Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH:15]=1)[C:7](=[O:14])[C:8]([C:11]([OH:13])=O)=[CH:9][N:10]=2.C(N(CC)CC)C.ClC(OC)=O.[CH:28]1([NH2:33])[CH2:32][CH2:31][CH2:30][CH2:29]1>C(Cl)(Cl)Cl>[CH:28]1([NH:33][C:11]([C:8]2[C:7](=[O:14])[N:6]3[CH:15]=[C:2]([CH3:1])[CH:3]=[CH:4][C:5]3=[N:10][CH:9]=2)=[O:13])[CH2:32][CH2:31][CH2:30][CH2:29]1
Reactant: NC1CCCC1
Reactant: Cc1ccc2ncc(C(=O)O)c(=O)n2c1
Agent: COC(=O)Cl
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: Cc1ccc2ncc(C(=O)NC3CCCC3)c(=O)n2c1
Reaction time: 0.08 h
Yield: 49.1 %

Procedure:
A mixture containing 1.22 g (0.006 mol) of 7-methyl-4-oxo-4H-pyrido[1,2-a]pyrimidine-3-carboxylic acid and 0.84 ml (0.006 mol) of triethylamine in 40 ml of chloroform is cooled below -10° C. by ice-salt. A solution of 0.46 ml (0.006 mol) of methyl chloroformate in 3 ml of chloroform is dropped to the above mixture at -18° C. during 10 minutes. After stirring for 5 minutes, 0.56 g (0.0066 mol) of cyclopentylamine dissolved in 6 ml of chloroform is dropped to the above solution which is then stirred at -10° C. for 1 hour and allowed to stand overnight under cooling by ice. For working up, the reaction mixture is washed 3 times with 15 ml of 5% sodium hydrogen carbonate solution each, then 3 times with 15 ml of water each. The organic phase is dried over anhydrous sodium sulfate, filtered and evaporated to give 0.8 g (49.2%) of the named compound as white crystals after recrystallization from ethanol, m.p.: 162°-164° C.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([N:8]2[CH2:29][CH2:28][C:11]3([CH2:15][N:14](C(OC(C)(C)C)=O)[C@H:13]([C:23]([O:25][CH2:26][CH3:27])=[O:24])[CH2:12]3)[CH2:10][CH2:9]2)[CH:5]=[C:4]([O:30][CH2:31][C:32]2[CH:37]=[CH:36][C:35]([Cl:38])=[CH:34][C:33]=2[C:39]2[CH:44]=[CH:43][CH:42]=[C:41]([S:45]([CH3:48])(=[O:47])=[O:46])[CH:40]=2)[N:3]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH2:1][C:2]1[N:7]=[C:6]([N:8]2[CH2:29][CH2:28][C:11]3([CH2:15][NH:14][C@H:13]([C:23]([O:25][CH2:26][CH3:27])=[O:24])[CH2:12]3)[CH2:10][CH2:9]2)[CH:5]=[C:4]([O:30][CH2:31][C:32]2[CH:37]=[CH:36][C:35]([Cl:38])=[CH:34][C:33]=2[C:39]2[CH:44]=[CH:43][CH:42]=[C:41]([S:45]([CH3:48])(=[O:46])=[O:47])[CH:40]=2)[N:3]=1
Reactant: CCOC(=O)[C@@H]1CC2(CCN(c3cc(OCc4ccc(Cl)cc4-c4cccc(S(C)(=O)=O)c4)nc(N)n3)CC2)CN1C(=O)OC(C)(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCOC(=O)[C@@H]1CC2(CCN(c3cc(OCc4ccc(Cl)cc4-c4cccc(S(C)(=O)=O)c4)nc(N)n3)CC2)CN1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of (S)-2-tert-butyl 3-ethyl 8-(2-amino-6-((5-chloro-3′-(methylsulfonyl)-[1,1′-biphenyl]-2-yl)methoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-2,3-dicarboxylate (200 mg, 0.25 mmol) in CH2Cl2 (5 ml) was added TFA (3 mL), and the resulting mixture was stirred at RT for 1 h. The reaction mixture was concentrated in vacuo, and the residue was partitioned between CH2Cl2 and saturated NaHCO3. The organic layer was dried over Na2SO4, filtered, and concentrated in vacuo. Purification by prep-TLC (CH2Cl2/MeOH) provided (S)-ethyl 8-(2-amino-6-((5-chloro-3′-(methylsulfonyl)-[1,1′-biphenyl]-2-yl)methoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylate as an off-white solid.
Reaction SMILES: [CH2:1]([NH:3][CH2:4][CH:5]([N:7]1[C:20]2[CH:19]=[C:18]([C:21]#[N:22])[CH:17]=[CH:16][C:15]=2[S:14][C:13]2[C:8]1=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH3:6])[CH3:2].C(=O)([O-])[O-].[Na+].[Na+].I[CH2:30][CH3:31]>CN(C)C=O>[CH2:1]([N:3]([CH2:30][CH3:31])[CH2:4][CH:5]([N:7]1[C:20]2[CH:19]=[C:18]([C:21]#[N:22])[CH:17]=[CH:16][C:15]=2[S:14][C:13]2[C:8]1=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH3:6])[CH3:2]
Reactant: CCNCC(C)N1c2ccccc2Sc2ccc(C#N)cc21
Reactant: CCI
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCN(CC)CC(C)N1c2ccccc2Sc2ccc(C#N)cc21
Temperature: 150 °C

