Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][CH:2]1[CH:7]2[CH2:8][CH2:9][N:4]([CH2:5][CH2:6]2)[CH2:3]1.CN1CCOCC1.[Cl:17][C:18]1[CH:19]=[C:20]([C:32](Cl)=[O:33])[C:21]2[O:26][CH:25]([CH2:27][CH3:28])[C:24](=[O:29])[N:23]([CH3:30])[C:22]=2[CH:31]=1>C(Cl)(Cl)Cl>[ClH:17].[Cl:17][C:18]1[CH:19]=[C:20]([C:32]([NH:1][CH:2]2[CH:7]3[CH2:8][CH2:9][N:4]([CH2:5][CH2:6]3)[CH2:3]2)=[O:33])[C:21]2[O:26][CH:25]([CH2:27][CH3:28])[C:24](=[O:29])[N:23]([CH3:30])[C:22]=2[CH:31]=1
Reactant: NC1CN2CCC1CC2
Reactant: CCC1Oc2c(C(=O)Cl)cc(Cl)cc2N(C)C1=O
Solvent: CN1CCOCC1
Solvent: ClC(Cl)Cl
Product: CCC1Oc2c(C(=O)NC3CN4CCC3CC4)cc(Cl)cc2N(C)C1=O
Product: Cl

Procedure:
To a solution of 2.43 g of 3-aminoquinuclidine and 2.5 g of N-methylmorpholine in 50 ml of chloroform is added 5.2 g of 6-chloro-2-ethyl-3,4-dihydro-4-methyl-3-oxo-2H-1,4-benzoxazine-8-carboxylic acid chloride under cooling and stirring followed by stirring for 2 hours. The resultant solution is washed with water, aqueous sodium hydrogen carbonate and then water, and dried over magnesium sulfate. After the solvent is distilled off under reduced pressure, the residue is recrystallized from ethanolisopropyl ether and treated with ethanolic hydrochloric acid to give 6-chloro-2-ethyl-3,4-dihydro-4-methyl-3-oxo-N-(3-quinuclidinyl)-2H-1,4-benzoxazine-8-carboxamide hydrochloride, melting at 295° C. with decomposition.
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[CH:8][C:7]([Cl:10])=[CH:6][C:3]=1[C:4]#[N:5].CN(C1C=CC=CN=1)C.[C:20](Cl)(=[O:23])[CH2:21][CH3:22].O>CC(N(C)C)=O>[Cl:10][C:7]1[CH:8]=[CH:9][C:2]([NH:1][C:20](=[O:23])[CH2:21][CH3:22])=[C:3]([C:4]#[N:5])[CH:6]=1
Reactant: CCC(=O)Cl
Reactant: N#Cc1cc(Cl)ccc1N
Agent: CN(C)c1ccccn1
Solvent: O
Solvent: CC(=O)N(C)C
Product: CCC(=O)Nc1ccc(Cl)cc1C#N
Reaction time: 8 h

Procedure:
(Step 1) To a solution of 2-amino-5-chlorobenzonitrile (5.0 g) and dimethylaminopyridine (0.12 g) in dimethylacetamide (25 ml) was added propionyl chloride (3.4 ml) at room temperature, and the mixture was stirred overnight. The reaction mixture was poured into water, and extracted twice with ethyl acetate. The organic layer was washed with saturated brine, dried over magnesium sulfate, and filtered. The solvent was evaporated under reduced pressure. The residue was recrystallized from ethanol and diisopropyl ether to give N-(4-chloro-2-cyanophenyl)propanamide (5.7 g).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([Br:8])=[CH:4][C:3]=1[NH:9][C:10]1[CH:15]=[CH:14][N:13]=[C:12]([NH2:16])[N:11]=1.CN([CH:20]=[O:21])C>>[NH2:16][C:12]1[N:11]=[C:10]([N:9]2[C:3]3[CH:4]=[C:5]([Br:8])[CH:6]=[CH:7][C:2]=3[NH:1][C:20]2=[O:21])[CH:15]=[CH:14][N:13]=1
Reactant: Nc1nccc(Nc2cc(Br)ccc2N)n1
Reactant: CN(C)C=O
Product: Nc1nccc(-n2c(=O)[nH]c3ccc(Br)cc32)n1
Temperature: 80 °C
Reaction time: 8 h

