Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([CH2:3][CH2:4][PH:5]([O:14][C@@H:15]1[C@@H:19]([CH2:20][O:21][C:22]([C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)([C:31]2[CH:36]=[CH:35][C:34]([O:37][CH3:38])=[CH:33][CH:32]=2)[C:23]2[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][CH:24]=2)[O:18][C@@H:17]([N:45]2[CH:52]=[CH:51][C:49](=O)[NH:48][C:46]2=[O:47])[C@@H:16]1[O:53][CH2:54][O:55][CH2:56][CH:57]([C:62]([F:65])([F:64])[F:63])[C:58]([F:61])([F:60])[F:59])([N:7]([CH:11]([CH3:13])[CH3:12])[CH:8]([CH3:10])[CH3:9])[OH:6])#[N:2].[C:66]([NH:69]C1C=CN([C@@H]2O[C@H](COC(C3C=CC=CC=3)(C3C=CC(OC)=CC=3)C3C=CC(OC)=CC=3)[C@@H](O)[C@H]2OCOCC(C(F)(F)F)C(F)(F)F)C(=O)N=1)(=[O:68])[CH3:67]>>[C:1]([CH2:3][CH2:4][PH:5]([O:14][C@@H:15]1[C@@H:19]([CH2:20][O:21][C:22]([C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)([C:23]2[CH:24]=[CH:25][C:26]([O:29][CH3:30])=[CH:27][CH:28]=2)[C:31]2[CH:32]=[CH:33][C:34]([O:37][CH3:38])=[CH:35][CH:36]=2)[O:18][C@@H:17]([N:45]2[CH:52]=[CH:51][C:49]([NH:69][C:66](=[O:68])[CH3:67])=[N:48][C:46]2=[O:47])[C@@H:16]1[O:53][CH2:54][O:55][CH2:56][CH:57]([C:62]([F:64])([F:65])[F:63])[C:58]([F:61])([F:60])[F:59])([N:7]([CH:8]([CH3:10])[CH3:9])[CH:11]([CH3:13])[CH3:12])[OH:6])#[N:2]
Reactant: COc1ccc(C(OC[C@H]2O[C@@H](n3ccc(NC(C)=O)nc3=O)[C@H](OCOCC(C(F)(F)F)C(F)(F)F)[C@@H]2O)(c2ccccc2)c2ccc(OC)cc2)cc1
Reactant: COc1ccc(C(OC[C@H]2O[C@@H](n3ccc(=O)[nH]c3=O)[C@H](OCOCC(C(F)(F)F)C(F)(F)F)[C@@H]2O[PH](O)(CCC#N)N(C(C)C)C(C)C)(c2ccccc2)c2ccc(OC)cc2)cc1
Product: COc1ccc(C(OC[C@H]2O[C@@H](n3ccc(NC(C)=O)nc3=O)[C@H](OCOCC(C(F)(F)F)C(F)(F)F)[C@@H]2O[PH](O)(CCC#N)N(C(C)C)C(C)C)(c2ccccc2)c2ccc(OC)cc2)cc1
Yield: 86 %

Procedure:
This compound was synthesized in the same manner as that used for the compound 3u by using the compound 2c instead of the compound 2u. Yield was 86% (white foam).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:22][CH2:21][C:12]2=[C:13](Cl)[N:14]3[C:18]([N:19]=[C:11]2[CH2:10][CH2:9]1)=[CH:17][CH:16]=[N:15]3)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.[NH:24]1[CH2:27][CH2:26][C@H:25]1[CH2:28][OH:29].CCN(C(C)C)C(C)C.CCOC(C)=O>C(O)C>[C:1]([O:5][C:6]([N:8]1[CH2:22][CH2:21][C:12]2=[C:13]([N:24]3[CH2:27][CH2:26][C@H:25]3[CH2:28][OH:29])[N:14]3[C:18]([N:19]=[C:11]2[CH2:10][CH2:9]1)=[CH:17][CH:16]=[N:15]3)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCc2nc3ccnn3c(Cl)c2CC1
Reactant: OC[C@@H]1CCN1
Agent: Cl
Solvent: CCO
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CCc2nc3ccnn3c(N3CC[C@H]3CO)c2CC1
Temperature: 80 °C

