Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH3:1].[CH:2]([C:5]1[CH:10]=[C:9]([C:11]([F:14])([F:13])[F:12])[C:8]([CH:15]([CH3:17])[CH3:16])=[CH:7][C:6]=1[S:18](F)(=[O:20])=[O:19])([CH3:4])[CH3:3]>>[CH:2]([C:5]1[CH:10]=[C:9]([C:11]([F:14])([F:13])[F:12])[C:8]([CH:15]([CH3:17])[CH3:16])=[CH:7][C:6]=1[S:18]([NH2:1])(=[O:20])=[O:19])([CH3:4])[CH3:3]
Reactant: N
Reactant: CC(C)c1cc(S(=O)(=O)F)c(C(C)C)cc1C(F)(F)F
Product: CC(C)c1cc(S(N)(=O)=O)c(C(C)C)cc1C(F)(F)F

Procedure:
A mixture of ammonia, 25 parts, and 2,5-diisopropyl-4-trifluoromethylbenzenesulfonyl fluoride, 7 parts, is heated for 4 hours at 100° in a Hastelloy-lined bomb. After removal of the ammonia, the crude product is stirred with water, filtered and dried. Pure product, m.p. 171°-174°, is obtained after vacuum sublimation.
Reaction SMILES: [CH3:1][C:2]1([C:45]([F:48])([F:47])[F:46])[CH2:7][C:6]([C:8]([N:10]2[C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=3[CH2:14][N:13]3[C:21]([C:24]([N:26]4[CH2:31][CH2:30][N:29](C(OC(C)(C)C)=O)[CH2:28][CH2:27]4)=[O:25])=[CH:22][CH:23]=[C:12]3[CH2:11]2)=[O:9])=[CH:5][CH:4]=[C:3]1[C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1.C(OCC)(=O)C.[ClH:55]>C(OCC)C>[ClH:55].[CH3:1][C:2]1([C:45]([F:47])([F:46])[F:48])[CH2:7][C:6]([C:8]([N:10]2[C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=3[CH2:14][N:13]3[C:21]([C:24]([N:26]4[CH2:27][CH2:28][NH:29][CH2:30][CH2:31]4)=[O:25])=[CH:22][CH:23]=[C:12]3[CH2:11]2)=[O:9])=[CH:5][CH:4]=[C:3]1[C:39]1[CH:40]=[CH:41][CH:42]=[CH:43][CH:44]=1
Reactant: CC(C)(C)OC(=O)N1CCN(C(=O)c2ccc3n2Cc2ccccc2N(C(=O)C2=CC=C(c4ccccc4)C(C)(C(F)(F)F)C2)C3)CC1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CCOCC
Product: CC1(C(F)(F)F)CC(C(=O)N2Cc3ccc(C(=O)N4CCNCC4)n3Cc3ccccc32)=CC=C1c1ccccc1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
The 4-[[10,11-dihydro-10-[[2-methyl-2-(trifluoromethyl)[1,1-biphenyl]-4-yl]carbonyl]-5H-pyrrolo[2,1-c][1,4]benzodiazepin-3-yl]carbonyl]-1-piperazinecarboxylic acid, tert-butyl ester of Step B (0.85 g, 1.29 mmol) was then added in one portion to stirred ethyl acetate (10 mL) saturated with hydrogen chloride gas at 0° C. The reaction mixture was stirred for 90 minutes under anhydrous conditions. A precipitate formed after several minutes. The reaction was then warmed to room temperature and diluted with diethyl ether. The precipitated product was collected by filtration and dried under high vacuum to provide 0.65 g of the desired title compound hydrochloride salt as an off-white foam.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][CH2:11][CH:10](C(N3CCN(C)CC3)=O)[CH2:9]2)=[CH:4][CH:3]=1.[CH3:23][N:24]1[CH2:29][CH2:28][N:27]([C:30](C2CCCN(C3C=CC([N+]([O-])=O)=CC=3)C2)=[O:31])[CH2:26][CH2:25]1>>[NH2:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[CH2:9][CH2:10][CH:11]([C:30]([N:27]3[CH2:28][CH2:29][N:24]([CH3:23])[CH2:25][CH2:26]3)=[O:31])[CH2:12][CH2:13]2)=[CH:6][CH:7]=1
Reactant: CN1CCN(C(=O)C2CCCN(c3ccc(N)cc3)C2)CC1
Reactant: CN1CCN(C(=O)C2CCCN(c3ccc([N+](=O)[O-])cc3)C2)CC1
Product: CN1CCN(C(=O)C2CCN(c3ccc(N)cc3)CC2)CC1