Procedure:
To a solution of 4-N-(2-amino-5-bromophenyl)pyrimidine-2,4-diamine (400 mg, 1.43 mmol) in DMF (4 mL) was added N,N′-carbonyldiimidazole (255 mg, 1.57 mmol). The reaction was stirred at 80° C. overnight. Another portion of N,N′-carbonyldiimidazole (69 mg, 0.43 mmol) was added and heating was continued for another 2 hr at 80° C. The reaction mixture was concentrated in vacuo, diluted with water (10 mL) and extracted with ethyl acetate (2×20 mL). The organics were dried over Na2SO4, filtered and concentrated in vacuo. The resulting yellow solid was slurried in ethyl acetate and filtered off to give the title compound as a yellow solid: 1H (500 MHz, DMSO) δ 6.93 (2H, br. s.), 7.00 (1H, d, J=8.35 Hz), 7.31 (1H, d, J=10.25 Hz), 7.45 (1H, d, J=5.67 Hz), 8.25 (1H, d, J=5.52 Hz), 8.58 (1H, s); LC-MS: m/z=+306.0, 307.9 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([CH3:11])[C:3]=1[C:4](O)=[O:5].S(Cl)([Cl:14])=O>CN(C=O)C>[CH3:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([CH3:11])[C:3]=1[C:4]([Cl:14])=[O:5]
Reactant: O=S(Cl)Cl
Reactant: Cc1cccc(C)c1C(=O)O
Solvent: CN(C)C=O
Product: Cc1cccc(C)c1C(=O)Cl
Reaction time: 2 h

Procedure:
DMF (2 drops) was added to 2,6-dimethylbenzoic acid (0.100 g, 0.666 mmol) in thionyl chloride (0.50 mL, 6.9 mmol). The reaction mixture was stirred for 2 h and concentrated to yield the titled compound, which was used in the next step without further purification.
Reaction SMILES: Br[C:2]1[N:7]2[N:8]=[C:9]([NH2:11])[N:10]=[C:6]2[CH:5]=[CH:4][CH:3]=1.[CH:12]1([NH2:17])[CH2:16][CH2:15][CH2:14][CH2:13]1>CC(N(C)C)=O.O>[CH:12]1([NH:17][C:2]2[N:7]3[N:8]=[C:9]([NH2:11])[N:10]=[C:6]3[CH:5]=[CH:4][CH:3]=2)[CH2:16][CH2:15][CH2:14][CH2:13]1
Reactant: Nc1nc2cccc(Br)n2n1
Reactant: NC1CCCC1
Solvent: CC(=O)N(C)C
Solvent: O
Product: Nc1nc2cccc(NC3CCCC3)n2n1
Temperature: 180 °C

Procedure:
To a solution of 5-bromo-[1,2,4]triazolo[1,5-a]pyridin-2-ylamine (0.5 g, 2.35 mmol) in dimethylacetamide (2 mL), cyclopentylamine (2.3 mL, 23.5 mmol) was added and the solution was heated under microwave irradiation (180° C., 180 min). The resulting mixture was diluted with water and extracted into ethyl acetate. The organics were washed with water then brine, and dried over magnesium sulfate. The solid (0.5 g) was used without further purification. LCMS1: 2.84 min, 218 [M+1].
Reaction SMILES: [N+]([O-])(O)=O.[NH2:5][NH:6][C:7]([NH2:9])=[NH:8].CO.C[O-].[Na+].[Br:15][C:16]1[CH:21]=[CH:20][C:19]([C:22]([CH3:28])([CH3:27])[C:23](OC)=O)=[CH:18][CH:17]=1>O>[Br:15][C:16]1[CH:21]=[CH:20][C:19]([C:22]([C:28]2[NH:5][N:6]=[C:7]([NH2:9])[N:8]=2)([CH3:27])[CH3:23])=[CH:18][CH:17]=1
Reactant: COC(=O)C(C)(C)c1ccc(Br)cc1
Reactant: N=C(N)NN
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Solvent: O
Solvent: O=[N+]([O-])O
Product: CC(C)(c1ccc(Br)cc1)c1nc(N)n[nH]1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 30.1 %