Procedure:
To 50 mg (0.155 mmol) 10-chloro-5,6,8,9-tetrahydro-1,4,7,10a-tetraaza-cyclohepta[f]indene-7-carboxylic acid tert-butyl ester (route 1, from step a to d) and 22 mg (0.17 mmol) (S)-azetidin-2-yl-methanol hydrogen chloride in 2 mL ethanol was added 2 mL (0.31 mmol) DIPEA, and the reaction mixture was heated at 80° C. for 19 hours. The reaction was cooled to room temperature and 20 mL EtOAc was added. The organic layer was washed with 10 mL citric acid (1 M), H2O (2×10 mL), 10 mL saturated brine, and dried over MgSO4. After evaporation of the solvent the product was purified by column chromatography (silica, heptane/EtOAc 1:5).
Reaction SMILES: [N:1]1[O:2][N:3]=[C:4]2[C:9]([CH:10]=O)=[CH:8][CH:7]=[CH:6][C:5]=12.[C:12]([O:18][CH3:19])(=[O:17])[CH2:13][C:14]([CH3:16])=[O:15].N1CC[CH2:23][CH2:22][CH2:21]1>C(OC(C)C)(C)C.C(O)(=O)C.O>[CH3:19][O:18][C:12](=[O:17])[C:13]([C:14](=[O:15])[CH3:16])=[CH:10][C:9]1[C:4]2=[N:3][O:2][N:1]=[C:5]2[CH:6]=[CH:7][CH:8]=1.[CH:22]([O:15][CH:14]([CH3:16])[CH3:13])([CH3:23])[CH3:21]
Reactant: O=Cc1cccc2nonc12
Reactant: COC(=O)CC(C)=O
Reactant: C1CCNCC1
Solvent: CC(C)OC(C)C
Solvent: CC(=O)O
Solvent: O
Product: COC(=O)C(=Cc1cccc2nonc12)C(C)=O
Reaction time: 10 h

Procedure:
In the first step, 2,1,3-benzoxadiazole-4-carboxaldehyde is reacted with methyl acetoacetate in the presence of acetic acid and piperidine in diisopropyl ether. The reaction is carried out in diisopropyl ether under reflux with simultaneous removal of water formed during the reaction. Removal of the water from the reaction mixture enables the reaction to proceed at a faster rate. The reaction is completed at the end of theoretical amount of water removal from the reaction mixture. The completion of the reaction is determined by qualitative HPLC analysis. In this reaction methyl acetoacetate 0.9 to 1.1 mol is used for every 1.0 mol of 2,1,3-benzoxadiazole-4-carboxaldehyde, preferably 0.95 to 1.0 mol methyl acetoacetate is used for every 1.0 mol of 2,1,3-benzoxadiazole-4-carboxaldehyde. Acetic acid and piperidine are used in catalytic amount, preferably acetic acid 0.25 to 0.30 mol and piperidine 0.08 to 0.06 mol is used for every 1.0 mol of 2,1,3-benzoxadiazole-4-carboxaldehyde. This reaction goes to completion after 8 to 12 hr at reflux. The reaction mixture is then washed with dilute hydrochloric acid, followed by dilute sodium bicarbonate solution and followed by water. The crude product 2-acetyl-3-benzofurazan-4-yl-acrylic acid methyl ester is then obtained by distillation of diisopropyl ether under vacuum.
Reaction SMILES: [CH2:1]([N:4]([CH2:18][CH2:19][CH3:20])[CH:5]1[CH2:14][CH2:13][C:12]2[C:7](=[C:8]([CH2:15][CH2:16][NH2:17])[CH:9]=[CH:10][CH:11]=2)[CH2:6]1)[CH2:2][CH3:3].[CH3:21][N:22]=[C:23]=[O:24]>C(N(CC)CC)C.C1(C)C=CC=CC=1>[CH2:18]([N:4]([CH2:1][CH2:2][CH3:3])[CH:5]1[CH2:14][CH2:13][C:12]2[C:7](=[C:8]([CH2:15][CH2:16][NH:17][C:23]([NH:22][CH3:21])=[O:24])[CH:9]=[CH:10][CH:11]=2)[CH2:6]1)[CH2:19][CH3:20]
Reactant: CCCN(CCC)C1CCc2cccc(CCN)c2C1
Reactant: CN=C=O
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: CCCN(CCC)C1CCc2cccc(CCNC(=O)NC)c2C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
1.3 g (4.7 mmol) of 2-dipropylamino-8-(2-aminoethyl)-1,2,3,4-tetrahydronaphthalene were initially introduced into 20 ml of toluene. The reaction was catalyzed using 3 drops of triethylamine, and 0.31 ml (5.17 mmol) of methyl isocyanate were then added dropwise. The mixture was stirred overnight at room temperature, and then evaporated. After subsequent chromatography over silica gel 60, 40-63 μm, using diisopropyl ether/ethanol/triethylamine, the product was stirred with petroleum ether and a little diisopropyl ether, and filtered off under suction.
Reaction SMILES: [NH2:1][CH:2]([C:22]1[CH:31]=[CH:30][C:29]2[C:28]([CH3:33])([CH3:32])[CH2:27][CH2:26][C:25]([CH3:35])([CH3:34])[C:24]=2[CH:23]=1)[C:3]([NH:5][C:6]1[CH:21]=[CH:20][C:9]([C:10]([O:12]CC2C=CC=CC=2)=[O:11])=[CH:8][CH:7]=1)=[O:4].C1C[O:39][CH2:38][CH2:37]1.C(N(CC)CC)C.C(Cl)(=O)C>O>[C:38]([NH:1][CH:2]([C:22]1[CH:31]=[CH:30][C:29]2[C:28]([CH3:33])([CH3:27])[CH2:32][CH2:34][C:25]([CH3:26])([CH3:35])[C:24]=2[CH:23]=1)[C:3]([NH:5][C:6]1[CH:7]=[CH:8][C:9]([C:10]([OH:12])=[O:11])=[CH:20][CH:21]=1)=[O:4])(=[O:39])[CH3:37]
Reactant: CC1(C)CCC(C)(C)c2cc(C(N)C(=O)Nc3ccc(C(=O)OCc4ccccc4)cc3)ccc21
Reactant: C1CCOC1
Solvent: CC(=O)Cl
Solvent: CCN(CC)CC
Solvent: O
Product: CC(=O)NC(C(=O)Nc1ccc(C(=O)O)cc1)c1ccc2c(c1)C(C)(C)CCC2(C)C
Temperature: 25 °C
Reaction time: 2 h
Yield: 94 %

