH2:5][CH2:4]1)#[N:2].C(Cl)(=O)C(Cl)=O.O1CCCC1.[NH2:26][C:27]1[C:28]([Cl:50])=[C:29]([C:46]([CH3:49])=[CH:47][CH:48]=1)[O:30][C:31]1[CH:32]=[CH:33][C:34]2[N:35]([CH:37]=[C:38]([NH:40][C:41]([CH:43]3[CH2:45][CH2:44]3)=[O:42])[N:39]=2)[N:36]=1>CN(C)C=O.CN1CCCC1=O>[Cl:50][C:28]1[C:29]([O:30][C:31]2[CH:32]=[CH:33][C:34]3[N:35]([CH:37]=[C:38]([NH:40][C:41]([CH:43]4[CH2:45][CH2:44]4)=[O:42])[N:39]=3)[N:36]=2)=[C:46]([CH3:49])[CH:47]=[CH:48][C:27]=1[NH:26][C:9](=[O:11])[C:8]1[CH:12]=[CH:13][CH:14]=[C:6]([C:3]([C:1]#[N:2])([CH3:4])[CH3:5])[CH:7]=1
Reactant: Cc1ccc(N)c(Cl)c1Oc1ccc2nc(NC(=O)C3CC3)cn2n1
Reactant: N#CC1(c2cccc(C(=O)O)c2)CC1
Agent: O=C(Cl)C(=O)Cl
Solvent: CN1CCCC1=O
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: Cc1ccc(NC(=O)c2cccc(C(C)(C)C#N)c2)c(Cl)c1Oc1ccc2nc(NC(=O)C3CC3)cn2n1
Yield: 49.5 %

Procedure:
Using 3-(1-cyanocyclopropyl)benzoic acid (95 mg, 0.50 mmol), oxalyl chloride (55 μL, 0.63 mmol), N,N-dimethylformamide (1 drop), tetrahydrofuran (3.0 mL), N-[6-(3-amino-2-chloro-6-methylphenoxy)imidazo[1,2-b]pyridazin-2-yl]cyclopropanecarboxamide (150 mg, 0.42 mmol) and N-methylpyrrolidone (3.0 mL) as starting materials and in the same manner as in Example 335, the title compound (110 mg, 51%) was obtained as a white powder.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH:7]=O)[CH:2]=1.[Cl:9][C:10]1[CH:15]=[CH:14][C:13]([S:16]([NH2:19])(=[O:18])=[O:17])=[CH:12][CH:11]=1.CC1C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH:7]=[N:19][S:16]([C:13]2[CH:12]=[CH:11][C:10]([Cl:9])=[CH:15][CH:14]=2)(=[O:18])=[O:17])[CH:2]=1
Reactant: NS(=O)(=O)c1ccc(Cl)cc1
Reactant: O=Cc1cccnc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: O=S(=O)(N=Cc1cccnc1)c1ccc(Cl)cc1
Yield: 65 %

Procedure:
In a similar manner to Example 2, 18.5 mmol of 3-pyridinecarboxaldehyde, 18.5 mmol of 4-chlorobenzenesulfonamide and 20 mg of TsOH in 100 mL of toluene reacted under reflux conditions to afford SULF-12 in 65% yield and high purity: 1H NMR (DSMO-d6, TMS ext std) δ 9.3 (s,1), 9.2 (d, 1), 8.9 (m, 1), 8.4 (m, 1), 8.0-7.8 (AB. 4).
Reaction SMILES: C[O:2][C:3](=[O:38])[C:4]1[CH:9]=[CH:8][C:7]([O:10][C:11]2[S:15][C:14]([NH:16][C:17](=[O:37])[CH:18]([C:25]3[CH:30]=[CH:29][C:28]([S:31]([CH:34]4[CH2:36][CH2:35]4)(=[O:33])=[O:32])=[CH:27][CH:26]=3)[O:19][C@@H:20]3[CH2:24][CH2:23][O:22][CH2:21]3)=[N:13][CH:12]=2)=[CH:6][CH:5]=1.[Li+].[OH-]>C1COCC1.CO.O>[CH:34]1([S:31]([C:28]2[CH:29]=[CH:30][C:25]([CH:18]([O:19][C@@H:20]3[CH2:24][CH2:23][O:22][CH2:21]3)[C:17]([NH:16][C:14]3[S:15][C:11]([O:10][C:7]4[CH:8]=[CH:9][C:4]([C:3]([OH:38])=[O:2])=[CH:5][CH:6]=4)=[CH:12][N:13]=3)=[O:37])=[CH:26][CH:27]=2)(=[O:33])=[O:32])[CH2:36][CH2:35]1
Reactant: COC(=O)c1ccc(Oc2cnc(NC(=O)C(O[C@@H]3CCOC3)c3ccc(S(=O)(=O)C4CC4)cc3)s2)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: O=C(O)c1ccc(Oc2cnc(NC(=O)C(O[C@@H]3CCOC3)c3ccc(S(=O)(=O)C4CC4)cc3)s2)cc1
Yield: 0.1 %