Procedure:
To a stirred mixture of N-aminoguanidine nitrate (2.1 g, 15 mmol) and anhydrous methanol (18 mL) cooled to 0° C. was added sodium methoxide solution (25% in methanol, 3.4 mL, 15 mmol) dropwise. The resulting mixture was stirred at 0° C. for 10 min before methyl 2-(4-bromophenyl)-2-methylpropanoate (1.0 g, 3.9 mmol) was added. The mixture was then stirred at 0° C. for 10 min, RT for 10 min, and 75 ° C. for 6 days. The reaction mixture was cooled and diluted with 20 mL of water. Methanol was removed under vacuum and the aqueous solution was acidified to pH=3-4 with 3 N aqueous HCl solution and extracted with ethyl acetate. The ethyl acetate layer was dried (Na2SO4) and concentrated. Silica gel flash chromatography purification gave 330 mg (31% yield) of the title compound as a yellow solid. (M+H)+=281.14
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[N+:9]([O-])=[CH:10][C:11]2[C:16]([CH:17]=1)=[CH:15][N:14]=[C:13]([NH:18][C:19]([CH:21]1[CH2:23][CH2:22]1)=[O:20])[CH:12]=2.P(Cl)(Cl)Cl>ClCCl>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:17]=[C:16]2[C:11]([CH:12]=[C:13]([NH:18][C:19]([CH:21]3[CH2:22][CH2:23]3)=[O:20])[N:14]=[CH:15]2)=[CH:10][N:9]=1
Reactant: O=C(Nc1cc2c[n+]([O-])c(-c3ccccc3Cl)cc2cn1)C1CC1
Solvent: ClCCl
Solvent: ClP(Cl)Cl
Product: O=C(Nc1cc2cnc(-c3ccccc3Cl)cc2cn1)C1CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 46.3 %

Procedure:
To a slurry of 3-(2-chlorophenyl)-7-(cyclopropanecarboxamido)-2,6-naphthyridine 2-oxide (170 mg, 0.5 mmol) in dichloromethane (2 mL) was added phosphorus trichloride (0.048 mL, 0.55 mmol) and the mixture was stirred at room temperature for 1 hour. The reaction mixture was then diluted with dichloromethane (50 mL) and washed with saturated sodium bicarbonate solution (30 mL). The organic layer was separated, dried over sodium sulfate, filtered, and evaporated in vacuo to afford a residue that was purified by flash chromatography (silica, 12 g, ISCO, 0-60% ethyl acetate in heptane) to afford the title compound as a white solid (75 mg, 46%). 1H NMR (400 MHz, DMSO) δ 11.17 (s, 1H), 9.46 (s, 1H), 9.35 (s, 1H), 8.66 (s, 1H), 8.23 (s, 1H), 7.76-7.67 (m, 1H), 7.63 (m, 1H), 7.55-7.43 (m, 2H), 2.14-2.06 (m, 1H), 0.88 (m, 4H). LCMS (Method D): RT=13.170 min, M+H+=324.0.
Reaction SMILES: [CH3:1][C:2]1([CH3:15])[C@@H:4]2[CH2:5][C:6]3[C:10]([C@H:3]12)=[C:9]([CH3:11])[S:8][C:7]=3[C:12]([OH:14])=O.CN(C([O:23]N1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C(N(C(C)C)C(C)C)C.[NH2:47][CH2:48][C:49]1[CH:59]=[CH:58][C:52]([O:53][CH:54](O)[CH2:55][CH3:56])=[CH:51][C:50]=1[O:60][CH3:61]>CN(C=O)C>[OH:23][CH2:56][CH2:55][CH2:54][O:53][C:52]1[CH:58]=[CH:59][C:49]([CH2:48][NH:47][C:12]([C:7]2[S:8][C:9]([CH3:11])=[C:10]3[C:6]=2[CH2:5][C@H:4]2[C:2]([CH3:1])([CH3:15])[C@H:3]23)=[O:14])=[C:50]([O:60][CH3:61])[CH:51]=1
Reactant: CCC(O)Oc1ccc(CN)c(OC)c1
Reactant: Cc1sc(C(=O)O)c2c1[C@H]1[C@@H](C2)C1(C)C
Reactant: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COc1cc(OCCCO)ccc1CNC(=O)c1sc(C)c2c1C[C@@H]1[C@H]2C1(C)C
Reaction time: 0.5 h
Yield: 42.3 %