Procedure:
1.5 g (3.2 mmol) of benzyl 4-[α-amino-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)acetamido]benzoate, 75 ml of THF and 490 μl (3.5 mmol) of triethylamine were introduced into a round-bottomed flask. 250 μl (3.5 mmol) of acetyl chloride were added dropwise and the mixture was stirred at room temperature for 2 hours. The reaction medium was poured into water, extracted with ethyl acetate, the organic phase decanted, dried over magnesium sulfate and evaporated. The residue obtained was triturated in hexane, filtered and dried. 1.6 g (94%) of the expected compound of melting point 258°-259° C. was obtained.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:9]2[CH:21]=[CH:20][C:12]([C:13]([O:15]C(C)(C)C)=[O:14])=[CH:11][N:10]=2)[CH:5]=[C:6]([F:8])[CH:7]=1.FC(F)(F)C(O)=O.C1(C)C=CC=CC=1>C(Cl)Cl>[F:8][C:6]1[CH:5]=[C:4]([C:9]2[CH:21]=[CH:20][C:12]([C:13]([OH:15])=[O:14])=[CH:11][N:10]=2)[CH:3]=[C:2]([F:1])[CH:7]=1
Reactant: CC(C)(C)OC(=O)c1ccc(-c2cc(F)cc(F)c2)nc1
Solvent: Cc1ccccc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(O)c1ccc(-c2cc(F)cc(F)c2)nc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 74 %

Procedure:
To tert-butyl 6-(3,5-difluorophenyl)nicotinate in DCM (80 mL) was added trifluroacetic acid (20 mL). After stirring at rt overnight, toluene was added (100 mL) and the solvent removed to give the crude product as a white powder. The solid was re-crystallized from MeOH to afford the title compound 1.269 g (74%) as a white solid. 1H NMR (400 MHz, DMSO-d6) □ ppm 9.16 (1H, d, J=1.7 Hz), 8.37 (1 H, dd, J=8.2, 2.0 Hz), 8.23 (1 H, d, J=8.2 Hz), 7.86-7.95 (2H, m), 7.36-7.47 (1H, m).
Reaction SMILES: C(N1C=CN=C1)(N1C=CN=C1)=O.ClCCl.[Cl:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[CH2:23][C:24]([OH:26])=O.[OH:27][C:28]1[CH:34]=[CH:33][CH:32]=[CH:31][C:29]=1[NH2:30]>O>[Cl:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[CH2:23][C:24]([NH:30][C:29]1[CH:31]=[CH:32][CH:33]=[CH:34][C:28]=1[OH:27])=[O:26]
Reactant: O=C(O)Cc1ccccc1Cl
Reactant: Nc1ccccc1O
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: O
Solvent: ClCCl
Product: O=C(Cc1ccccc1Cl)Nc1ccccc1O
Reaction time: 1 h
Yield: 95.8 %