Procedure:
A mixture of 10-(1-ethylamino-2-propyl)-2-phenothiazinecarbonitrile acid fumarate, D series (4 g), sodium carbonate (1.32 g) and iodoethane (1 cc) in dimethylformamide (50 cc) is heated to a temperature in the region of 150° C. for 6 hours. After cooling, the reaction mixture is concentrated to dryness (30 m Hg; 4 kPa) at 50° C. and the residue is taken up with ethyl acetate (100 cc) and washed successively with distilled water (50 cc) and with saturated aqueous sodium chloride solution (50 cc). The organic phase is dried over magnesium sulphate, filtered and concentrated to dryness under reduced pressure (30 mm Hg; 4 kPa) at 40° C. 10-(1-diethylamino-2-propyl)-2-phenothiazinecarbonitrile, D series (3.4 g) is thereby obtained in the form of a yellow oil.
Reaction SMILES: [H-].[Na+].[N+:3]([C:6]1[C:14]2[N:13]=[CH:12][NH:11][C:10]=2[CH:9]=[CH:8][CH:7]=1)([O-:5])=[O:4].F[C:16]1[CH:23]=[CH:22][C:19]([C:20]#[N:21])=[CH:18][CH:17]=1.O>CN(C=O)C>[N+:3]([C:6]1[C:14]2[N:13]=[CH:12][N:11]([C:16]3[CH:23]=[CH:22][C:19]([C:20]#[N:21])=[CH:18][CH:17]=3)[C:10]=2[CH:9]=[CH:8][CH:7]=1)([O-:5])=[O:4]
Reactant: O=[N+]([O-])c1cccc2[nH]cnc12
Reactant: N#Cc1ccc(F)cc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: N#Cc1ccc(-n2cnc3c([N+](=O)[O-])cccc32)cc1
Reaction time: 1 h
Yield: 83.9 %

Procedure:
To a stirred suspension of sodium hydride (665 mg, 16.64 mmol) in DMF (90 mL) at rt was added 4-nitro-1H-benzimidazole (2714 mg, 16.64 mmol) in several portions. After stirring for 1 h, 4-fluorobenzonitrile (1350 mg, 11.146 mmol) was added and the mixture was stirred for 15 h at 130° C. After cooling, water was added, the precipitate was filtered off, washed with water and dried to yield 4-(4-nitro-benzoimidazol-1-yl)-benzonitrile (2.47 g, 47.76%).
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([CH:10]3[CH:19]([C:20]([O:22][CH3:23])=[O:21])[C:18](=[O:24])[C:17]4[C:12](=[CH:13][CH:14]=[C:15]([O:25][CH2:26][CH2:27][CH2:28][CH3:29])[CH:16]=4)[O:11]3)=[CH:9][C:4]=2[O:3][CH2:2]1.[C:30]1(P(C2C=CC=CC=2)C2C=CC=CC=2)[CH:35]=CC=C[CH:31]=1.C(O)(C)C.CCOC(/N=N/C(OCC)=O)=O>C1COCC1>[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([CH:10]3[C:19]([C:20]([O:22][CH3:23])=[O:21])=[C:18]([O:24][CH:30]([CH3:35])[CH3:31])[C:17]4[C:12](=[CH:13][CH:14]=[C:15]([O:25][CH2:26][CH2:27][CH2:28][CH3:29])[CH:16]=4)[O:11]3)=[CH:9][C:4]=2[O:3][CH2:2]1
Reactant: CCCCOc1ccc2c(c1)C(=O)C(C(=O)OC)C(c1ccc3c(c1)OCO3)O2
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Agent: CCOC(=O)/N=N/C(=O)OCC
Solvent: C1CCOC1
Solvent: CC(C)O
Product: CCCCOc1ccc2c(c1)C(OC(C)C)=C(C(=O)OC)C(c1ccc3c(c1)OCO3)O2
Temperature: -10 °C
Reaction time: 2 h