Procedure:
The compound of example B30 was obtained by similar method described in example B28 using 4-(2-{2-(4-Cyclopropanesulfonyl-phenyl)-2-[(R)-(tetrahydro-furan-3-yl)oxy]-acetylamino}-thiazol-5-yloxy)-benzoic acid methyl ester (0.180 g, 0.32mmol), LiOH (0.067 g, 1.61 mmol) in THF: MeOH: Water (1:1:1, 9 mL) to provide the title compound (0.160 mg, 92%).
Reaction SMILES: [C:1]1([CH:7]2[CH2:13][C:12](=[O:14])[O:11][C:9](=[O:10])[CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl.CN.[CH2:18]([N:20](CC)CC)C>C1COCC1>[CH3:18][NH:20][C:9]([CH2:8][CH:7]([C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)[CH2:13][C:12]([OH:11])=[O:14])=[O:10]
Reactant: O=C1CC(c2ccccc2)CC(=O)O1
Reactant: CCN(CC)CC
Agent: CN
Agent: Cl
Solvent: C1CCOC1
Product: CNC(=O)CC(CC(=O)O)c1ccccc1
Reaction time: 1.5 h
Yield: 89 %

Procedure:
A solution of 3-phenylglutaric anhydride (500 mg, 2.63 mmol) in THF was added to a mixture of methylamine hydrochloride (266 mg, 3.94 mmol) and triethylamine (1.1 mL, 0.80 g, 7.9 mmol) in 4.0 mL of THEF. After 1.5 h, additional methylamine hydrochloride (177 mg, 2.62 mmol) and triethylamine (0.36 mL, 0.26 g, 2.6 mmol) were added and stirring was continued overnight at room temperature. The reaction was partitioned between 50 mL of ethyl acetate and 25 mL of 2.0 N aqueous HCl. The aqueous layer was extracted with 2×25 mL of ethyl acetate. The combined ethyl acetate layers were washed with 50 mL of brine, dried over sodium sulfate, and evaporated to give 518 mg of the title compound as a white solid. 1NMR (400 MHz, CD3OD): δ 7.29-7.22 (m, 4H), 7.20-7.14 (m, 1H), 3.58 (tt, 1H, J=9, 7 Hz), 2.68 (dd, 1H, J=15, 7 Hz), 2.59 (dd, 1H, J=15, 9 Hz), 2.57 (s, 3H), 2.55 (dd, 1H, J=15, 7 Hz), 2.44 (dd, 1H, J=15, 9 Hz). Mass spectrum (NH3 /CI): m/z=222 (M+1).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][N:6]=[C:5]2[C:12]1[S:16][C:15]([S:17](Cl)(=[O:19])=[O:18])=[CH:14][CH:13]=1.[CH3:21][NH2:22]>O1CCCC1>[CH3:21][NH:22][S:17]([C:15]1[S:16][C:12]([C:5]2[C:4]3[C:9](=[CH:10][CH:11]=[C:2]([Br:1])[CH:3]=3)[N:8]=[CH:7][N:6]=2)=[CH:13][CH:14]=1)(=[O:19])=[O:18]
Reactant: CN
Reactant: O=S(=O)(Cl)c1ccc(-c2ncnc3ccc(Br)cc23)s1
Solvent: C1CCOC1
Product: CNS(=O)(=O)c1ccc(-c2ncnc3ccc(Br)cc23)s1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
800 mg of 5-(6-bromoquinazolin-4-yl)-thiophen-2-sulfonyl chloride (compound in Production Example 377) was dissolved in 15 mL tetrahydrofuran, and 1.78 mL methylamine was added thereto and stirred at room temperature for 1 hour. The solvent was removed, and the residue was purified by silica gel column chromatography (ethyl acetate/hexane), to give 752 mg of the title compound (pale skin-colored crystals).
Reaction SMILES: [OH:1][CH:2]([CH2:11][OH:12])[CH2:3][S:4][CH2:5][C@@H:6]([C:8]([OH:10])=[O:9])[NH2:7].[C:13]1([CH2:26][O:27][C:28](C2CC(=O)N(O)C2=O)=[O:29])[C:25]2[CH2:24][C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[C:17]=2[CH:16]=[CH:15][CH:14]=1>C(=O)([O-])[O-].[Na+].[Na+].C(#N)C.O>[C:13]1([CH2:26][O:27][C:28]([NH:7][C@H:6]([C:8]([OH:10])=[O:9])[CH2:5][S:4][CH2:3][CH:2]([OH:1])[CH2:11][OH:12])=[O:29])[C:25]2[CH2:24][C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[C:17]=2[CH:16]=[CH:15][CH:14]=1
Reactant: O=C(OCc1cccc2c1Cc1ccccc1-2)C1CC(=O)N(O)C1=O
Reactant: N[C@@H](CSCC(O)CO)C(=O)O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC#N
Solvent: O
Product: O=C(N[C@@H](CSCC(O)CO)C(=O)O)OCc1cccc2c1Cc1ccccc1-2
Reaction time: 2 h
Yield: 63.8 %