Procedure:
To a mixture of 1,1′-carbonyl diimidazole (12.45 g, 0.077 mol) and dichloromethane (50 ml) was added 2-chlorophenylacetic acid (12.5 g, 0.073 mol) in portions. The mixture was stirred for 1 h and 2-hydroxyaniline (7.99 g, 0.073 mol) was added in one portion. After stirring overnight, the reaction mixture was diluted with water and filtered to give the title compound (18.3 g after drying).
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[C:11](Cl)=[O:12].C[O:15][P:16]1[C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=2[C:19]2[CH:26]=[CH:27][CH:28]=[CH:29][C:18]=2[O:17]1>C1(C)C=CC=CC=1>[CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[C:11]([P:16]1(=[O:15])[C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=2[C:19]2[CH:26]=[CH:27][CH:28]=[CH:29][C:18]=2[O:17]1)=[O:12]
Reactant: O=C(Cl)c1ccc2ccccc2c1
Reactant: COP1Oc2ccccc2-c2ccccc21
Solvent: Cc1ccccc1
Product: O=C(c1ccc2ccccc2c1)P1(=O)Oc2ccccc2-c2ccccc21
Temperature: 125 °C

Procedure:
50 g (0.262 mol) of 2 -naphthoyl chloride were warmed to 80° C. under a nitrogen atmosphere. 60.3 g (0.262 mol) of 6-methoxy-(6H)-dibenz[c,e][1,2]oxaphosphorin were added dropwise over the course of two hours while stirring. The internal temperature was subsequently increased gradually to 125° C. When the reaction was complete, 110 ml of toluene were added. After crystallization, 87 g (90% of theory) of the abovementioned compound of melting point 151° to 153° C. were obtained.
Reaction SMILES: [CH2:1]([O:8][C@@H:9]1[C@@H:17]([CH:18]=[O:19])[O:16][C@H:15]2[C@H:11]([N:12]=[C:13]([N:20]([CH3:22])[CH3:21])[S:14]2)[CH2:10]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:23][Mg+].[Br-]>C1COCC1.O>[CH2:1]([O:8][C@@H:9]1[C@@H:17]([CH:18]([OH:19])[CH3:23])[O:16][C@H:15]2[C@H:11]([N:12]=[C:13]([N:20]([CH3:22])[CH3:21])[S:14]2)[CH2:10]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C[Mg+]
Reactant: CN(C)C1=N[C@@H]2C[C@H](OCc3ccccc3)[C@@H](C=O)O[C@@H]2S1
Agent: [Br-]
Solvent: C1CCOC1
Solvent: O
Product: CC(O)[C@H]1O[C@@H]2SC(N(C)C)=N[C@@H]2C[C@@H]1OCc1ccccc1
Temperature: 25 °C
Reaction time: 20 h
Yield: 76.9 %