Procedure:
The compound (VII-3) was converted to methyl 2-(benzo[1,3]dioxol-5-yl)-6-butoxy-4-oxo-chroman-3-carboxylate (IV-3) by a similar method as Step 5 of Reference Example 2. Compound (V-3) (250 mg, 0.628 mmol), triphenylphosphine (247 mg, 0.943 mmol) and isopropanol (57 mg, 0.943 mmol) were dissolved in 7 ml of THF and cooled to −10° C. A solution of diethylazodicarboxylate (164 mg, 0.943 mmol) in THF (2 ml) was added dropwise and stirred for 2 h at the same temperature. After the solvent was removed under reduced pressure, the residue was purified by 10 g of silica gel chromatography (ethyl acetate/hexane=1:4) to give the compound (Ia-11) (220 mg, 80%) as a yellow oil.
Reaction SMILES: [F:1][C:2]([F:9])([F:8])[C:3](=[CH2:7])[C:4]([OH:6])=[O:5].[C:10]1([NH:16][C:17]([NH2:19])=[O:18])[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>CN(C=O)C>[OH:5][C:4]([CH:3]([C:2]([F:9])([F:8])[F:1])[CH2:7][NH:19][C:17]([NH:16][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)=[O:18])=[O:6]
Reactant: NC(=O)Nc1ccccc1
Reactant: C=C(C(=O)O)C(F)(F)F
Solvent: CN(C)C=O
Product: O=C(NCC(C(=O)O)C(F)(F)F)Nc1ccccc1
Temperature: 90 °C
Reaction time: 8 h
Yield: 78.9 %

Procedure:
A mixture of α-trifluoromethylacrylic acid (700 mg; 5.0 mmoles) and phenylurea (776 mg; 5.7 mmoles) in DMF (5 ml) was heated at 90° C. with stirring for 8 hours. DMF was evaporated under reduced pressure, and the residue was purified by a column chromatography on silica gel (ethyl acetate) to give 1.09 g (yield: 79%) of 1-(2-hydroxycarbonyl-3,3,3-trifluoropropyl)-3-phenylurea. m.p.: 180.5°-181° C.
Reaction SMILES: [H-].[Na+].[C:3]([O:7][C:8](=[O:20])[NH:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[N:17]=[N+:18]=[N-:19])([CH3:6])([CH3:5])[CH3:4].Br[CH2:22][C:23]#[C:24][C:25]1[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=1>CCCCCC.CN(C=O)C>[C:3]([O:7][C:8]([N:9]1[CH2:22][C:23]2[N:17]([N:18]=[N:19][C:24]=2[C:25]2[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=2)[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[CH2:10]1)=[O:20])([CH3:6])([CH3:4])[CH3:5]
Reactant: Fc1ccc(C#CCBr)cc1
Reactant: CC(C)(C)OC(=O)NCc1ccccc1N=[N+]=[N-]
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCCCCC
Product: CC(C)(C)OC(=O)N1Cc2ccccc2-n2nnc(-c3ccc(F)cc3)c2C1
Reaction time: 0.5 h
Yield: 18.4 %

