Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:6]=[CH:7][C:8]2[O:12][C:11]3([CH3:19])[CH:13]4[CH2:17][C:16]([CH3:18])([C:10]3([CH3:20])[C:9]=2[CH:21]=1)[CH2:15][CH2:14]4)=[O:4].[OH:22][C:23]1[CH:24]=[C:25]([CH:30]=[CH:31][C:32]=1[I:33])[C:26]([O:28][CH3:29])=[O:27].C(=O)([O-])[O-].[K+].[K+]>C(C(C)=O)C>[CH3:18][C:16]12[CH2:17][CH:13]([C:11]3([CH3:19])[C:10]1([CH3:20])[C:9]1[CH:21]=[C:5]([C:3]([CH2:2][O:22][C:23]4[CH:24]=[C:25]([CH:30]=[CH:31][C:32]=4[I:33])[C:26]([O:28][CH3:29])=[O:27])=[O:4])[CH:6]=[CH:7][C:8]=1[O:12]3)[CH2:14][CH2:15]2
Reactant: COC(=O)c1ccc(I)c(O)c1
Reactant: CC12CCC(C1)C1(C)Oc3ccc(C(=O)CBr)cc3C21C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: COC(=O)c1ccc(I)c(OCC(=O)c2ccc3c(c2)C2(C)C4(C)CCC(C4)C2(C)O3)c1

Procedure:
A solution of 1,2,3,4-tetrahydro-1,4a,9b-trimethyl-1,4-methanodibenzofur-8-yl bromomethyl ketone (2.5 g, 6.86 mmol), methyl 3-hydroxy-4-iodobenzoate (1.9 g, 6.83 mmol) and potassium carbonate (0.95 g, 6.88 mmol) in methyl ethyl ketone (50 ml) is refluxed for five hours. The reaction medium is filtered, after which 40 ml of water and 40 ml of ethyl ether are added. After stirring and separation of the phases by settling, the organic phase is washed twice with 40 ml of water, dried over magnesium sulphate and concentrated on a rotary evaporator under vacuum at 40° C. The product is purified by flash chromatography on a column of silica (30% ethyl acetate, 70% heptane).
Reaction SMILES: [CH:1]([NH:3][C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([C:13]([F:16])([F:15])[F:14])[CH:11]=2)[NH:6][N:5]=1)=[O:2].[CH3:17][N:18]([CH3:22])[C:19](Cl)=[O:20].O>N1C=CC=CC=1>[CH3:17][N:18]([CH3:22])[C:19]([N:6]1[C:7]2[C:12](=[CH:11][C:10]([C:13]([F:16])([F:14])[F:15])=[CH:9][CH:8]=2)[C:4]([NH:3][CH:1]=[O:2])=[N:5]1)=[O:20]
Reactant: O=CNc1n[nH]c2ccc(C(F)(F)F)cc12
Reactant: CN(C)C(=O)Cl
Solvent: c1ccncc1
Solvent: O
Product: CN(C)C(=O)n1nc(NC=O)c2cc(C(F)(F)F)ccc21
Yield: 57 %

Procedure:
0.2 mol of 3-formylamino-5-trifluoromethylindazole and 0.05 mol of dimethylcarbamic acid chloride in 20 ml of pyridine are heated for 4 hours to 50° C. After cooling, 150 ml of water are allowed to run in and the reaction product which has crystallized out is isolated by filtration. Recrystallization from ethanol gives 3formylamino-5-trifluoromethylindazole-1-carboxylic acid dimethylamide (melting point: 198°-200° C; 57% of theory).
Reaction SMILES: O.[NH2:2][NH2:3].Cl[C:5]1[CH:18]=[CH:17][C:8]([C:9]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[O:10])=[CH:7][C:6]=1[N+:19]([O-:21])=[O:20]>C(O)C>[C:9]([C:8]1[CH:17]=[CH:18][C:5]([NH:2][NH2:3])=[C:6]([N+:19]([O-:21])=[O:20])[CH:7]=1)(=[O:10])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: NN
Reactant: O=C(c1ccccc1)c1ccc(Cl)c([N+](=O)[O-])c1
Solvent: O
Solvent: CCO
Product: NNc1ccc(C(=O)c2ccccc2)cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 1.25 h
Yield: 75 %