Procedure:
To a solution of (3aR,5S,6S,7aR)-6-(benzyloxy)-2-(dimethylamino)-5,6,7,7a-tetrahydro-3aH-pyrano[3,2-d]thiazole-5-carbaldehyde (1.04 g) in anhydrous THF (30 mL) at 0° C. was added a solution of MeMgBr (1.4 M in 1:3 THF/toluene, 5.80 mL, 8.13 mmol) dropwise. The reaction was then stirred at room temperature for 20 h. The mixture was diluted with H2O (50 mL), extracted with EtOAc (2×40 mL). The combined extract was dried over anhydrous Na2SO4. The solvents were evaporated under reduced pressure, and the residue was purified by silica gel column chromatography, eluted with 2%-5% 2 M NH3 MeOH solution in DCM to give 1-((3aR,5R,6S,7aR)-6-(benzyloxy)-2-(dimethylamino)-5,6,7,7a-tetrahydro-3aH-pyrano[3,2-d]thiazol-5-yl)ethanol (0.840 g, 77%) as a pale yellow foam. MS m/z 337.2 (M+1, 100%); 1H NMR (400 MHz, CDCl3) shown this was a mixture of two diastereomers with a ratio ˜60:40.
Reaction SMILES: [NH2:1][C:2]1[NH:6][N:5]=[C:4]([NH:7][C:8]2[CH:13]=[CH:12][C:11]([C:14]([CH3:17])([CH3:16])[CH3:15])=[CH:10][CH:9]=2)[C:3]=1[C:18]([NH2:20])=[O:19].[OH:21][C:22]1[CH:29]=[CH:28][C:25]([CH:26]=O)=[CH:24][CH:23]=1>CCO.N1CCCCC1>[C:14]([C:11]1[CH:10]=[CH:9][C:8]([NH:7][C:4]2[C:3]([C:18]([NH2:20])=[O:19])=[C:2]([N:1]=[CH:26][C:25]3[CH:28]=[CH:29][C:22]([OH:21])=[CH:23][CH:24]=3)[NH:6][N:5]=2)=[CH:13][CH:12]=1)([CH3:17])([CH3:15])[CH3:16]
Reactant: CC(C)(C)c1ccc(Nc2n[nH]c(N)c2C(N)=O)cc1
Reactant: O=Cc1ccc(O)cc1
Solvent: C1CCNCC1
Solvent: CCO
Product: CC(C)(C)c1ccc(Nc2n[nH]c(N=Cc3ccc(O)cc3)c2C(N)=O)cc1

Procedure:
5-amino-3-((4-(tert-butyl)phenyl)amino)-1H-pyrazole-4-carboxamide was then suspended in 8 mL EtOH and 4-hydroxybenzaldehyde (325 mg, 1 eq.) and piperidine (4 drops) were added. Stirred at reflux until intermediate was absent (HPLC). After reaction was complete (18 hrs) it was brought to room temperature and filtered to obtain 3-((4-(tert-butyl)phenyl)amino)-5-((4-hydroxybenzylidene)amino)-1H-pyrazole-4-carboxamide as a yellow powder. Powder was washed with EtOH to remove any excess 4-hydroxybenzaldehyde. Product was allowed to dry under vacuum for 1 hr.
Reaction SMILES: C(O[C:4]([C:6]1([CH2:12][CH2:13]OC)[CH2:11][CH2:10][NH:9][CH2:8][CH2:7]1)=[O:5])C.[CH3:16][C:17]([CH3:24])([CH3:23])[CH2:18][S:19](Cl)(=[O:21])=[O:20].[NH2:25][C:26]1[CH:31]=[CH:30][C:29]([O:32][S:33]([CH3:36])(=[O:35])=[O:34])=[CH:28][CH:27]=1>>[CH3:16][C:17]([CH3:24])([CH3:23])[CH2:18][S:19]([N:9]1[CH2:8][CH2:7][C:6]2([C:4](=[O:5])[N:25]([C:26]3[CH:31]=[CH:30][C:29]([O:32][S:33]([CH3:36])(=[O:35])=[O:34])=[CH:28][CH:27]=3)[CH2:13][CH2:12]2)[CH2:11][CH2:10]1)(=[O:21])=[O:20]
Reactant: CCOC(=O)C1(CCOC)CCNCC1
Reactant: CC(C)(C)CS(=O)(=O)Cl
Reactant: CS(=O)(=O)Oc1ccc(N)cc1
Product: CC(C)(C)CS(=O)(=O)N1CCC2(CCN(c3ccc(OS(C)(=O)=O)cc3)C2=O)CC1

Procedure:
Off-white solid. MS (ESI): 459.16 (MH+). This example was prepared in analogy to example 1 step C) to D) from 4-(2-methoxy-ethyl)-piperidine-4-carboxylic acid ethyl ester (example 1 step B)), 2,2-dimethyl-propane-1-sulfonyl chloride and methanesulfonic acid 4-amino-phenyl ester.
Reaction SMILES: [CH3:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH:8]=[CH2:9].[C:10](#[N:13])[CH:11]=[CH2:12].C1C2NC3C(=CC=CC=3)SC=2C=CC=1.S(=O)(=O)(O)[OH:29]>>[CH2:9]([NH:13][C:10](=[O:29])[CH:11]=[CH2:12])[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][CH3:1]
Reactant: C=CC#N
Reactant: O=S(=O)(O)O
Reactant: C=CCCCCCCC
Agent: c1ccc2c(c1)Nc1ccccc1S2
Product: C=CC(=O)NCCCCCCCCC
Reaction time: 4 h