Procedure:
Sodium hydride (80.0 mg, 2.0 mmol; 60% suspension in mineral oil) was washed with hexane (2 mL) in a flame dried round bottomed flask under nitrogen atmosphere. To the resulting free floating powder, was added a solution of (2-azido-benzyl)-carbamic acid tert-butyl ester (250 mg, 1.0 mmol) in dry DMF (3 mL) dropwise at 0° C. under nitrogen atmosphere. The reaction mixture was stirred at this temperature for 30 min followed by dropwise addition of a solution of 1-(3-bromo-prop-1-ynyl)-4-fluoro-benzene (318.0 mg, 1.50 mmol) in dry DMF (1.5 mL). The reaction mixture was stirred at r.t. for 2 h. After the completion of the reaction as confirmed by TLC, the crude compound was extracted with ethylacetate (2×10 mL). The combined organic layer was washed with water (2×10 mL). Organic layer was separated, dried over Na2SO4 and concentrated in vacuo to afford the crude compound which was purified by column chromatography (silica gel, 1:9 EtOAc:Pet.Ether) to afford 3-(4-fluoro-phenyl)-4H,6H-1,2,5,10b-tetraaza-benzo[e]azulene-5-carboxylic acid tert-butyl ester (70 mg, 12.2%) as a viscous oil.
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[CH:9][C:8]([N:11]([CH3:20])[S:12]([C:15]2[S:16][CH:17]=[CH:18][CH:19]=2)(=[O:14])=[O:13])=[C:7]2[C:3]=1[CH:4]=[C:5]([C:21](=[S:23])[NH2:22])[NH:6]2.Br[CH2:25][CH:26](OCC)OCC.CN(C)C(=O)C>C(OCC)(=O)C>[CH3:20][N:11]([C:8]1[CH:9]=[CH:10][C:2]([CH3:1])=[C:3]2[C:7]=1[NH:6][C:5]([C:21]1[S:23][CH:25]=[CH:26][N:22]=1)=[CH:4]2)[S:12]([C:15]1[S:16][CH:17]=[CH:18][CH:19]=1)(=[O:14])=[O:13]
Reactant: CCOC(CBr)OCC
Reactant: Cc1ccc(N(C)S(=O)(=O)c2cccs2)c2[nH]c(C(N)=S)cc12
Solvent: CC(=O)N(C)C
Solvent: CCOC(C)=O
Product: Cc1ccc(N(C)S(=O)(=O)c2cccs2)c2[nH]c(-c3nccs3)cc12
Yield: 43 %

Procedure:
A mixed solution of 4-methyl-7-[methyl(2-thienylsulfonyl)amino]-1H-indole-2-carbothioamide (0.20 g), 1-bromo-2,2-diethoxyethane (0.23 mL) and N,N-dimethylacetamide (10 ml) was stirred at 100° C. for 6 hr. The reaction solution was diluted with ethyl acetate, washed with water and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained residue was subjected to silica gel column chromatography (ethyl acetate:hexane=25:75-35:65), and the obtained oil was crystallized from ethyl acetate-hexane to give the title compound (92 mg, yield 43%) as pale-yellow prism crystals. melting point 159-160° C.
Reaction SMILES: C(OC([N:8]([CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][C:37]([F:40])([F:39])[F:38])[C:9]1[CH:21]=[CH:20][C:12]([C:13](C2N=CNC=2)=[O:14])=[CH:11][CH:10]=1)=O)(C)(C)C.[OH-].[Na+].[NH2:43][CH2:44][CH:45]([OH:48])[CH2:46][OH:47]>C(Cl)(Cl)Cl>[OH:48][CH:45]([CH2:46][OH:47])[CH2:44][NH:43][C:13](=[O:14])[C:12]1[CH:11]=[CH:10][C:9]([NH:8][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][C:37]([F:38])([F:39])[F:40])=[CH:21][CH:20]=1
Reactant: CC(C)(C)OC(=O)N(CCCCCCCCCCCCCCCC(F)(F)F)c1ccc(C(=O)c2c[nH]cn2)cc1
Reactant: NCC(O)CO
Agent: [Na+]
Agent: [OH-]
Solvent: ClC(Cl)Cl
Product: O=C(NCC(O)CO)c1ccc(NCCCCCCCCCCCCCCCC(F)(F)F)cc1
Temperature: 40 °C
Reaction time: 24 h