Procedure:
A solution of (1aS,5aR)-1,1,2-trimethyl-1,1a,5,5a-tetrahydro-3-thia-cyclopropa[a]pentalene-4-carboxylic acid (8.2 mg, 0.037 mmol), TBTU (11.9 mg, 0.037 mmol) and ethyl-diisopropylamine (19 μL, 0.111 mmol) in DMF (1 mL) is allowed to stand at rt for 30 min. The solution is added to 1-(4-aminomethyl-3-methoxy-phenoxy)-propanol (7.8 mg, 0.037 mmol) and the mixture is allowed to stand at rt for 1 h. The mixture is separated by prep. HPLC to afford (1aS,5aR)-1,1,2-trimethyl-1,1a,5,5a-tetrahydro-3-thia-cyclopropa[a]pentalene-4-carboxylic acid 4-(3-hydroxy-propoxy)-2-methoxy-benzylamide (6.5 mg) as a colourless lyophilisate. LC-MS: tR=1.01 min, [M+1]+=416.12.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([C:8]([OH:10])=[O:9])[CH:5]=[CH:4][CH:3]=1.[C:11](Cl)(=O)C>CO>[NH2:1][C:2]1[N:7]=[C:6]([C:8]([O:10][CH3:11])=[O:9])[CH:5]=[CH:4][CH:3]=1
Reactant: CC(=O)Cl
Reactant: Nc1cccc(C(=O)O)n1
Solvent: CO
Product: COC(=O)c1cccc(N)n1

Procedure:
6-Aminopyridine-2-carboxylic acid (5.0 g, 36 mmol) was dissolved in 50 ml of MeOH. To this was added acetyl chloride (9.0 ml, 126 mmol) in 50 ml of MeOH. The reaction was heated to reflux overnight. Concentrate to an orange oil and partition with EtOAc and water. The organic portions were washed with brine, dried (MgSO4) and concentrated to a yellow solid.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([C:12]([F:15])([F:14])[F:13])[CH:10]=2)[CH:5]=[N:4][N:3]=1.[NH2:16][CH2:17][C:18]([NH:20][CH:21]1[CH2:24][N:23]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:22]1)=[O:19].C(N(CC)CC)C>COCCOCCOC>[F:13][C:12]([F:15])([F:14])[C:9]1[C:10]([NH:16][CH2:17][C:18]([NH:20][CH:21]2[CH2:24][N:23]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:22]2)=[O:19])=[C:11]2[C:6](=[CH:7][CH:8]=1)[CH:5]=[N:4][N:3]=[CH:2]2
Reactant: CC(C)(C)OC(=O)N1CC(NC(=O)CN)C1
Reactant: FC(F)(F)c1ccc2cnnc(Cl)c2c1
Solvent: CCN(CC)CC
Solvent: COCCOCCOC
Product: CC(C)(C)OC(=O)N1CC(NC(=O)CNc2c(C(F)(F)F)ccc3cnncc23)C1
Temperature: 100 °C
Reaction time: 8 h

Procedure:
Into a 50 mL round-bottom flask, was placed a solution of 1-chloro-7-(trifluoromethyl)phthalazine (prepared as described in the previous step, 1.5 g, 6.47 mmol, 1.00 equiv) in 2-methoxyethyl ether (10 mL), tert-butyl 3-(2-aminoacetamido)azetidine-1-carboxylate (prepared as described in Example 1, Step E) (1.5 g, 6.55 mmol, 1.22 equiv) and triethylamine (1.95 g, 19.31 mmol, 2.99 equiv). The reaction mixture was stirred overnight at 100° C. in an oil bath. The reaction progress was monitored by LCMS. The resulting mixture was concentrated under vacuum. The residue was purified by chromatography over a silica gel column with CH3CN:H2O (3:1). The title compound was obtained as a white solid.
Reaction SMILES: [H-].[Na+].[C:3]([C:5]1[CH:10]=[CH:9][C:8]([C@@:11]2([CH3:22])[C:15](=[O:16])[N:14]([CH2:17][C:18]([OH:20])=[O:19])[C:13](=[O:21])[NH:12]2)=[CH:7][CH:6]=1)#[N:4].[CH2:23](Br)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>CN(C=O)C>[C:3]([C:5]1[CH:6]=[CH:7][C:8]([C@@:11]2([CH3:22])[C:15](=[O:16])[N:14]([CH2:17][C:18]([O:20][CH2:23][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)=[O:19])[C:13](=[O:21])[N:12]2[CH2:3][C:5]2[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=2)=[CH:9][CH:10]=1)#[N:4]
Reactant: C[C@@]1(c2ccc(C#N)cc2)NC(=O)N(CC(=O)O)C1=O
Reactant: BrCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: C[C@]1(c2ccc(C#N)cc2)C(=O)N(CC(=O)OCc2ccccc2)C(=O)N1Cc1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 69 %