Procedure:
To a mixture of propylene trimer (504 parts by weight (pbw)) acrylonitrile (232 pbw), and phenothiazine (0.4 pbw) is added 85% sulfuric acid (510 pbw) at 40°-45° C. over a period of one hour. The reaction is held at this temperature for an additional four hours, cooled and the upper layer (unreacted olefin, 95 pbw) separated. The lower aqueous layer is decanted into ice water (1500 pbw) and toluene (250 pbw) added. The upper organic layer is washed twice with 100 pbw portions of water, then with 20% sodium carbonate solution (35 pbw) dried over anhydrous sodium sulfate (40 pbw) and evaporated under vacuum to give the title product as a liquid residue (575 pbw).
Reaction SMILES: [NH2:1][C:2]1[C:7]([Cl:8])=[CH:6][C:5]([C:9](=[O:18])[CH2:10][CH2:11][CH:12]2[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]2)=[C:4]([O:19][CH3:20])[CH:3]=1.C(N(CC)CC)C.Br[CH2:29][CH2:30][CH3:31]>CN(C=O)C>[NH2:1][C:2]1[C:7]([Cl:8])=[CH:6][C:5]([C:9](=[O:18])[CH2:10][CH2:11][CH:12]2[CH2:13][CH2:14][N:15]([CH2:29][CH2:30][CH3:31])[CH2:16][CH2:17]2)=[C:4]([O:19][CH3:20])[CH:3]=1
Reactant: CCCBr
Reactant: COc1cc(N)c(Cl)cc1C(=O)CCC1CCNCC1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCCN1CCC(CCC(=O)c2cc(Cl)c(N)cc2OC)CC1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
1-(4-Amino-5-chloro-2-methoxyphenyl)-3-(piperidin-4-yl)propan-1-one (0.2 g, 0.67 mmol), prepared as in Example 3 or Example 7, triethylamine (0.2 mL), and 1-bromopropane (0.065 mL, 0.75 mmol) were dissolved in DMF (4 mL) and the solution was stirred at room temperature for 12 hours. The solution was partitioned between aqueous ammonium hydroxide and ethyl acetate. The ethyl acetate layer was separated, washed with water and then brine, dried over sodium sulfate, and evaporated. Purification of the residue by silica gel chromatography (10% CH3OH--CH2Cl2) gave 1-(4-amino-5-chloro-2-methoxyphenyl)-3-(1-(prop-1-yl) piperidin-4-yl]propan-1-one which was then dissolved in ethanolic hydrochloric acid. Crystallization with ether gave 1-(4-amino-5-chloro-2-methoxyphenyl)-3-[1-(prop-1-yl) piperidin-4-yl]propan-1-one hydrochloride (0.15 g, 0.4 mmol), m.p. 200°-201° C.
Reaction SMILES: [F:1][C:2]1[CH:25]=[C:24]([N+:26]([O-:28])=[O:27])[CH:23]=[CH:22][C:3]=1[O:4][C:5]1[CH:10]=[CH:9][N:8]=[C:7]2[CH:11]=[C:12]([C:14]3[CH:15]=[C:16]([CH2:20]O)[CH:17]=[CH:18][CH:19]=3)[S:13][C:6]=12.S(Cl)([Cl:31])=O>>[Cl:31][CH2:20][C:16]1[CH:15]=[C:14]([C:12]2[S:13][C:6]3[C:7](=[N:8][CH:9]=[CH:10][C:5]=3[O:4][C:3]3[CH:22]=[CH:23][C:24]([N+:26]([O-:28])=[O:27])=[CH:25][C:2]=3[F:1])[CH:11]=2)[CH:19]=[CH:18][CH:17]=1
Reactant: O=[N+]([O-])c1ccc(Oc2ccnc3cc(-c4cccc(CO)c4)sc23)c(F)c1
Reactant: O=S(Cl)Cl
Product: O=[N+]([O-])c1ccc(Oc2ccnc3cc(-c4cccc(CCl)c4)sc23)c(F)c1
Temperature: 25 °C
Yield: 93 %