Procedure:
20 ml of hydrazine hydrate were added to the suspension of 52.33 g of 4-chloro-3-nitrobenzophenone in 200 ml of abs. ethanol under stirring. The reaction mixture was stirred at room temperature for 75 minutes, then slowly heated to the boiling point. After completion of the violent reaction, the mixture was refluxed for an additional 1 hour. After cooling down, the crystals were filtered by suction, thoroughly washed with water and dried at 80° C. Thus, 38.62 g (75%) of 4-benzoyl-2-nitrophenylhydrazine were obtained as orange-red crystals, m.p.: 163°-164° C.
Reaction SMILES: [F:1][C:2]1[CH:30]=[CH:29][CH:28]=[CH:27][C:3]=1[CH2:4][C:5]1[N:6]=[C:7]([C:14]2[N:15]=[C:16](I)[C:17]3[C:22]([CH3:24])([CH3:23])[C:21](=[O:25])[NH:20][C:18]=3[N:19]=2)[N:8]2[CH:13]=[CH:12][CH:11]=[N:10][C:9]=12.[F:31][C:32]([F:37])([F:36])[CH2:33][CH2:34][NH2:35]>CN1C(=O)CCC1>[F:1][C:2]1[CH:30]=[CH:29][CH:28]=[CH:27][C:3]=1[CH2:4][C:5]1[N:6]=[C:7]([C:14]2[N:15]=[C:16]([NH:35][CH2:34][CH2:33][C:32]([F:37])([F:36])[F:31])[C:17]3[C:22]([CH3:24])([CH3:23])[C:21](=[O:25])[NH:20][C:18]=3[N:19]=2)[N:8]2[CH:13]=[CH:12][CH:11]=[N:10][C:9]=12
Reactant: CC1(C)C(=O)Nc2nc(-c3nc(Cc4ccccc4F)c4ncccn34)nc(I)c21
Reactant: NCCC(F)(F)F
Solvent: CN1CCCC1=O
Product: CC1(C)C(=O)Nc2nc(-c3nc(Cc4ccccc4F)c4ncccn34)nc(NCCC(F)(F)F)c21
Temperature: 150 °C
Reaction time: 1.5 h

Procedure:
Under an argon atmosphere, 200 mg (purity 69%, 0.27 mmol) of 2-[8-(2-fluorobenzyl) imidazo[1,5-a]pyrimidin-6-yl]-4-iodo-5,5-dimethyl-5,7-dihydro-6H-pyrrolo[2,3-d]pyrimidin-6-one (example 52A) was suspended in 3.2 ml of absolute NMP and 607 mg (5.37 mmol) of 3,3,3-trifluoropropan-1-amine was added. The mixture was stirred for 1.5 h at 150° C. in the microwave. The reaction solution was filtered and purified by preparative HPLC (eluent: acetonitrile/water with 0.1% hydrochloric acid, gradient 20:80→100:0). 41 mg (31% of theor.) of the target compound was obtained.
Reaction SMILES: [F:1][C:2]1([F:13])[CH2:6][CH2:5][CH:4]([C:7](N(OC)C)=[O:8])[CH2:3]1.[CH3:14][Mg]Br.C(OCC)C>C1COCC1>[F:1][C:2]1([F:13])[CH2:6][CH2:5][CH:4]([C:7](=[O:8])[CH3:14])[CH2:3]1
Reactant: CON(C)C(=O)C1CCC(F)(F)C1
Reactant: C[Mg]Br
Solvent: CCOCC
Solvent: C1CCOC1
Product: CC(=O)C1CCC(F)(F)C1
Reaction time: 1.5 h