Procedure:
To a mixture containing 4.3 g. of 1-{4-[N-(tert-butyloxycarbonyl)-4-[15-(trifluoromethyl)pentadecylamino]benzoyl}imidazole, 50 ml. of chloroform, and 50 ml. of 5 N sodium hydroxide is added 1.1 g. of 3-amino-1,2-propanediol. The solution is vigorously stirred for 24 hours, the layers are separated, and the chloroform solution is washed once with 50 ml. of 1 N sodium hydroxide. The solvent is evaporated and the residue is heated for 30 minutes at 40° C. in 50 ml. of anhydrous trifluoroacetic acid. The solvent is again evaporated and the oil is crystallized from acetone to yield the product as a light yellow solid.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH:8]1[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]1>C1(C)C=CC=CC=1>[C:2]1([N:8]2[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C1CCNCC1
Reactant: Clc1ccccc1
Solvent: Cc1ccccc1
Product: c1ccc(N2CCCCC2)cc1
Temperature: 25 °C
Yield: 43.4 %

Procedure:
A 50 mL of reactor equipped with magnetic stir bar was charged with 340 mg (0.50 mmol) of {[(t-Bu)2P(OH)]PdCl2}2 (from Experiment 8), 1.12 g (10.0 mmol) of chlorobenzene, 1.02 g (12.0 mmol) of piperidine and 1.35 g (14.0 mmol) of NaO(t-Bu) in 20.0 mL of toluene. The resulting mixture was refluxed for 16 h before the reaction was cooled to room temperature and quenched with 50 mL of H2O. The mixture was transferred to a separatory funnel, and diluted with 300 mL of diethyl ether. The layers were separated, and organic layer was washed with H2O (2×30 mL), brine (30 mL), and dried over mgSO4, filtered, and the ether removed from the filtrate by rotary evaporation. The resulting residue was chromatographed on silicon gel with hexane/ethyl acetate (50:1 volume ratio). The eluate was concentrated by rotary evaporation followed by high vacuum to give 700 mg (43% yield) of 1-phenylpiperidine.
Reaction SMILES: [OH:1][CH2:2][CH2:3][O:4][C:5]1[N:10]=[C:9](S(C)(=O)=O)[N:8]=[C:7]([NH:15][S:16](=[O:26])(=[O:25])[NH:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:6]=1[O:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=1[O:34][CH3:35].[NH:36]1[CH2:41][CH2:40][O:39][CH2:38][CH2:37]1.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>C1COCC1>[OH:1][CH2:2][CH2:3][O:4][C:5]1[N:10]=[C:9]([N:36]2[CH2:41][CH2:40][O:39][CH2:38][CH2:37]2)[N:8]=[C:7]([NH:15][S:16](=[O:26])(=[O:25])[NH:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:6]=1[O:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=1[O:34][CH3:35]
Reactant: C1COCCN1
Reactant: COc1ccccc1Oc1c(NS(=O)(=O)NCc2ccccc2)nc(S(C)(=O)=O)nc1OCCO
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Solvent: C1CCOC1
Product: COc1ccccc1Oc1c(NS(=O)(=O)NCc2ccccc2)nc(N2CCOCC2)nc1OCCO
Temperature: 45 °C
Reaction time: 48 h

Procedure:
Benzylsulfamic acid [6-(2-hydroxy-ethoxy)-2-methanesulfonyl-5-(2-methoxy-phenoxy)-pyrimidin-4-yl]-amide (85 mg) were dissolved in THF (2 ml) and morpholine (2 ml) was added. The reaction mixture was stirred at 45° C. for 48 hours, poured onto water, acidified with solid citric acid and extracted with EtOAc (2×). The combined EtOAc layers were washed with 10% citric acid solution and with brine, dried over magnesium sulfate, filtered and the solvent was evaporated. The crude product was purified by chromatography on plates with toluene/EtOAc=1/1 to give benzylsulfamic acid [6-(2-hydroxy-ethoxy)-5-(2-methoxy-phenoxy)-2-morpholin-4-yl-pyrimidin-4-yl]-amide (Example 205) (60 mg). LC-MS: tR=4.69; [M+H]+=532.15.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([CH:8]=O)[CH:5]=[CH:4][N:3]=1.C(O)(=O)[CH2:11][C:12]([OH:14])=[O:13].N1CCCCC1>N1C=CC=CC=1>[Br:1][C:2]1[CH:7]=[C:6]([CH:8]=[CH:11][C:12]([OH:14])=[O:13])[CH:5]=[CH:4][N:3]=1
Reactant: O=Cc1ccnc(Br)c1
Reactant: O=C(O)CC(=O)O
Solvent: c1ccncc1
Solvent: C1CCNCC1
Product: O=C(O)C=Cc1ccnc(Br)c1
Temperature: 100 °C
Reaction time: 1 h
Yield: 74.2 %