Procedure:
S-(2,3-dihydroxypropyl)cysteine (2.45 g, 12.6 mmole) was dissolved in 9% sodium carbonate (20 ml). A solution of fluorenylmethoxycarbonyl-N-hydroxysuccinimide (3.45 g, 10.5 mmole) in acetonitrile (20 ml) was added and the mixture stirred for 2 h, then diluted with water (240 ml), and extracted with diethyl ether (25 ml×3). The aqueous phase was acidified to pH 2 with concentrated hydrochloric acid and was then extracted with ethyl acetate (70 ml×3). The extract was washed with water (50 ml×2) and saturated sodium chloride solution (50 ml×2), dried over sodium sulfate and evaporated to dryness. Recrystallisation from ether and ethyl acetate at −20° C. yielded a colourless powder (2.8 g, 6.7 mmole, 63.8%).
Reaction SMILES: [H-].[Na+].[CH3:3][N:4]1[CH2:9][CH2:8][CH:7]([CH2:10][CH2:11][OH:12])[CH2:6][CH2:5]1.[CH3:13][C:14]1[CH:19]=[CH:18][C:17]([N:20]2[CH2:25][CH2:24][N:23]([C:26](OC3C=CC([N+]([O-])=O)=CC=3)=[O:27])[CH2:22][CH2:21]2)=[CH:16][CH:15]=1>CCCCCCC.C1COCC1>[CH3:13][C:14]1[CH:15]=[CH:16][C:17]([N:20]2[CH2:21][CH2:22][N:23]([C:26]([O:12][CH2:11][CH2:10][CH:7]3[CH2:8][CH2:9][N:4]([CH3:3])[CH2:5][CH2:6]3)=[O:27])[CH2:24][CH2:25]2)=[CH:18][CH:19]=1
Reactant: CN1CCC(CCO)CC1
Reactant: Cc1ccc(N2CCN(C(=O)Oc3ccc([N+](=O)[O-])cc3)CC2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CCCCCCC
Solvent: C1CCOC1
Product: Cc1ccc(N2CCN(C(=O)OCCC3CCN(C)CC3)CC2)cc1
Temperature: 0 °C
Reaction time: 48 h
Yield: 8.6 %