Procedure:
To a solution of (rac)-3,3-difluoro-N-methoxy-N-methylcyclopentane-carboxamide (1.90 g, 9.83 mmol) in 20 mL THF at 0° C. was added methylmagnesium bromide 3.0 m in diethyl ether (6.56 mL, 19.67 mmol) slowly dropwise. The reaction mixture became white and cloudy. After 1.5 h, the reaction mixture was quenched carefully with ice and 1N HCl, and diluted with Et2O. The organic layer was washed with brine, dried over magnesium sulfate, filtered, and concentrated in vacuo to give (rac)-1-(3,3-difluorocyclopentyl)ethanone as a light yellow oil. 1H NMR (400 MHz, CDCl3-d) δ ppm 3.03-3.19 (m, 1 H), 2.22-2.48 (m, 2 H), 2.20 (s, 3 H), 2.03-2.16 (m, 3 H), 1.90-1.99 (m, 1 H).
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4](Cl)[C:5]2[CH:10]=[CH:9][N:8]([S:11]([C:14]3[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][CH:15]=3)(=[O:13])=[O:12])[C:6]=2[N:7]=1.[NH2:22][C:23]1[CH:31]=[CH:30][CH:29]=[CH:28][C:24]=1[C:25]([OH:27])=[O:26].CCN(C(C)C)C(C)C>CC(O)C>[Cl:1][C:2]1[N:3]=[C:4]([NH:22][C:23]2[CH:31]=[CH:30][CH:29]=[CH:28][C:24]=2[C:25]([OH:27])=[O:26])[C:5]2[CH:10]=[CH:9][N:8]([S:11]([C:14]3[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][CH:15]=3)(=[O:13])=[O:12])[C:6]=2[N:7]=1
Reactant: Nc1ccccc1C(=O)O
Reactant: Cc1ccc(S(=O)(=O)n2ccc3c(Cl)nc(Cl)nc32)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(C)O
Product: Cc1ccc(S(=O)(=O)n2ccc3c(Nc4ccccc4C(=O)O)nc(Cl)nc32)cc1
Temperature: 85 °C

Procedure:
A mixture of 2,4-dichloro-7-[(4-methylphenyl)sulfonyl]-7H-pyrrolo[2,3-d]pyrimidine (25 g, 73.1 mmol), 2-aminobenzoic acid (10.02 g, 73.1 mmol) and DIPEA (63.8 mL, 365 mmol) in iPrOH (300 mL) was heated at 85° C. bath for 17 h. The resulting mixture was allowed to cool to rt and was concentrated to about half volume. EtOAc (400 mL) was added, followed by a 1N aqueous HCl solution (400 mL). The resulting slurry was filtered, the solids were washed with EtOAc and triturated using Et2O to obtain 2-({2-chloro-7-[(4-methylphenyl)sulfonyl]-7H-pyrrolo[2,3-d]pyrimidin-4-yl}amino)benzoic acid as a yellow solid (28.44 g 88%). 1H NMR (400 MHz, DMSO-d6) δ ppm 2.36 (s, 3H), 7.11-7.23 (m, 1H), 7.47 (d. J=8.61 Hz, 2H), 7.56-7.67 (m, 1H), 7.76 (d, J=3.85 Hz, 1H), 7.95 (dd, J=7.69 Hz, 1.46 Hz, 1H), 7.97-8.02 (m, 2H), 8.29-8.36 (m, 1H), 11.36 (s, 1H); ESIMS (M+H)+=443.06.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([CH:14]=O)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.Cl.[CH3:18][C:19]1[N:24]=[C:23]([N:25]2[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]2)[CH:22]=[CH:21][N:20]=1.C([BH3-])#N.[Na+]>CO.C(O)(=O)C>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][N:28]2[CH2:29][CH2:30][N:25]([C:23]3[CH:22]=[CH:21][N:20]=[C:19]([CH3:18])[N:24]=3)[CH2:26][CH2:27]2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCC(C=O)CC1
Reactant: Cc1nccc(N2CCNCC2)n1
Agent: Cl
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: Cc1nccc(N2CCN(CC3CCN(C(=O)OC(C)(C)C)CC3)CC2)n1
Yield: 24.1 %

Procedure:
To a solution of 1-(tert-butoxycarbonyl)-4-(formyl)piperidine (7.14 g) and 1-(2-methylpyrimidin-4-yl)piperazine dihydrochloride (8.38 g) in methanol/acetic acid (99:1) (150 ml) was added sodium cyanoborohydride (6.32 g) portionwise over 30 minutes and the resultant suspension stirred at arnbient temperature for 3 hours. The suspension was quenched by addition of saturated aqueous sodium bicarbonate solution and the resulting mixture extracted with ethyl acetate. The organic phase was dried (Na2SO4) and evaporated. The residue was purified by chromatography eluting with 5% methanol in dichloromethane to give 1-tert-butoxycarbonyl-4-[1-(2-methylpyrimidin-4-yl)piperazin-4-ylmethyl]piperidine (3.02 g) as a foam.
Reaction SMILES: [C:1]([C:3]1[CH:13]=[CH:12][CH:11]=[CH:10][C:4]=1[O:5][CH2:6][CH:7]1[O:9][CH2:8]1)#[N:2].[NH2:14][CH2:15][CH2:16][O:17][C:18]1[CH:23]=[CH:22][C:21]([C:24]2[CH:25]([CH3:31])[CH2:26][C:27](=[O:30])[NH:28][N:29]=2)=[CH:20][CH:19]=1>>[C:1]([C:3]1[CH:13]=[CH:12][CH:11]=[CH:10][C:4]=1[O:5][CH2:6][CH:7]([OH:9])[CH2:8][NH:14][CH2:15][CH2:16][O:17][C:18]1[CH:19]=[CH:20][C:21]([C:24]2[CH:25]([CH3:31])[CH2:26][C:27](=[O:30])[NH:28][N:29]=2)=[CH:22][CH:23]=1)#[N:2]
Reactant: N#Cc1ccccc1OCC1CO1
Reactant: CC1CC(=O)NN=C1c1ccc(OCCN)cc1
Product: CC1CC(=O)NN=C1c1ccc(OCCNCC(O)COc2ccccc2C#N)cc1