Procedure:
2-Bromo-pyridin-4-carbaldehyde (20.0 g, 107.5 mmol), malonic acid (25.2 g, 241.9 mmol), and piperidine (8.8 mL, 89.2 mmol) were added to pyridine (65.2 mL). The reaction mixture was stirred at 100° C. for 1 hour, concentrated under reduced pressure, and then distilled water was added thereto. The mixture was filtered and then the resulting solid dried under reduced pressure to give 18.2 g of the titled compound as a white solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1[CH:14]=[CH:13][C:12]([CH:15]([CH3:20])[CH2:16][C:17](Cl)=[O:18])=[CH:11][CH:10]=1.[CH2:21]([OH:24])[CH2:22][CH3:23]>>[CH2:21]([O:24][C:17](=[O:18])[CH2:16][CH:15]([C:12]1[CH:11]=[CH:10][C:9]([C:3]2[CH:4]=[CH:5][C:6]([F:8])=[CH:7][C:2]=2[F:1])=[CH:14][CH:13]=1)[CH3:20])[CH2:22][CH3:23]
Reactant: CCCO
Reactant: CC(CC(=O)Cl)c1ccc(-c2ccc(F)cc2F)cc1
Product: CCCOC(=O)CC(C)c1ccc(-c2ccc(F)cc2F)cc1

Procedure:
1 g. of crude 3-(2',4'-difluoro-4-biphenylyl)butyryl chloride and 10 ml. of n-propanol are warmed to 95° for 3 hours and the mixture is evaporated and worked up in the customary manner to give 3-(2',4'-difluoro-4-biphenylyl)butyric acid n-propyl ester.
Reaction SMILES: [CH3:1][C:2]([CH3:29])([CH3:28])[CH2:3][N:4]1[C:12]2[C:7](=[N:8][C:9]([C:13]3[CH2:18][N:17]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:16][CH2:15][CH:14]=3)=[CH:10][CH:11]=2)[N:6]([CH3:26])[C:5]1=[O:27].[H][H]>[Pd].CCO>[CH3:1][C:2]([CH3:29])([CH3:28])[CH2:3][N:4]1[C:12]2[C:7](=[N:8][C:9]([CH:13]3[CH2:14][CH2:15][CH2:16][N:17]([C:19]([O:21][C:22]([CH3:24])([CH3:23])[CH3:25])=[O:20])[CH2:18]3)=[CH:10][CH:11]=2)[N:6]([CH3:26])[C:5]1=[O:27]
Reactant: [H][H]
Reactant: Cn1c(=O)n(CC(C)(C)C)c2ccc(C3=CCCN(C(=O)OC(C)(C)C)C3)nc21
Agent: [Pd]
Solvent: CCO
Product: Cn1c(=O)n(CC(C)(C)C)c2ccc(C3CCCN(C(=O)OC(C)(C)C)C3)nc21
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a round bottom flask containing tert-butyl 5-[1-(2,2-dimethylpropyl)-3-methyl-2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyridin-5-yl]-3,6-dihydropyridine-1(2H)-carboxylate (17-27) (1 g, 2.497 mmol), was added EtOH (25 mL) & Palladium on Carbon (10% by weight on carbon) (0.25 g, 0.2349 mmol). A balloon containing hydrogen gas was then attached and purged 3× with vacuum/hydrogen. The reaction mixture was permitted to stir at room temperature for 1 hour, then purged 3× with vacuum/nitrogen, diluted with EtOH, filtered & concentrated to yield tert-butyl 3-[1-(2,2-dimethylpropyl)-3-methyl-2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyridin-5-yl]piperidine-1-carboxylate (18-1). LRMS (M+H)+: observed=403.3, calculated=403.5.
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8]([O:10]C2C=CC([N+]([O-])=O)=CC=2)=O)=[C:6]([O:20][C:21]2[N:26]=[C:25]([O:27][CH3:28])[CH:24]=[C:23]([O:29][CH3:30])[N:22]=2)[CH:5]=[CH:4][CH:3]=1.[CH3:31][CH:32]([S:34]([NH2:37])(=[O:36])=[O:35])[CH3:33].C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[Cl:1][C:2]1[C:7]([C:8]([NH:37][S:34]([CH:32]([CH3:33])[CH3:31])(=[O:36])=[O:35])=[O:10])=[C:6]([CH:5]=[CH:4][CH:3]=1)[O:20][C:21]1[N:22]=[C:23]([O:29][CH3:30])[CH:24]=[C:25]([O:27][CH3:28])[N:26]=1
Reactant: CC(C)S(N)(=O)=O
Reactant: COc1cc(OC)nc(Oc2cccc(Cl)c2C(=O)Oc2ccc([N+](=O)[O-])cc2)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: COc1cc(OC)nc(Oc2cccc(Cl)c2C(=O)NS(=O)(=O)C(C)C)n1
Yield: 38.5 %