Procedure:
NaH (60% dispersion in mineral-oil, 0.81 g, 42.2 mmol) was suspended in heptane (10 mL) under an argon atmosphere. The heptane was decanted off, and the flask was charged with THF (20 mL) and cooled to 0° C. A solution of 2-(1-methyl-piperidin-4-yl)-ethanol (1.01 g, 7.03 mmol) in THF (20 mL) was added drop-wise, followed by a solution of 4-nitrophenyl 4-(4-methylphenyl)piperazine-1-carboxylate (2.89 g, 8.46 mmol) in THF (20 mL). The reaction mixture was allowed to warm to room temperature and stirred for 48 hours. The reaction mixture was then cooled to 0° C. and quenched with the drop-wise addition of sat aq NaHCO3 solution and concentrated in vacuo. The residue was dissolved in EtOAc (200 mL), washed with a NaHCO3 solution (4×50 mL), dried (MgSO4) and concentrated in vacuo. The residue was purified by normal phase column chromatography (eluting with DCM, followed by a 90:10 mixture of DCM:MeOH) followed by reverse phase chromatography (gradient eluting with MeOH in water, with 1% formic acid in each solvent, 0-20%). The resulting residue was dissolved in DCM (50 mL) and stirred with solid K2CO3 for 20 minutes, filtered and concentrated in vacuo to give the title compound 2-(1-methylpiperidin-4-yl)ethyl 4-(4-methylphenyl)piperazine-1-carboxylate (0.21 g, 7%) as a cream solid.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([C:14]3[C:15]([CH3:20])=[N:16][O:17][C:18]=3[CH3:19])=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][C:3]=1[N+:21]([O-:23])=[O:22].CCN(C(C)C)C(C)C.[O:33]1[CH2:38][CH2:37][CH:36]([CH2:39][NH2:40])[CH2:35][CH2:34]1>CN1C(=O)CCC1.O>[CH3:20][C:15]1[C:14]([C:8]2[CH:7]=[C:6]3[C:11]([C:2]([NH:40][CH2:39][CH:36]4[CH2:37][CH2:38][O:33][CH2:34][CH2:35]4)=[C:3]([N+:21]([O-:23])=[O:22])[CH:4]=[N:5]3)=[CH:10][C:9]=2[O:12][CH3:13])=[C:18]([CH3:19])[O:17][N:16]=1
Reactant: COc1cc2c(Cl)c([N+](=O)[O-])cnc2cc1-c1c(C)noc1C
Reactant: NCC1CCOCC1
Solvent: CN1CCCC1=O
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: COc1cc2c(NCC3CCOCC3)c([N+](=O)[O-])cnc2cc1-c1c(C)noc1C
Reaction time: 0.08 h
Yield: 93 %

Procedure:
4-Chloro-7-(3,5-dimethyl-4-isoxazolyl)-6-(methyloxy)-3-nitroquinoline (for a preparation see Intermediate 8) (1.06 g, 3.18 mmol) was dissolved in NMP (5 ml), then DIPEA (0.56 ml, 3.18 mmol) and (tetrahydro-2H-pyran-4-yl)methanamine (0.75 g, 6.51 mmol) were added at room temperature. The reaction mixture immediately changed colour and within 5 minutes, a thick yellow precipitate was formed. The mixture was stirred for 20 min, then diluted with water (30 ml) and stirred for 10 min. The precipitate was collected by filtration and washed with water (2×20 ml), then dried in vacuo to give 7-(3,5-dimethylisoxazol-4-yl)-6-methoxy-3-nitro-N-((tetrahydro-2H-pyran-4-yl)methyl)quinolin-4-amine (1.22 g, 2.96 mmol, 93% yield) as a bright yellow solid. LCMS (formate) Rt 0.88 min, MH+ 413
Reaction SMILES: Cl[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10]([C:12]2[CH2:21][CH2:20][C:19]3[C:14](=[CH:15][C:16]([C:22]4[CH:27]=[CH:26][C:25]([CH3:28])=[CH:24][CH:23]=4)=[CH:17][CH:18]=3)[CH:13]=2)=[O:11])=[CH:5][CH:4]=1.[CH:29]([N:42]1[CH2:47][CH2:46][NH:45][CH2:44][CH2:43]1)([C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1.C(=O)([O-])[O-].[K+].[K+].O>CN(C=O)C>[CH:29]([N:42]1[CH2:47][CH2:46][N:45]([CH2:2][C:3]2[CH:8]=[CH:7][C:6]([NH:9][C:10]([C:12]3[CH2:21][CH2:20][C:19]4[C:14](=[CH:15][C:16]([C:22]5[CH:27]=[CH:26][C:25]([CH3:28])=[CH:24][CH:23]=5)=[CH:17][CH:18]=4)[CH:13]=3)=[O:11])=[CH:5][CH:4]=2)[CH2:44][CH2:43]1)([C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1
Reactant: Cc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(CCl)cc2)CC3)cc1
Reactant: c1ccc(C(c2ccccc2)N2CCNCC2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(CN4CCN(C(c5ccccc5)c5ccccc5)CC4)cc2)CC3)cc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 60 %