Procedure:
Prepared analogously to Example 1 from 1-(2-cyano- phenoxy)-2,3-epoxypropane and 6-[4-(2-aminoethoxy)phenyl]-4,5-dihydro-5-methyl-3(2H)-pyridazinone.
Reaction SMILES: [Cl:1][C:2]1[C:18]([F:19])=[CH:17][C:5]([C:6]([NH:8][C:9]2[CH:14]=[CH:13][N:12]=[C:11]([O:15]C)[CH:10]=2)=[O:7])=[C:4]([F:20])[CH:3]=1.Br.O>CC(O)=O>[Cl:1][C:2]1[C:18]([F:19])=[CH:17][C:5]([C:6]([NH:8][C:9]2[CH:14]=[CH:13][NH:12][C:11](=[O:15])[CH:10]=2)=[O:7])=[C:4]([F:20])[CH:3]=1
Reactant: COc1cc(NC(=O)c2cc(F)c(Cl)cc2F)ccn1
Agent: Br
Solvent: CC(=O)O
Solvent: O
Product: O=C(Nc1cc[nH]c(=O)c1)c1cc(F)c(Cl)cc1F
Temperature: 90 °C
Reaction time: 5 h
Yield: 33.9 %

Procedure:
To 4-chloro-2,5-difluoro-N-(2-methoxy-4-pyridyl)benzamide (3 g, 10.04 mmol) in HOAc (15.9 mL) was added HBr 33% in HOAc (12.31 mL of 33% w/v, 50.20 mmol) and the mixture was stirred at 90° C. for 5 h. Additional HBr (10 mL, 33% in HOAc) was added and the mixture was stirred at 90° C. overnight. The mixture was cooled to room temperature and was poured into water (100 mL). The mixture was stirred and the solid was collected by filtration. The solid was washed with water (2×50 mL). The solid was slurried in hexanes (2×50 mL) and filtered to give 4-chloro-2,5-difluoro-N-(2-oxo-1H-pyridin-4-yl)benzamide (969.7 mg, 34%) as a cream colored solid. ESI-MS m/z calc. 284.02. found 285.3 (M+1)+; Retention time: 1.36 minutes (3 min run).
Reaction SMILES: [S:1](=[O:26])(=[O:25])([O:3][CH2:4][C@@H:5]1[C@@H:12]2[C@@H:8]([O:9][C:10]([CH3:14])([CH3:13])[O:11]2)[C@H:7]([N:15]2[CH:23]=[N:22][C:21]3[C:16]2=[N:17][CH:18]=[N:19][C:20]=3Cl)[O:6]1)[NH2:2].[Na+].[I-:28].FC(F)(F)C(O)=O>CC(=O)CC>[S:1](=[O:26])(=[O:25])([O:3][CH2:4][C@@H:5]1[C@@H:12]2[C@@H:8]([O:9][C:10]([CH3:14])([CH3:13])[O:11]2)[C@H:7]([N:15]2[CH:23]=[N:22][C:21]3[C:16]2=[N:17][CH:18]=[N:19][C:20]=3[I:28])[O:6]1)[NH2:2]
Reactant: [I-]
Reactant: CC1(C)O[C@@H]2[C@H](O1)[C@@H](COS(N)(=O)=O)O[C@H]2n1cnc2c(Cl)ncnc21
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: CCC(C)=O
Product: CC1(C)O[C@@H]2[C@H](O1)[C@@H](COS(N)(=O)=O)O[C@H]2n1cnc2c(I)ncnc21
Temperature: -10 °C
Reaction time: 4.5 h
Yield: 81.2 %