Procedure:
The hydroxy-compound 147 (685 mg, 1.73 mmol) was suspended in thionyl chloride (8.6 mL) and the reaction mixture was refluxed for about one hour. The mixture was cooled to RT then poured into an ice/water mixture. The resultant solid was collected by filtration, washed with water and well dried to afford title compound 148 as a yellow solid (730 mg, 93% yield). MS (m/z): 415.0 (M+H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([I:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:10]1[N:15]([CH3:16])[C:14](=[O:17])[N:13]([CH3:18])[C:12](=[O:19])[C:11]=1[C:20](OC1C=CC=CC=1)=[O:21].ClC(=O)[C:31]([O:33]C)=[O:32]>>[F:1][C:2]1[CH:7]=[C:6]([I:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:10]1[N:15]([CH3:16])[C:14](=[O:17])[N:13]([CH3:18])[C:12](=[O:19])[C:11]=1[C:20](=[O:21])[C:31]([OH:33])=[O:32]
Reactant: COC(=O)C(=O)Cl
Reactant: Cn1c(Nc2ccc(I)cc2F)c(C(=O)Oc2ccccc2)c(=O)n(C)c1=O
Product: Cn1c(Nc2ccc(I)cc2F)c(C(=O)C(=O)O)c(=O)n(C)c1=O

Procedure:
The title compound was synthesized following a similar procedure described in the synthesis of compound 2A from reaction of Example 1 with methyl 2-chloro-2-oxoacetate (hydrolysis of the crude upon column chromatography afforded Example 31). 1H NMR (400 MHz, DMSO-d6) δ ppm 2.95 (s, 3H) 3.17 (s, 3H) 7.28 (s, 1H) 7.61 (m, 1H) 7.84 (m, 1H) [M+H] calc'd for C14H11FIN3O5, 448; found, 448.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:13]([F:16])([F:15])[F:14])[CH:5]=[C:6]2[C:11]=1[N:10]=[C:9](Cl)[N:8]=[CH:7]2.[S:17]([NH2:27])(=[O:26])([C:19]1[CH:24]=[CH:23][C:22]([NH2:25])=[CH:21][CH:20]=1)=[O:18]>CC(O)C>[Br:1][C:2]1[CH:3]=[C:4]([C:13]([F:16])([F:15])[F:14])[CH:5]=[C:6]2[C:11]=1[N:10]=[C:9]([NH:25][C:22]1[CH:23]=[CH:24][C:19]([S:17]([NH2:27])(=[O:18])=[O:26])=[CH:20][CH:21]=1)[N:8]=[CH:7]2
Reactant: FC(F)(F)c1cc(Br)c2nc(Cl)ncc2c1
Reactant: Nc1ccc(S(N)(=O)=O)cc1
Solvent: CC(C)O
Product: NS(=O)(=O)c1ccc(Nc2ncc3cc(C(F)(F)F)cc(Br)c3n2)cc1
Temperature: 110 °C
Reaction time: 14 h