Procedure:
In DMF (3 ml) was dissolved N-[4—(chloromethyl)-phenyl]-7—(4-methylphenyl)-3,4-dihydronaphthalene-2-carboxamide (150 mg), and to the solution were added 1-benzhydrylpiperazine (127 mg) and potassium carbonate (268 mg). The mixture was stirred at room temperature for 24 hours, and to the mixture was added water (50 ml). The mixture was extracted with ethyl acetate. The organic layer was washed with saturated sodium chloride solution, dried with anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was recrystallized from acetone-diisopropylether to give N-[4—(4-benzhydryl-1-piperazinyl-methyl)phenyl]-7—(4-methylphenyl)-3,4-dihydronaphthalene-2-carboxamide (Compound 43) (140 mg) as colorless crystals.
Reaction SMILES: [Na].[F:2][C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][C:10]=1[CH3:11])[CH:6]=O.[CH2:12]([O:14][C:15](=[O:20])[CH2:16][N:17]=[N+:18]=[N-:19])[CH3:13].[Cl-].[NH4+]>C(O)C.O.C(OCC)(=O)C>[CH2:12]([O:14][C:15](=[O:20])/[C:16](/[N:17]=[N+:18]=[N-:19])=[CH:6]/[C:5]1[CH:8]=[CH:9][C:10]([CH3:11])=[C:3]([F:2])[CH:4]=1)[CH3:13]
Reactant: Cc1ccc(C=O)cc1F
Reactant: CCOC(=O)CN=[N+]=[N-]
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na]
Solvent: CCO
Solvent: CCOC(C)=O
Solvent: O
Product: CCOC(=O)/C(=C/c1ccc(C)c(F)c1)N=[N+]=[N-]
Yield: 54.6 %

Procedure:
To ethanol (200 ml) was added portionwise 6.7 g sodium metal in such a way that the temperature stayed below 50° C. After all sodium had dissolved, the temperature was brought to −5° C. and a solution of 3-fluoro-4-methylbenzaldehyde (10.0 g, 0.072 mol) and azido acetic acid ethyl ester (37.4 g, 0.29 mol) in 100 ml ethanol was added while maintaining the temperature below 5° C. After 3 h the orange-red solution was poured on saturated aqueous ammonium chloride solution and ethyl acetate (300 ml) and water (100 ml) was added. The phases were separated, the aqueous phase was reextracted three times with ethyl acetate (300 ml each) and the combined organic layers were washed with brine (400 ml) and dried over magnesium sulfate. The crude reaction product was purified by column chromatography over silical gel (0.030–0.063 mm) with n-hexane/tert-butyl methyl ether (50/1) as eluent to yield the title product as a yellow oil (9.8 g, 54.2%). EI-MS: m/e=249.1 (M)
Reaction SMILES: C1(N)C(F)=C(F)C(F)=C([NH2:10])C=1F.Cl.Cl.[CH3:15][N:16]1[CH2:21][CH2:20][C:19](=[C:22]2[C:28]3[CH:29]=[C:30]([CH2:33]N)[CH:31]=[CH:32][C:27]=3[CH:26]=[CH:25][C:24]3[CH:35]=[CH:36][CH:37]=[CH:38][C:23]2=3)[CH2:18][CH2:17]1.CO[C:41]1[CH:42]=[C:43]([CH:47]=[C:48](OC)[C:49]=1OC)[C:44](Cl)=[O:45].[OH-].[Na+]>C1(C)C=CC=CC=1>[CH3:15][N:16]1[CH2:17][CH2:18][C:19](=[C:22]2[C:28]3[CH:29]=[C:30]([CH2:33][C:47]4[CH:48]=[CH:49][CH:41]=[CH:42][C:43]=4[C:44]([NH2:10])=[O:45])[CH:31]=[CH:32][C:27]=3[CH:26]=[CH:25][C:24]3[CH:35]=[CH:36][CH:37]=[CH:38][C:23]2=3)[CH2:20][CH2:21]1
Reactant: COc1cc(C(=O)Cl)cc(OC)c1OC
Reactant: CN1CCC(=C2c3ccccc3C=Cc3ccc(CN)cc32)CC1
Reactant: Nc1c(F)c(N)c(F)c(F)c1F
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1
Product: CN1CCC(=C2c3ccccc3C=Cc3ccc(Cc4ccccc4C(N)=O)cc32)CC1
Reaction time: 0.08 h