Procedure:
To a solution of ((3aR,4R,6R,6aR)-6-(6-chloro-9H-purin-9-yl)-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl)methyl sulfamate (645 mg, 1.59 mmol) in 2-butanone (30.0 mL) was added NaI (4.77 g, 31.79 mmol). The reaction was cooled to −10° C. and trifluoroacetic acid (612 μL, 7.94 mmol) was added. The reaction was stirred for 4.5 hours, quenched with saturated aq NaHCO3 and extracted with DCM. The crude product was purified by flash chromatography (40% EtOAc/DCM) to isolate the title compound (0.642 g, 81%).
Reaction SMILES: [CH3:1][C:2]1[N:3]([NH:8][C:9]2[N:10]=[N:11][C:12]([N:15]3[CH2:20][CH2:19][O:18][CH2:17][CH2:16]3)=[CH:13][CH:14]=2)[C:4]([CH3:7])=[CH:5][CH:6]=1.[H-].[Na+].[CH3:23]I>CN(C)C=O>[CH3:1][C:2]1[N:3]([N:8]([CH3:23])[C:9]2[N:10]=[N:11][C:12]([N:15]3[CH2:16][CH2:17][O:18][CH2:19][CH2:20]3)=[CH:13][CH:14]=2)[C:4]([CH3:7])=[CH:5][CH:6]=1
Reactant: CI
Reactant: Cc1ccc(C)n1Nc1ccc(N2CCOCC2)nn1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1ccc(C)n1N(C)c1ccc(N2CCOCC2)nn1
Temperature: 55 °C
Reaction time: 0.5 h

Procedure:
To 1.36 g (5 m moles) of N-(2,5-dimethyl-1H-pyrrol-1-yl)-6-morpholino-3-pyridazineamine in 13.6 ml of dimethylformamide, 0.26 g (5.5 m moles) of 55% sodium hydride are added. The mixture is stirred for 30 minutes at room temperature and for additional 30 minutes at 55° C. Then, a solution of 0.78 g (5.5 m moles) of methyl iodide in 2 ml of dimethylformamide is gradually added at 10° C. When the addition is completed the mixture is heated at 50° C. for 45 minutes. The dimethylformamide is evaporated off in vacuo and the residue is dissolved in ethyl acetate. The organic layer is washed with water and then evaporated to dryness to give a solid which is crystallized from hexane. Yield 0.7 g (54%) of the product of the title which melts at 119°-122° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:23][OH:24])[CH:6]=[CH:7][C:8]=1[O:9][CH2:10][C:11]1[S:15][C:14]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[N:13][C:12]=1[CH3:22].O[C:26]1[C:30]([CH:31]=[O:32])=[CH:29][N:28]([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[N:27]=1.C(P(CCCC)CCCC)CCC.N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O>O1CCCC1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:6]=[CH:7][C:8]=1[O:9][CH2:10][C:11]1[S:15][C:14]([C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)=[N:13][C:12]=1[CH3:22])[CH2:23][O:24][C:26]1[C:30]([CH:31]=[O:32])=[CH:29][N:28]([C:33]2[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=2)[N:27]=1
Reactant: COc1cc(CO)ccc1OCc1sc(-c2ccccc2)nc1C
Reactant: O=Cc1cn(-c2ccccc2)nc1O
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: C1CCOC1
Product: COc1cc(COc2nn(-c3ccccc3)cc2C=O)ccc1OCc1sc(-c2ccccc2)nc1C
Reaction time: 15 h
Yield: 73.8 %