Procedure:
7.73 g (160.8 ,, mol) of sodium hydride were added to a solution of 20 g (73.1 mmol) of ((S)-4-(4-cyanophenyl)-4-methyl-2,5-dioxoimidazolidin-1-yl)-acetic acid in 120 ml of absolute DMF with ice-cooling. After stirring at room temperature for 30 min, 19 ml (160.8 mmol) of benzyl bromide were added. The reaction mixture was stirred at room temperature for 2 h, allowed to stand overnight, the solvent was removed in vacuo and the residue was chromatographed on silica gel using heptane/ethyl acetate (2:1). 11.43 g (35%) of 8.1 were obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[S:8][CH2:7][CH:6]([C:12]([O:14]C)=[O:13])[C:5]2=O.[Cl:17][C:18]1[CH:23]=[CH:22][C:21]([NH:24][NH2:25])=[CH:20][CH:19]=1.[Br:26][C:27]1[CH:32]=[CH:31][C:30]([NH:33][NH2:34])=[CH:29][CH:28]=1>>[Cl:1][C:2]1[CH:11]=[CH:10][C:9]2[S:8][CH2:7][C:6]3[C:12](=[O:14])[N:24]([C:21]4[CH:22]=[CH:23][C:18]([Cl:17])=[CH:19][CH:20]=4)[NH:25][C:5]=3[C:4]=2[CH:3]=1.[Cl:1][C:2]1[CH:11]=[CH:10][C:9]2[S:8][CH2:7][C:6]3[C:12](=[O:13])[N:33]([C:30]4[CH:31]=[CH:32][C:27]([Br:26])=[CH:28][CH:29]=4)[NH:34][C:5]=3[C:4]=2[CH:3]=1
Reactant: COC(=O)C1CSc2ccc(Cl)cc2C1=O
Reactant: NNc1ccc(Cl)cc1
Reactant: NNc1ccc(Br)cc1
Product: O=c1c2c([nH]n1-c1ccc(Br)cc1)-c1cc(Cl)ccc1SC2
Product: O=c1c2c([nH]n1-c1ccc(Cl)cc1)-c1cc(Cl)ccc1SC2

Procedure:
By the same procedure methyl 6-chloro-4-oxothiochroman-3-carboxylate was reacted with 4-chlorophenylhydrazine and 4-bromophenylhydrazine to yield 8-chloro-2-(4-chlorophenyl)-1,2,3,4-tetrahydro[1]benzothiopyrano[4,3-c]pyrazol-3-one (m.p. 237°-240° C.) and 8-chloro-2-(4-bromophenyl)-1,2,3,4-tetrahydro[1]benzothiopyrano[4,3-c]pyrazol-3-one (m.p. 257°-260° C.), respectively.
Reaction SMILES: [NH2:1][CH:2]([C:6]1[S:7][CH:8]=[CH:9][CH:10]=1)[C:3]([OH:5])=[O:4].[C:11](O)(=[O:13])C.O>C(O)=O>[CH:11]([NH:1][CH:2]([C:6]1[S:7][CH:8]=[CH:9][CH:10]=1)[C:3]([OH:5])=[O:4])=[O:13]
Reactant: CC(=O)O
Reactant: NC(C(=O)O)c1cccs1
Solvent: O
Solvent: O=CO
Product: O=CNC(C(=O)O)c1cccs1
Temperature: 25 °C
Reaction time: 6 h