Procedure:
To a mixture of 0.50 g (1.26 mmol) of the dihydrochloride salt of 1-methyl-4-(3-aminomethyl-5H-dibenzo[a,d]cycloheptene-5-ylidene)piperidine and 0.25 g (1.08 mmol) 3,4,5-trimethoxybenzoyl chloride in 25 ml of toluene was added 1 ml of 10% aqueous sodium hydroxide. The mixture was shaken vigorously for 5 minutes. The toluene was removed by evaporation under reduced pressure and the residual gum was redissolved in chloroform. This chloroform phase was separated, dried over magnesium sulfate, filtered, and the chloroform was removed by evaporation. The crystalline residue was recrystallized from acetonitrile to give 3,4,5-trimethoxy-N-((5-(1-methyl-4-piperidinylidene)-5H-dibenzo[a,d]cyclohepten-3-yl)methylbenzamide, mp 200°-202° C.
Reaction SMILES: [CH:1]([NH:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)([CH3:3])[CH3:2].[C:11](Cl)([Cl:13])=[O:12]>C1C=CC=CC=1>[C:5]1([N:4]([CH:1]([CH3:3])[CH3:2])[C:11]([Cl:13])=[O:12])[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1
Reactant: O=C(Cl)Cl
Reactant: CC(C)Nc1ccccc1
Solvent: c1ccccc1
Product: CC(C)N(C(=O)Cl)c1ccccc1

Procedure:
A solution of N-isopropylaniline (30 g) in dry benzene (150 ml) was cooled to 5°-10° C and phosgene passed therethrough slowly for 11/2 hours. The mixture was refluxed for 1 hour to remove excess phosgene, cooled and the amine hydrochloride was filtered off. The solvent was evaporated and the residue recrystallised from benzene-petroleum ether 1:1, giving 21.6 g, m.p. 89°-90° C.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:16]3[C:15]([NH2:17])=[N:14][CH:13]=[N:12][C:11]=3[N:10]([CH:18]3[CH2:23][CH2:22][O:21][CH2:20][CH2:19]3)[CH:9]=2)=[CH:4][C:3]=1[O:24][CH3:25].N1C=CC=C[CH:27]=1.[CH:32]1([C:37](Cl)=[O:38])[CH2:36]CC[CH2:33]1>ClCCl>[NH2:17][C:15]1[C:16]2[C:8]([C:5]3[CH:6]=[CH:7][C:2]([NH:1][C:37](=[O:38])[C:32]([CH3:27])([CH3:36])[CH3:33])=[C:3]([O:24][CH3:25])[CH:4]=3)=[CH:9][N:10]([CH:18]3[CH2:19][CH2:20][O:21][CH2:22][CH2:23]3)[C:11]=2[N:12]=[CH:13][N:14]=1
Reactant: O=C(Cl)C1CCCC1
Reactant: c1ccncc1
Reactant: COc1cc(-c2cn(C3CCOCC3)c3ncnc(N)c23)ccc1N
Solvent: ClCCl
Product: COc1cc(-c2cn(C3CCOCC3)c3ncnc(N)c23)ccc1NC(=O)C(C)(C)C
Temperature: 25 °C
Reaction time: 2 h