Procedure:
A stirred solution of 0.43 grams (0.001 mole) of 4-nitrophenyl 6-chloro-2-(4,6-dimethoxypyrimidin-2-yloxy)benzoate (prepared in Steps F and G), 0.12 gram (0.001 mole) of 1-methylethylsulfonamide, and 0.14 gram (0.001 mole) of potassium carbonate in 5 mL of acetonitrile was heated at reflux for five hours. The reaction mixture was then cooled and concentrated under reduced pressure to a residue. The residue was stirred with ethyl acetate and water, and the aqueous layer was separated. The aqueous layer was acidified with aqueous dilute hydrochloric acid and then was extracted with ethyl acetate. The extract was dried with magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure to a residue. The residue was crystallized from diethyl ether. The solid was collected by filtration to yield 0.16 gram of 2-[3-chloro-2-(1-methylethylsulfonylaminocarbonyl)phenoxy]-4,6dimethoxypyrimidine; m.p. 150°-152° C., Compound 10 in Table 1. The nmr spectrum was consistent with the proposed structure.
Reaction SMILES: [BH4-].[Na+].[CH:3]1([C:9]2[C:10]3[CH:11]=[CH:12][C:13]([C:28]([O:30][CH3:31])=[O:29])=[CH:14][C:15]=3[N:16]3[CH2:22][C:21](=[O:23])[CH2:20][C:19]4[CH:24]=[CH:25][CH:26]=[CH:27][C:18]=4[C:17]=23)[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]1>CO.O1CCCC1>[CH:3]1([C:9]2[C:10]3[CH:11]=[CH:12][C:13]([C:28]([O:30][CH3:31])=[O:29])=[CH:14][C:15]=3[N:16]3[CH2:22][CH:21]([OH:23])[CH2:20][C:19]4[CH:24]=[CH:25][CH:26]=[CH:27][C:18]=4[C:17]=23)[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8]1
Reactant: COC(=O)c1ccc2c(C3CCCCC3)c3n(c2c1)CC(=O)Cc1ccccc1-3
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Product: COC(=O)c1ccc2c(C3CCCCC3)c3n(c2c1)CC(O)Cc1ccccc1-3
Reaction time: 0.5 h
Yield: 95.4 %

Procedure:
Sodium borohydride (50 mg, 1.3 mmol) was added to a solution of methyl 13-cyclohexyl-6,7-dihydro-6-oxo-5H-indolo[2,1-a][2]benzazepine-10-carboxylate (29 mg, 0.074 mmol) in methanol (4 mL) and tetrahydrofuran (2 mL) at rt. The evolution of H2 was instantaneous and stirring was continued for 30 min at rt. The mixture was concentrated on a rotary evaporator and and the residue purified on the Shimadzu preparative liquid chromatograph. The product containing fraction was concentrated on a Speed Vac® to leave the titled compound as a white solid (27.5 mg, 96%). ESI-MS m/z 390 (MH+); 1H NMR (500 MHz, CHLOROFORM-D) δ 1.18-1.31 (m, 1 H) 1.32-1.53 (m, 2 H) 1.60-1.70 (m, 1 H) 1.71-1.84 (m, 2 H) 1.86-2.18 (m, 4 H) 2.38-3.12 (m, 3 H) 3.36-3.83 (m, 1 H) 3.94 (m, 3 H) 4.39-4.68 (m, 2 H) 7.32-7.48 (m, 4 H) 7.76 (t, J=8.39 Hz, 1 H) 7.88 (t, J=8.09 Hz, 1 H) 8.14 (m, 1 H).
Reaction SMILES: [C:1]12([OH:11])[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.[C:12](Cl)(=[O:15])[CH:13]=[CH2:14]>>[C:12]([O:11][C:1]12[CH2:8][CH:7]3[CH2:6][CH:5]([CH2:4][CH:3]([CH2:9]3)[CH2:2]1)[CH2:10]2)(=[O:15])[CH:13]=[CH2:14]
Reactant: OC12CC3CC(CC(C3)C1)C2
Reactant: C=CC(=O)Cl
Product: C=CC(=O)OC12CC3CC(CC(C3)C1)C2