Procedure:
To a solution of amino-thiophen-2-yl-acetic acid (5 g) in formic acid (50 ml) was added acetic acid (18 ml). After stirring at room temperature for 6 h, water (25 ml) was added. The reaction mixture was stirred for 30 min. The mixture was concentrated in vacuo and triturated with water. The solids were collected by filtration and dried in vacuo (50° C.).
Reaction SMILES: C(O[C:6]([N:8]1[CH2:12][C:11](=[N:13][O:14][CH2:15][C:16]2[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=2)[CH2:10][C@H:9]1[C:24]([OH:26])=O)=[O:7])(C)(C)C.[N:27]([C:30]1[CH:35]=[CH:34][CH:33]=[C:32]([CH3:36])[CH:31]=1)=C=O.[NH:37]1[CH2:42][CH2:41][O:40][CH2:39][CH2:38]1>>[CH3:23][O:22][C:19]1[CH:18]=[CH:17][C:16]([CH2:15][O:14][N:13]=[C:11]2[CH2:12][N:8]([C:6]([NH:27][C:30]3[CH:35]=[CH:34][CH:33]=[C:32]([CH3:36])[CH:31]=3)=[O:7])[C@H:9]([C:24]([N:37]3[CH2:42][CH2:41][O:40][CH2:39][CH2:38]3)=[O:26])[CH2:10]2)=[CH:21][CH:20]=1
Reactant: C1COCCN1
Reactant: COc1ccc(CON=C2C[C@@H](C(=O)O)N(C(=O)OC(C)(C)C)C2)cc1
Reactant: Cc1cccc(N=C=O)c1
Product: COc1ccc(CON=C2C[C@@H](C(=O)N3CCOCC3)N(C(=O)Nc3cccc(C)c3)C2)cc1

Procedure:
Following the general method as outlined in Example 22, starting from (2S,4EZ)-1-(tert-butoxycarbonyl)-4-{[(4-methoxybenzyl)oxy]imino}-2-pyrrolidinecarboxylic acid, 1-isocyanato-3-methylbenzene, and morpholine the title compound was obtained in 41% purity by LC/MS. MS(ESI+): m/z=467.4.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][C:5]([C:7]1[CH:12]=[CH:11][C:10]([C:13]([CH3:19])([CH3:18])[C:14]([O:16][CH3:17])=[O:15])=[CH:9][CH:8]=1)=[O:6].[C:20]1([C:26]([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)([CH:28]2[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]2)[OH:27])[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>C1(C)C=CC=CC=1>[ClH:1].[OH:27][C:26]([C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)([C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1)[CH:28]1[CH2:33][CH2:32][N:31]([CH2:2][CH2:3][CH2:4][C:5]([C:7]2[CH:12]=[CH:11][C:10]([C:13]([CH3:19])([CH3:18])[C:14]([O:16][CH3:17])=[O:15])=[CH:9][CH:8]=2)=[O:6])[CH2:30][CH2:29]1
Reactant: COC(=O)C(C)(C)c1ccc(C(=O)CCCCl)cc1
Reactant: OC(c1ccccc1)(c1ccccc1)C1CCNCC1
Solvent: Cc1ccccc1
Product: COC(=O)C(C)(C)c1ccc(C(=O)CCCN2CCC(C(O)(c3ccccc3)c3ccccc3)CC2)cc1
Product: Cl
Yield: 76.3 %

Procedure:
Dissolve 2-[4-(4-chloro-butyryl)-phenyl]-2-methyl-propionic acid, methyl ester (2.82 g, 10.0 mmol) and α,α-diphenyl-4-piperidinemethanol (5.58 g, 21.0 mmol) in toluene (20 mL). Reflux for 29 hours, cool in an ice bath, filter, filter the filtrate though silica gel (5 g) and wash the gel with toluene (10 mL). Evaporate the solvent in vacuo and dissolve the residue in ethyl ether (100 mL). Add anhydrous hydrogen chloride and filter to give the title compound as an off-white powder (4.2 g, 76%); mp 165-175° C.
Reaction SMILES: C([N:20]1[C:24]2[CH:25]=[N:26][C:27]3[CH:28]=[CH:29][CH:30]=[CH:31][C:32]=3[C:23]=2[N:22]=[CH:21]1)(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C([Li])CCC.[CH:38]1([C:41](Cl)=[O:42])[CH2:40][CH2:39]1.FC(F)(F)C(O)=O>C1COCC1.CCCCCC>[CH:38]1([C:41]([C:21]2[NH:22][C:23]3[C:32]4[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=4[N:26]=[CH:25][C:24]=3[N:20]=2)=[O:42])[CH2:40][CH2:39]1
Reactant: c1ccc(C(c2ccccc2)(c2ccccc2)n2cnc3c4ccccc4ncc32)cc1
Reactant: O=C(Cl)C1CC1
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: O=C(O)C(F)(F)F
Solvent: C1CCOC1
Product: O=C(c1nc2cnc3ccccc3c2[nH]1)C1CC1
Reaction time: 0.5 h
Yield: 55.7 %