Procedure:
To a mixture of {3-methoxy-4-[(4-methyl-2-phenyl-1,3-thiazol-5-yl)methoxy]phenyl}methanol (2.35 g), 3-hydroxy-1-phenyl-1H-pyrazole-4-carbaldehyde (1.43 g), tributylphosphine (1.43 g) and tetrahydrofuran (50 mL) was added 1,1′-(azodicarbonyl)dipiperidine (2.62 g) at room temperature, and the mixture was stirred for 15 hrs. The precipitated crystals were removed by filtration and the filtrate was concentrated. The residue was subjected to silica gel column chromatography to give 3-({3-methoxy-4-[(4-methyl-2-phenyl-1,3-thiazol-5-yl)methoxy]benzyl}oxy)-1-phenyl-1H-pyrazole-4-carbaldehyde as pale-yellow crystals (2.60 g, yield 74%) from a fraction eluted with ethyl acetate-hexane (3:2, v/v). Recrystallization from ethyl acetate-hexane gave colorless prism crystals. melting point: 171-172° C.
Reaction SMILES: [ClH:1].[N+](=[CH:4][C:5](=[O:16])[C@H:6]([NH:8][C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])[CH3:7])=[N-]>C(OCC)C>[Cl:1][CH2:4][C:5](=[O:16])[C@H:6]([NH:8][C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])[CH3:7]
Reactant: C[C@@H](NC(=O)OC(C)(C)C)C(=O)C=[N+]=[N-]
Reactant: Cl
Solvent: CCOCC
Product: C[C@@H](NC(=O)OC(C)(C)C)C(=O)CCl
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
Hydrochloric acid (2.0 M in water, 21.4 mL, 42.8 mmol) was added to a mixture of (R)-tert-butyl (4-diazo-3-oxobutan-2-yl)carbamate (1.89 g, 8.86 mmol) in diethyl ether (19.27 mL) at 0° C.0. The mixture was stirred vigorously for 20 minutes and then allowed to warm to room temperature and stirred vigorously until the mixture went from yellow to colorless. The mixture was washed with saturated aqueous sodium bicarbonate, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure to afford (R)-tert-butyl (4-chloro-3-oxobutan-2-yl)carbamate. 1H NMR (500 MHz, DMSO-d6) δ 7.34 (d, J=7.0 Hz, 1H), 4.64-4.51 (m, 2H), 4.23-4.02 (m, 1H), 1.36 (s, 9H), 1.16 (d, J=7.2 Hz, 3H).
Reaction SMILES: O=P(Cl)(Cl)Cl.[CH2:6]([O:14][C:15]1[CH:19]=[CH:18][S:17][CH:16]=1)[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH3:13].[OH-].[Na+].CN([CH:25]=[O:26])C>>[CH:25]([C:16]1[S:17][CH:18]=[CH:19][C:15]=1[O:14][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH3:13])=[O:26]
Reactant: CN(C)C=O
Reactant: CCCCCCCCOc1ccsc1
Agent: [Na+]
Agent: [OH-]
Solvent: O=P(Cl)(Cl)Cl
Product: CCCCCCCCOc1ccsc1C=O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To the stirred solution of anhydrous DMF (10 mL) at 0° C. in 100 mL three neck flask under Nitrogen atmosphere, POCl3 (0.53 mL, 5.76 mmol) was added dropwise for 5 minutes. After addition, the reaction mixture was stirred at room temperature for 1 hour. Then 3-octyloxythiophene (1.02 g, 4.80 mmol) in 2 mL DMF was added dropwise at 0° C. for 5 minutes. This solution was stirred at 70° C. for 90 minutes and poured it into ice water and then slowly neutralized with 10% NaOH solution (20 mL). The resultant mixture was heated in a steam-bath for 20 min. The aqueous layer was extracted with CHCl3 (3×50 mL), followed by drying over anhydrous Na2SO4. After the removal of solvents, the crude mixture was chromatographed on silica gel (10% ethyl acetate in hexane) to give 3′ as a colourless oil. (1.0 g, 86%). 1H NMR (CDCl3, 300 MHz, ppm): δ 10.01 (s, 1H), 7.62 (d, 1H, 5.4 Hz), 6.84 (d, 1H, 5.4 Hz), 4.15 (t, 2H, 6.6 Hz), 1.76-1.86 (m, 2H), 1.29-1.46 (m, 10H), 0.89 (t, 3H, 6.6 Hz). M/e 240.12.
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[CH3:6][O:7][C:8](=[O:34])/[CH:9]=[CH:10]/[C:11]1[CH:12]=[C:13]2[C:30](=[CH:31][CH:32]=1)[O:29][C:16]1([CH2:21][CH2:20][N:19](C(OC(C)(C)C)=O)[CH2:18][CH2:17]1)[CH2:15][C:14]2=[O:33]>C(Cl)Cl>[CH3:6][O:7][C:8](=[O:34])/[CH:9]=[CH:10]/[C:11]1[CH:12]=[C:13]2[C:30](=[CH:31][CH:32]=1)[O:29][C:16]1([CH2:17][CH2:18][N:19]([S:2]([CH3:1])(=[O:4])=[O:3])[CH2:20][CH2:21]1)[CH2:15][C:14]2=[O:33]
Reactant: COC(=O)/C=C/c1ccc2c(c1)C(=O)CC1(CCN(C(=O)OC(C)(C)C)CC1)O2
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Product: COC(=O)/C=C/c1ccc2c(c1)C(=O)CC1(CCN(S(C)(=O)=O)CC1)O2
Temperature: 25 °C
Reaction time: 8 h
Yield: 97 %