Procedure:
To a 0.30 M solution of 8-bromo-2-chloro-6-(trifluoromethyl)quinazoline in 2-propanol was added sulfanilamide (1.0 eq). The reaction was stirred at 110° C. for 14 h. The hydrochloride was collected by vacuum filtration and then stirred in aqueous sodium bicarbonate. The solid was collected by vacuum filtration and rinsed with water. The light yellow solid was dried in a desiccator to give 343 mg of the desired product. ES/MS m/z 447, 449 (MH+).
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[C:3]1[CH:10]=[CH:9][C:6]([CH:7]=O)=[CH:5][CH:4]=1.[CH3:13][C:14]1([CH3:22])[O:21][C:19](=[O:20])[CH2:18][C:16](=[O:17])[O:15]1.N1CCCC1C(O)=O.[CH3:31][S:32][CH2:33][C:34]1[CH:35]=[CH:36][CH:37]=[C:38]2[C:42]=1[NH:41][CH:40]=[CH:39]2>C(#N)C>[CH3:13][C:14]1([CH3:22])[O:21][C:19](=[O:20])[CH:18]([CH:7]([C:39]2[C:38]3[C:42](=[C:34]([CH2:33][S:32][CH3:31])[CH:35]=[CH:36][CH:37]=3)[NH:41][CH:40]=2)[C:6]2[CH:9]=[CH:10][C:3]([C:2]([F:12])([F:11])[F:1])=[CH:4][CH:5]=2)[C:16](=[O:17])[O:15]1
Reactant: CSCc1cccc2cc[nH]c12
Reactant: CC1(C)OC(=O)CC(=O)O1
Reactant: O=Cc1ccc(C(F)(F)F)cc1
Agent: O=C(O)C1CCCN1
Solvent: CC#N
Product: CSCc1cccc2c(C(c3ccc(C(F)(F)F)cc3)C3C(=O)OC(C)(C)OC3=O)c[nH]c12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
268 mg (1.54 mmol) of 4-(trifluoromethyl)benzaldehyde, 222 mg (1.54 mmol) of Meldrum's acid and 8.4 mg (0.07 mmol) of D,L-proline were added to a solution of 260 mg (1.47 mmol) of the compound from Example 8A in 12 ml of acetonitrile. The reaction mixture was stirred at RT overnight. It was concentrated, and the crude product was purified by preparative HPLC (RP18 column; mobile phase: acetonitrile/water gradient with addition of 0.1% formic acid) to result in 504 mg (72% of theory) of the title compound.
Reaction SMILES: [CH2:1]([O:3][C:4]([CH:6]([CH2:14][CH3:15])[CH2:7][NH:8][C@H:9]([C:11]([OH:13])=[O:12])[CH3:10])=[O:5])[CH3:2].C(=O)([O-])[O-].[K+].[K+].Cl[C:23]([O:25][CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)=[O:24]>CC(C)=O.O>[CH2:1]([O:3][C:4]([CH:6]([CH2:14][CH3:15])[CH2:7][N:8]([C:23]([O:25][CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)=[O:24])[C@H:9]([C:11]([OH:13])=[O:12])[CH3:10])=[O:5])[CH3:2]
Reactant: O=C(Cl)OCc1ccccc1
Reactant: CCOC(=O)C(CC)CN[C@@H](C)C(=O)O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC(C)=O
Product: CCOC(=O)C(CC)CN(C(=O)OCc1ccccc1)[C@@H](C)C(=O)O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a suspension of N-[2-(ethoxycarbonyl)butyl]alanine (2.2 g, 10 mmol) and potassium carbonate (2.2 g, 16 mmol) in a mixture of acetone (30 mL) and water (2.5 mL) was added benzyl chloroformate (2.0 mL, 2.4 g, 14 mmol) at 0-5° C. After stirring for 2 h at ambient temperature the solid was filtered off, the solvent was evaporated, the residue was stirred with cold aqueous sodium hydroxide solution [prepared from ice (20 g) and aqueous sodium hydroxide solution (1N, 40 mL)] and extracted with ethyl acetate (40 mL). The aqueous layer was acidified with an aqueous solution of hydrochloric acid 1/1 (20 mL) and the mixture was extracted with ethyl acetate (40 mL). After drying and evaporation N-[2-(ethoxycarbonyl)butyl]-N-benzyloxycarbonylalanine (1.66 g, 47%) was obtained as a yellow oil which can be used in the next reaction without further purification.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([OH:9])[CH:5]=[C:6]([CH3:8])[CH:7]=1.S(=O)(=O)(O)[OH:11].CC1C=C(C)C=C(O)C=1O>>[CH3:8][C:6]1[CH:5]=[C:4]([OH:9])[CH:3]=[C:2]([CH3:1])[C:7]=1[OH:11]
Reactant: O=S(=O)(O)O
Reactant: Cc1cc(C)cc(O)c1
Agent: Cc1cc(C)c(O)c(O)c1
Product: Cc1cc(O)cc(C)c1O
Reaction time: 0.33 h

Procedure:
In a vessel used in Example 55, 100 g. (819 m.moles) of 3,5-dimethylphenol, 5.68 g. (P=42.11) of 4-methyl-2-pentanone peroxide and 0.01 g. of 98% sulfuric acid were placed and the reaction was carried out at 100° C. for 20 minutes in the same manner as in Example 55 and analyzed. 3.67 g. (26.6 m.moles) of 3,5-dimethylcatechol and 1.52 g. (11.0 m.moles) of 2,6-dimethylhydroquinone were obtained. The yield of dihydric alkylphenols was 89.3%.