Procedure:
To a cold solution (-70° C.) of 1.23 g of 3-trityl-3H-imidazo[4,5-c]quinoline (III-1) in 25 ml of THF was added dropwise a mixture of 3 ml of 1.6M solution of n-butyl lithium in hexane and 3 ml of THF while being kept at -72°~-68° C. The mixture was stirred at the same temperature for 30 min., whereby a yellow solution of 2-lithio form (III-1') was obtained. All the 2-lithio form used in the Examples hereafter are prepared according to the same reaction conditions. To the yellow solution of the compound (III-1') was added 1.04 g of cyclopropanecarbonyl chloride all at once. The temperature of the reaction solution was gradually elevated to room temperature, and the solvent was evaporated under reduced pressure. The residue was partitioned between ethyl acetate and aqueous ammonia. The organic layer was washed with water and saturated brine, successively, and dried. The ethyl acetate was removed by evaporation, and the residue was crystallized from n-hexane--ethyl acetate to give 900 mg of the crude crystals (Ib-1). The compound (Ib-1) was deprotected by mixing with 4 ml of trifluoroacetic acid. After stirring for 30 min. at room temperature, the reaction mixture was concentrated under reduced pressure, and the residue was partitioned between ethyl acetate and saturated aqueous sodium hydrogencarbonate. The organic layer was washed with water and saturated brine, and dried. The ethyl acetate was removed by evaporation, and the residue was chromatographed on a column of silica gel for purification. The fraction eluted with chloroform--methanol (30:1 v/v) was concentrated and crystallized from -hexane to give 395 mg (yield: 56%) of the titled compound (Ic-1). This was recrystallized from ethanol to give colorless crystals melting at 230° C. (dec.).
Reaction SMILES: [C:1]1([OH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH:8]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1O)([CH3:10])[CH3:9]>P([O-])([O-])([O-])=O.[Ni+2].[Ca+2].O>[C:8]([C:4]1[CH:5]=[CH:6][C:1]([OH:7])=[CH:2][CH:3]=1)([CH3:10])=[CH2:9].[CH:8]([C:11]1[CH:16]=[CH:15][C:14]([OH:7])=[CH:13][CH:12]=1)([CH3:10])[CH3:9]
Reactant: Oc1ccccc1
Reactant: CC(C)c1ccccc1O
Agent: [Ni+2]
Agent: O=P([O-])([O-])[O-]
Agent: [Ca+2]
Solvent: O
Product: C=C(C)c1ccc(O)cc1
Product: CC(C)c1ccc(O)cc1
Temperature: 0 °C
Reaction time: 17 h

Procedure:
A quartz tube 40 cm×16 mm, inside diameter, with Vigreux indentations 1" above the top of the bottom joint was packed with 3 cm of quartz rings, 28 cm (equivalent to 44.16 grams) of the calcium-nickel phosphate catalyst of formula I, which had previously been calcined at about 800° for a period of about 17 hours and then filled with additional quartz rings (for heat transfer). Thermocouples were placed on the side of the tube and the tube placed in a vertical furnace. At the top of the tube was placed a manifold from which the air and liquid feeds were added. At the bottom of the tube were placed in series three three-necked flasks, the first two being immersed in ice/water baths. The catalyst bed was heated to a temperature between 300°-500° with an air flow of 0.15 ft3 /hr. Then the liquid feed composed of phenol, water, and isopropylphenol in the molar ratio of 2.8:2.0:1.0 was introduced to provide an addition rate of 0.15 ml/min. After specified volumes of feed had been introduced, the products (phenol, water, the propylphenol and propenylphenol) were collected from the receiver and analyzed for para-isopropenylphenol content by NHMR spectroscopy (proton nuclear magnetic resonance). Table I shows the results of para-isopropenylphenol formation as a function of the moles of para-isopropylphenol used.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[N:4][N:5]([CH3:22])[C:6]=1[O:7][CH2:8][CH:9]1[CH2:14][CH2:13][N:12](C(OC(C)(C)C)=O)[CH2:11][CH2:10]1.[NH2:23][C:24]1[C:25]([C:31](O)=[O:32])=[N:26][C:27]([Br:30])=[CH:28][CH:29]=1>>[NH2:23][C:24]1[C:25]([C:31]([NH:1][C:2]2[CH:3]=[N:4][N:5]([CH3:22])[C:6]=2[O:7][CH2:8][CH:9]2[CH2:10][CH2:11][NH:12][CH2:13][CH2:14]2)=[O:32])=[N:26][C:27]([Br:30])=[CH:28][CH:29]=1
Reactant: Nc1ccc(Br)nc1C(=O)O
Reactant: Cn1ncc(N)c1OCC1CCN(C(=O)OC(C)(C)C)CC1
Product: Cn1ncc(NC(=O)c2nc(Br)ccc2N)c1OCC1CCNCC1