Procedure:
1-Adamantanol and acrylic acid chloride were subjected to desalting reaction by using a basic catalyst to obtain adamantyl acrylate (Compound (III-h)).
Reaction SMILES: Cl.Cl.[NH2:3][C:4]1([CH2:10][NH:11][C:12](=[O:20])[C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=2)[CH2:9][CH2:8][NH:7][CH2:6][CH2:5]1.Cl[C:22]1[C:23]2[CH:30]=[CH:29][NH:28][C:24]=2[N:25]=[CH:26][N:27]=1.C(N(CC)CC)C>C(O)CCC>[NH2:3][C:4]1([CH2:10][NH:11][C:12](=[O:20])[C:13]2[CH:14]=[CH:15][C:16]([Cl:19])=[CH:17][CH:18]=2)[CH2:9][CH2:8][N:7]([C:22]2[C:23]3[CH:30]=[CH:29][NH:28][C:24]=3[N:25]=[CH:26][N:27]=2)[CH2:6][CH2:5]1
Reactant: NC1(CNC(=O)c2ccc(Cl)cc2)CCNCC1
Reactant: Clc1ncnc2[nH]ccc12
Agent: Cl
Solvent: CCCCO
Solvent: CCN(CC)CC
Product: NC1(CNC(=O)c2ccc(Cl)cc2)CCN(c2ncnc3[nH]ccc23)CC1
Temperature: 100 °C
Reaction time: 17 h
Yield: 56.3 %

Procedure:
A degassed mixture of crude N-(4-amino-piperidin-4-ylmethyl)-4-chloro-benzamide dihydrochloride (6.1 mg), 4-chloro-7H-pyrrolo[2,3-d]pyrimidine (2.6 mg, 0.016 mmol), triethylamine (16 μL, 0.09 mmol) and n-butanol (0.3 mL) was stirred at 100° C. for 17 hours. The solvents were concentrated. The crude mixture was first purified on an SCX-II acidic resin, eluting with methanol then 2M ammonia-methanol, and then by preparative TLC, eluting with 15% methanol-dichloromethane, to give N-[4-amino-1-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-piperidin-4-ylmethyl]-4-chloro-benzamide (3.3 mg, 0.009 mmol, 69% over 2 steps).
Reaction SMILES: [CH2:1]([NH:5][C:6]1[C:7]([C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:8][C:9]2[C:10]([N:16]=1)=[CH:11][N:12]=[N:13][C:14]=2O)[CH2:2][CH2:3][CH3:4].P(Cl)(Cl)([Cl:24])=O>>[CH2:1]([NH:5][C:6]1[C:7]([C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:8][C:9]2[C:10]([N:16]=1)=[CH:11][N:12]=[N:13][C:14]=2[Cl:24])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCNc1nc2cnnc(O)c2cc1C(=O)OCC
Reactant: O=P(Cl)(Cl)Cl
Product: CCCCNc1nc2cnnc(Cl)c2cc1C(=O)OCC

Procedure:
5.8 g of 2-butylamino-5-hydroxy-pyrido[2,3-d]pyridazine-3-carboxylic acid, ethyl ester (0.02 mol) are treated with 20 ml of phosphorous oxychloride for 5 days at room temperature with permanent stirring. The excess of phosphorous oxychloride in distilled off in vacuo and the remaining residue is extracted with 20 ml of hot ethyl acetate. 2-butylamino-5-chloro-pyrido[2,3-d]pyridazine-3-carboxylic acid, ethyl ester crystallizes on cooling. Yield 5.5 g (83%); m.p. 126.7° C. (ligroin).