Procedure:
[1-(4-Amino-phenyl)-piperidin-4-yl]-(4-methyl-piperazin-1-yl)-methanone was prepared in a similar manner as [1-(4-Amino-phenyl)-piperidin-3-yl]-(4-methyl-piperazin-1-yl)-methanone of Example 443b after substituting (4-Methyl-piperazin-1-yl)-[1-(4-nitro-phenyl)-piperidin-4-yl]-methanone for (4-Methyl-piperazin-1-yl)-[1-(4-nitro-phenyl)-piperidin-3-yl]-methanone (250 mg, 98%). LC/MS (E/I+) 303.19 (M+H).
Reaction SMILES: C(O[C:4]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1[NH:16][CH:17]1[CH2:21][CH2:20][CH2:19][CH2:18]1)=[CH:13][CH:12]=[CH:11][C:10]=2[O:22][CH3:23])=[O:5])C.[N:24]([C:27]1[S:28][CH:29]=[CH:30][CH:31]=1)=[C:25]=[O:26]>>[CH:17]1([N:16]2[C:15]3[C:14]4[CH:13]=[CH:12][CH:11]=[C:10]([O:22][CH3:23])[C:9]=4[N:8]=[CH:7][C:6]=3[C:4](=[O:5])[N:24]([C:27]3[S:28][CH:29]=[CH:30][CH:31]=3)[C:25]2=[O:26])[CH2:18][CH2:19][CH2:20][CH2:21]1
Reactant: O=C=Nc1cccs1
Reactant: CCOC(=O)c1cnc2c(OC)cccc2c1NC1CCCC1
Product: COc1cccc2c1ncc1c(=O)n(-c3cccs3)c(=O)n(C3CCCC3)c12
Yield: 48.3 %

Procedure:
1-Cyclopentyl-7-methoxy-3-thiophen-2-yl-1H-pyrimido[5,4-c]quinoline-2,4-dione (19 mg) was prepared from 4-cyclopentylamino-8-methoxy-quinoline-3-carboxylic acid ethyl ester (0.10 mmol) and 2-isocyanatothiophene (0.4 mmol) following general procedure C. LCMS: m/z 394 [M+1]+.
Reaction SMILES: [F:1][C:2]1[C:16]([CH2:17][NH:18][C:19](=[O:25])[O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[CH:15][C:5]2[N:6]([CH:9]3[CH2:14][CH2:13][CH2:12][CH2:11][O:10]3)[CH:7]=[N:8][C:4]=2[CH:3]=1.[H-].[Na+].[CH3:28]I>C1COCC1>[F:1][C:2]1[C:16]([CH2:17][N:18]([CH3:28])[C:19](=[O:25])[O:20][C:21]([CH3:22])([CH3:24])[CH3:23])=[CH:15][C:5]2[N:6]([CH:9]3[CH2:14][CH2:13][CH2:12][CH2:11][O:10]3)[CH:7]=[N:8][C:4]=2[CH:3]=1
Reactant: CI
Reactant: CC(C)(C)OC(=O)NCc1cc2c(cc1F)ncn2C1CCCCO1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CN(Cc1cc2c(cc1F)ncn2C1CCCCO1)C(=O)OC(C)(C)C
Temperature: -60 °C
Reaction time: 0.5 h
Yield: 82.1 %