Procedure:
Following the procedures for Example 141, tert-butyl 4-((4-amino-1-methyl-1H-pyrazol-5-yloxy)methyl)piperidine-1-carboxylate and 3-amino-6-bromopicolinic acid were reacted to give 3-amino-6-bromo-N-(1-methyl-5-(piperidin-4-ylmethoxy)-1H-pyrazol-4-yl)picolinamide, which was reacted with 2-fluorophenylboronic acid under palladium catalyzed Suzuki conditions to give 117 as a white solid (6.7 mg, 7.2%) over three steps. 1H NMR (400 MHz, DMSO) δ 9.66 (s, 1H), 8.10 (t, J=7.2, 1H), 7.71 (dt, J=37.9, 19.0, 1H), 7.60-7.25 (m, 5H), 7.03 (s, 2H), 3.97 (d, J=6.2, 2H), 3.72-3.42 (m, 3H), 2.76 (t, J=31.9, 2H), 2.36 (t, J=12.2, 2H), 1.88-1.53 (m, 3H), 1.25-0.99 (m, 2H). ESIMS m/z=425.1 (M+1)
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([C:14](O)=O)[CH2:13][CH2:12][CH2:11][CH2:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8].[CH3:17][NH2:18]>>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([CH2:14][NH:18][CH3:17])[CH2:13][CH2:12][CH2:11][CH2:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: CN
Reactant: O=C(O)C1(c2ccc(Cl)c(Cl)c2)CCCC1
Product: CNCC1(c2ccc(Cl)c(Cl)c2)CCCC1
Yield: 49 %

Procedure:
The title compound was synthesized from 1-(3,4-dichlorophenyl)-cyclopentanecarboxylic acid and methyl amine using General Procedure G1, followed by General Procedure E in 49% yield. LCMS Rt=11.16 min, m/z=258 (M+1). 1H NMR (CDCl3, δ): 7.4 (m, 2H), 7.17 (dd, J=2.2, 8.4 Hz, 1H), 2.65 (s, 2H), 2.34 (s, 3H), 2.1-1.6 (m, 8H). 13C NMR (CDCl3, δ, mult): 148.3(0), 132.1(0), 129.9(1), 129.7(0), 129.1(1), 126.5(1), 62.1(2), 51.6(0), 37.3(3), 36.2(2), 23.5(2).
Reaction SMILES: [CH3:1][CH:2]1[N:15]2[C:6](=[N:7][C:8]3[CH2:9][CH2:10][CH2:11][CH2:12][C:13]=3[C:14]2=[O:16])[C:5](=[N:17]NC2C=CC=CC=2)[CH2:4][CH2:3]1>O>[CH3:1][CH:2]1[N:15]2[C:6](=[N:7][C:8]3[CH2:9][CH2:10][CH2:11][CH2:12][C:13]=3[C:14]2=[O:16])[C:5]2[NH:17][C:8]3[C:9]([C:4]=2[CH2:3]1)=[CH:10][CH:11]=[CH:12][CH:13]=3
Reactant: CC1CCC(=NNc2ccccc2)c2nc3c(c(=O)n21)CCCC3
Solvent: O
Product: CC1Cc2c([nH]c3ccccc23)-c2nc3c(c(=O)n21)CCCC3
Temperature: 170 °C
Reaction time: 0.33 h
Yield: 84.5 %

Procedure:
1 g of 9-methyl-6-phenylhydrazono-1,2,3,4,6,7,8,9-octahydro-pyrido[2,1-b]quinazoline-11-one is added to 15 g of polyphosphoric acid heated to 170° C. and the mixture is stirred for 20 minutes at 180° C. After cooling, the dark melt is diluted with 50 ml of water. Greenish-yellow crystals are precipitated, which are filtered and washed with water. After drying, the product is recrystallized from ethanol. 0.4 g of 7-methyl-5-oxo-1,2,3,4,7,8-hexahydro-5H,13H-indolo[2',3';3,4]pyrido[2,1-b]quinazoline are obtained melting at 232° C.