Procedure:
TEA (0.185 ml, 1.33 mmol) and methanesulfonyl chloride (0.067 ml, 0.88 mmol) were added to a suspension of (E)-3-{4-oxo-spiro[chromane-2,4′-piperidine]-6-yl}-acrylic acid methyl ester hydrochloride (150 mg, 0.44 mmol, Intermediate 1) in DCM (3 ml), and the mixture was stirred at RT overnight. The solvent was removed under vacuum and the residue was purified by column chromatography (eluent:DCM/MeOH 97:3) to give (E)-3-{1′-methanesulfonyl-4-oxo-spiro[chromane-2,4′-piperidine]-6-yl}-acrylic acid methyl ester (162 mg).
Reaction SMILES: [C:1]1([C:7]([C:9]2[CH:10]=[N:11][C:12]([N:15]3[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]3)=[N:13][CH:14]=2)=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(N(CC)CC)C.Cl[C:29]([O:31][CH2:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)=[O:30]>ClCCl>[C:7]([C:9]1[CH:14]=[N:13][C:12]([N:15]2[CH2:20][CH2:19][N:18]([C:29]([O:31][CH2:32][C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)=[O:30])[CH2:17][CH2:16]2)=[N:11][CH:10]=1)(=[O:8])[C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C(c1ccccc1)c1cnc(N2CCNCC2)nc1
Reactant: O=C(Cl)OCc1ccccc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(c1ccccc1)c1cnc(N2CCN(C(=O)OCc3ccccc3)CC2)nc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 57.3 %

Procedure:
To a solution of phenyl(2-(piperazin-1-yl)pyrimidin-5-yl)methanone (crude, 2.6 mmol assumed) and triethylamine (780 mg, 7.8 mmol) in dichloromethane (10 mL) was added benzyl chloroformate (663 mg, 3.9 mmol). The reaction mixture was stirred at room temperature for 2 hours, and diluted with dichloromethane (100 mL). The organic phase was washed with water (100 mL) and brine (50 mL), dried over sodium sulfate, filtered and concentrated. The residue was purified by silica gel chromatography (etroleum ether/ethyl acetate=4:1˜2:1) to give benzyl 4-(5-benzoylpyrimidin-2-yl)piperazine-1-carboxylate (600 mg, 57%) as a yellow solid. MS (ES+) C23H22N4O3 requires: 402, found: 403 [M+H]+.
Reaction SMILES: [C:1]1([C:7]2[CH:25]=[C:24]3[C:10]([C:11](=[O:27])[C:12](=[O:26])[C:13]4[S:23][CH2:22][C:16]5([CH2:21][CH2:20][NH:19][CH2:18][CH2:17]5)[O:15][C:14]=43)=[CH:9][CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Cl:28][C:29]1[CH:39]=[CH:38][C:32]([O:33][CH2:34][C@@H:35]2[CH2:37][O:36]2)=[CH:31][CH:30]=1>>[Cl:28][C:29]1[CH:39]=[CH:38][C:32]([O:33][CH2:34][C@@H:35]([OH:36])[CH2:37][N:19]2[CH2:20][CH2:21][C:16]3([O:15][C:14]4[C:24]5[C:10]([C:11](=[O:27])[C:12](=[O:26])[C:13]=4[S:23][CH2:22]3)=[CH:9][CH:8]=[C:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[CH:25]=5)[CH2:17][CH2:18]2)=[CH:31][CH:30]=1
Reactant: O=C1C(=O)c2ccc(-c3ccccc3)cc2C2=C1SCC1(CCNCC1)O2
Reactant: Clc1ccc(OC[C@@H]2CO2)cc1
Product: O=C1C(=O)c2ccc(-c3ccccc3)cc2C2=C1SCC1(CCN(C[C@H](O)COc3ccc(Cl)cc3)CC1)O2