Procedure:
5-(4-Amino-3-methoxyphenyl)-7-tetrahydro-2H-4-pyranyl-7H-pyrrolo[2,3-d]pyrimidin-4-amine (50mg, 0.147 mmol) was dissolved in dichloromethane (1.5 mL). Pyridine (1.5 mL) was added followed by 1-cyclopentanecarbonyl chloride (31 mg, 0.221 mmol). After stirring at room temperature for 2 hours, the solvent was removed and the residue was dissolved in 1 ml DMSO, methanol (1 mL) was added and precipitate was formed. The solid was collected by filtration to give N1-[4-(4-amino-7-tetrahydro-2H-4-pyranyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-2-methoxyphenyl]-2,2-dimethylpropanamide (33 mg, 0.076 mmol). 1H NMR (CDCl3-d) δ 1.66 (m, 2H), 1.81 (m, 2H), 1.95 (m, 4H), 2.06 (m, 4H), 2.77 (m, 1H), 3.65 (m, 2H), 3.94 (s, 3H), 4.15 9m, 2H), 4.96 (m, 1H), 5.37(bs, 2H), 6.98 (s, 1H), 7.03 (s, 1H), 7.07 (d, J=8.2 Hz, 1H), 7.84 (s, 1H), 8.30 (s, 1H), 8.49(d, J=8.2 Hz, 1H). LC/MS: MH+=437.
Reaction SMILES: [OH:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[C:4](O)[CH:3]=1.[NH3:13]>>[OH:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[C:4]([NH2:13])[CH:3]=1
Reactant: Oc1cc(O)c2ccccc2c1
Reactant: N
Product: Nc1cc(O)c2ccccc2c1
Temperature: 135 °C
Reaction time: 14 h

Procedure:
A solution of 1,3-dihydroxynaphthalene (1, 50 g, 0.312 mol) in liquid ammonia (200 mL) at −78° C. was sealed in a 1 L steel bomb containing a glass liner. The reaction mixture was warmed to 135±10° C. and 1300 psi for 14 h with vigorous stirring. The vessel was allowed to cool to 60° C., and the ammonia was released slowly. The remaining traces of ammonia were removed by co-evaporation with THF (2×150 mL) under a stream of argon at 60° C. The intermediate 4-hydroxy-2-naphthylamine (2) was not isolated but was immediately converted to the di-tert-butyloxycarbonyl protected compound 3. A solution of di-tert-butyl dicarbonate (175 g, 0.801 mol) in dry THF (300 mL) and N,N-diisopropylethylamine (140 mL, 0.803 mol) were sequentially added to the bomb. The bomb was re-sealed, and the contents were warmed at 100° C. with stirring for 4 h. The bomb was cooled to room temperature, opened, and the residue partitioned between saturated aqueous NaCl (800 mL) and ethyl acetate (500 mL). The aqueous phase was extracted with ethyl acetate (200 mL×2). The combined organic layers were dried (magnesium sulfate), filtered, and concentrated under reduced pressure. Chromatography on silica gel (1:8 to 1:4 ethyl acetate/hexane) and recrystallization with ethyl acetate/ethanol/hexane provided pure 77.41 g (69%) of the title compound (3). 1H NMR (CDCl3, 400 MHz) 8.14 (d, 1H, J=8.1 Hz), 7.66 (d, 1H, J=8.1 Hz), 7.43 (dd, 1H, J=6.8, 8.2Hz), 7.35 (dd, 1H, J=6.8, 82 Hz), 7.22 (d, 1H, J=1.8 Hz), 7.15 (br, 1H, NH), 6.69 (s, 1H), 1.59 (s, 9H), 1.37 (s, 9H); 13C NMR(CDCl3) 153.71, 152.9, 136.11, 135.20, 128.12, 128.01, 126.81, 126.03, 123.61, 107.94, 102.95, 82.98, 82.10, 28.93, 27.69; MS m/z 382.52 (M+Na)+.
Reaction SMILES: C([O:9][C@H:10]1[CH2:15][CH2:14][C@@H:13]([N:16]2[CH2:20][CH2:19][C@:18]3([CH2:25][CH2:24][CH2:23][NH:22][CH2:21]3)[C:17]2=[O:26])[CH2:12][CH2:11]1)(=O)C1C=CC=CC=1.Cl[C:28]1[N:35]=[CH:34][CH:33]=[CH:32][C:29]=1[C:30]#[N:31].C(N(CC)C(C)C)(C)C.CN1CCCC1=O.[OH-].[Li+]>CO>[OH:9][C@@H:10]1[CH2:11][CH2:12][C@H:13]([N:16]2[CH2:20][CH2:19][C@:18]3([CH2:25][CH2:24][CH2:23][N:22]([C:28]4[N:35]=[CH:34][CH:33]=[CH:32][C:29]=4[C:30]#[N:31])[CH2:21]3)[C:17]2=[O:26])[CH2:14][CH2:15]1
Reactant: N#Cc1cccnc1Cl
Reactant: O=C(O[C@H]1CC[C@@H](N2CC[C@]3(CCCNC3)C2=O)CC1)c1ccccc1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: CN1CCCC1=O
Solvent: CCN(C(C)C)C(C)C
Product: N#Cc1cccnc1N1CCC[C@]2(CCN([C@H]3CC[C@@H](O)CC3)C2=O)C1
Temperature: 25 °C