Procedure:
Compound 226 was synthesized using 9-phenylspiro[naphtho[1,2-b][1,4]oxathiine-2,4′-piperidine]-5,6-dione, (2S)-2-[(4-chlorophenoxy)methyl]oxirane and conditions outlined in procedure Z. M.p.=93-98° C.; 400 MHz 1H NMR (DMSO-d6) δ: 8.01-7.97 (m, 2H), 7.87 (dd, J=1.6, 7.6 Hz, 1H), 7.77 (d, J=7.2 Hz, 2H), 7.59-7.47 (m, 3H), 7.31 (d, J=9.2 Hz, 2H), 6.96 (d, J=9.2 Hz, 2H), 4.90 (d, J=4.0 Hz, 1H), 4.04-3.90 (m, 2H), 3.90-3.84 (m, 1H), 3.11 (s, 2H), 2.88-2.72 (m, 2H), 2.52-2.38 (m, 4H), 2.03 (d, J=14.0 Hz, 2H), 1.88-1.80 (m, 2H); LCMS: 562 [M+H].
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([F:20])=[C:6]([C@:8]2([CH3:19])[C:13]([F:15])([F:14])[C:12]([CH3:17])([CH3:16])[O:11][C:10]([NH2:18])=[N:9]2)[CH:7]=1.[F:21][C:22]([F:33])([F:32])[C:23]1[CH:24]=[CH:25][C:26]([C:29](O)=[O:30])=[N:27][CH:28]=1>>[NH2:18][C:10]1[O:11][C:12]([CH3:16])([CH3:17])[C:13]([F:14])([F:15])[C@:8]([C:6]2[CH:7]=[C:2]([NH:1][C:29]([C:26]3[CH:25]=[CH:24][C:23]([C:22]([F:33])([F:21])[F:32])=[CH:28][N:27]=3)=[O:30])[CH:3]=[CH:4][C:5]=2[F:20])([CH3:19])[N:9]=1
Reactant: CC1(C)OC(N)=N[C@](C)(c2cc(N)ccc2F)C1(F)F
Reactant: O=C(O)c1ccc(C(F)(F)F)cn1
Product: CC1(C)OC(N)=N[C@](C)(c2cc(NC(=O)c3ccc(C(F)(F)F)cn3)ccc2F)C1(F)F

Procedure:
The condensation of (R)-4-(5-amino-2-fluoro-phenyl)-5,5-difluoro-4,6,6-trimethyl-5,6-dihydro-4H-[1,3]oxazin-2-ylamine (intermediate XI-2) and 5-trifluoromethyl-pyridine-2-carboxylic acid following procedure I yielded the title compound as a white foam. MS (ISP): m/z=461.2 [M+H]+.
Reaction SMILES: C[O:2][C:3]([C:5]1[C:6]([OH:36])=[C:7]2[C:12](=[C:13]([C:15]3[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=3)[N:14]=1)[N:11]([CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[C:10](=[O:28])[C:9]([CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)=[CH:8]2)=O.[NH2:37][CH2:38][CH2:39][C:40]([OH:42])=[O:41].C[O-].[Na+]>>[CH2:21]([N:11]1[C:12]2[C:7](=[C:6]([OH:36])[C:5]([C:3]([NH:37][CH2:38][CH2:39][C:40]([OH:42])=[O:41])=[O:2])=[N:14][C:13]=2[C:15]2[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=2)[CH:8]=[C:9]([CH2:29][C:30]2[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=2)[C:10]1=[O:28])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: NCCC(=O)O
Reactant: COC(=O)c1nc(-c2cccnc2)c2c(cc(Cc3ccccc3)c(=O)n2Cc2ccccc2)c1O
Agent: C[O-]
Agent: [Na+]
Product: O=C(O)CCNC(=O)c1nc(-c2cccnc2)c2c(cc(Cc3ccccc3)c(=O)n2Cc2ccccc2)c1O
Temperature: 25 °C
Yield: 74.8 %

Procedure:
A mixture of 1,3-dibenzyl-5-hydroxy-2-oxo-8-pyridin-3-yl-1,2-dihydro-[1,7]naphthyridine-6-carboxylic acid methyl ester (24 mg, 0.050 mmol), β-alanine (2.39 g, 26.8 mmol) and NaOMe solution (40 mL, 20 mmol, 0.5 M in MeOH) was refluxed for 16 h. After the mixture was cooled to r.t., the solvent was evaporated in vacuo. The residue was dissolved in saturated NaHCO3 and washed with ether. The aqueous layer was acidified to pH about 3, and the resulting mixture was extracted with EtOAc. The organic layer was dried over MgSO4 and concentrated. The residue was further purified by silica gel chromatography (0-80% EtOAc/hexanes+2% AcOH) to give 20 mg of the title compound. MS: (+) m/z 535.21 (M+1).