Procedure:
A mixture of cis-4-[(5S)-1-oxo-2,7-diazaspiro[4.5]dec-2-yl]cyclohexyl benzoate (19.0 mg, 0.0000533 mol), 2-chloronicotinonitrile (8.12 mg, 0.0000586 mol) and N,N-diisopropylethylamine (20.0 μL, 0.000115 mol) in N-methylpyrrolidinone (0.6 mL, 0.006 mol) was irradiated by microwave at 180° C. for 20 min. After cooling to rt, lithium hydroxide aqueous solution (1.0 M, 0.150 mL) was added, followed by methanol (0.2 mL). The mixture was heated at 100° C. for 5 h. The crude reaction mixture was then purified by prep-HPLC under basic conditions to afford the desired product. LC-MS: 355.2 (M+H)+.
Reaction SMILES: P([O-])([O-])([O-])=O.[F:6][C:7]1[C:12]([C:13]([F:16])([F:15])[F:14])=[C:11]([F:17])[CH:10]=[CH:9][C:8]=1[C:18]1[N:19]=[C:20]([NH:23][C:24](=[O:39])[CH2:25][C:26]2[C:34]3[C:33](=[O:35])[N:32]([CH3:36])[C:31](=[O:37])[N:30]([CH3:38])[C:29]=3[S:28][CH:27]=2)[S:21][CH:22]=1.[P:40]([O:52][CH2:53]I)([O:47][C:48]([CH3:51])([CH3:50])[CH3:49])([O:42][C:43]([CH3:46])([CH3:45])[CH3:44])=[O:41].[H-].[Na+].[CH3:57]N(C=O)C>>[P:40]([O:52][CH2:53][N:19]1[C:18]([C:8]2[CH:9]=[CH:10][C:11]([F:17])=[C:12]([C:13]([F:15])([F:14])[F:16])[C:7]=2[F:6])=[CH:22][S:21][C:20]1=[N:23][C:24](=[O:39])[CH2:25][C:26]1[C:34]2[C:33](=[O:35])[N:32]([CH3:36])[C:31](=[O:37])[N:30]([CH3:38])[C:29]=2[S:28][C:27]=1[CH3:57])([O:47][C:48]([CH3:51])([CH3:50])[CH3:49])([O:42][C:43]([CH3:46])([CH3:45])[CH3:44])=[O:41]
Reactant: Cn1c(=O)c2c(CC(=O)Nc3nc(-c4ccc(F)c(C(F)(F)F)c4F)cs3)csc2n(C)c1=O
Reactant: CN(C)C=O
Reactant: CC(C)(C)OP(=O)(OCI)OC(C)(C)C
Agent: O=P([O-])([O-])[O-]
Agent: [H-]
Agent: [Na+]
Product: Cc1sc2c(c1CC(=O)N=c1scc(-c3ccc(F)c(C(F)(F)F)c3F)n1COP(=O)(OC(C)(C)C)OC(C)(C)C)c(=O)n(C)c(=O)n2C

Procedure:
The title compound was prepared according to the general procedure as described in method A for the preparation of phosphate derivatives by coupling N-{4-[2,4-Difluoro-3-(trifluoromethyl)phenyl]-1,3-thiazol-2-yl}-2-(1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydrothieno[2,3-d]pyrimidin-5-yl)acetamide (1.10 g, 2.07 mmol) with freshly prepared di-tert-butyl iodomethyl phosphate (intermediate 2) (1.459 g, 4.15 mmol) in dry DMF (11 ml) in presence of sodium hydride (60% dispersion in mineral oil, 0.0745 g, 3.113 mmol) to yield 0.85 g of pure product as an off-white solid. 1H NMR (300 MHz, CDCl3): δ 1.46 (s, 18H), 2.42 (s, 3H), 3.33 (s, 3H), 3.52 (s, 3H), 4.40 (s, 2H), 6.47 (d, J=7.8 Hz, 2H), 7.07 (t, J=8.7 Hz, 1H), 7.46 (s, 1H), 8.47 (q, J=9.0 Hz, 1H); APCI (m/z): 752.72 (M+H)+.