Procedure:
To a mixture of tert-butyl (5-fluoro-1-(tetrahydro-2H-pyran-2-yl)-1H-benzo[d]imidazol-6-yl)methylcarbamate (200 mg, 0.57 mmol) in anhydrous THF (2 mL) cooled to −60° C. was added NaH (60% in mineral oil, 21.6 mg, 0.9 mmol). After stirring at −60° C. for 30 min, CH3I (127 mg, 0.9 mmol) was added, followed by stirring at RT overnight. The reaction mixture was filtered and concentrated in vacuo. The residue was purified by SiO2 chromatography eluting with petroleum ether/EtOAc (3:1) to afford tert-butyl (5-fluoro-1-(tetrahydro-2H-pyran-2-yl)-1H-benzo[d]imidazol-6-yl)methyl(methyl)carbamate as white solid (170 mg, 97%). MS (ESI): m/z=364 [M+1]+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]=[CH:10][C:11](=[O:13])[CH3:12])=[CH:5][CH:4]=1.[OH-].[Na+].O.[CH:17](=O)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>CO>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]=[CH:10][C:11](=[O:13])[CH:12]=[CH:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[CH:5][CH:4]=1
Reactant: COc1ccc(C=CC(C)=O)cc1
Reactant: O=Cc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: COc1ccc(C=CC(=O)C=Cc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 96.9 %

Procedure:
1-(4-Methoxyphenyl)-1-buten-3-one (35e, 0.29 g, 1.6 mmol) was dissolved in methanol (5 ml) and stirred for 5 min at room temperature. A solution of sodium hydroxide (0.14 g, 3.5 mmol) and water (5 ml) was added and the mixture stirred for 30 min at room temperature. Benzaldehyde (1b, 0.17 ml, 1.7 mmol) was added dropwise and the mixture stirred for 18 hr at room temperature. The resulting precipitate was filtered and recrystallized from ethanol to give 0.41 g (94%) of a yellow solid: mp 85-89° C. [expected mp 118-119° C.]; 1H NMR: δ 3.82 (s, 3H), 6.91 (d, 2H, J=8.5 Hz), 6.94 (d, 1H, J=15.9 Hz), 7.06 (d, 1H, J=16.1 Hz), 7.38 (m, 4H), 7.57 (m, 3H), 7.71 (dd, 2H, J=15.9, 2.0 Hz); 13C NMR: δ 55.4, 114.4, 123.3, 125.5, 127.4, 128.2, 128.8, 130.0, 130.2, 134.8, 142.6, 143.0, 161.5, 188.6.
Reaction SMILES: [C:1]([CH2:4][CH2:5][CH2:6][N:7]([CH3:68])[C@H:8]([C:12]([NH:14][C@H:15]([C:19]([N:21]([C@@H:23]([C@@H:64]([CH3:67])[CH2:65][CH3:66])[C@H:24]([O:62][CH3:63])[CH2:25][C:26]([N:28]1[CH2:32][CH2:31][CH2:30][C@H:29]1[C@H:33]([O:60][CH3:61])[C@@H:34]([CH3:59])[C:35]([NH:37][C@@H:38]([CH2:52][C:53]1[CH:58]=[CH:57][CH:56]=[CH:55][CH:54]=1)[CH2:39][O:40][CH2:41][C:42]1[CH:47]=[CH:46][C:45]([C:48]([O:50]C)=[O:49])=[CH:44][CH:43]=1)=[O:36])=[O:27])[CH3:22])=[O:20])[CH:16]([CH3:18])[CH3:17])=[O:13])[CH:9]([CH3:11])[CH3:10])([OH:3])=[O:2].[OH-].[Li+].Cl>C1COCC1.O>[C:1]([CH2:4][CH2:5][CH2:6][N:7]([CH3:68])[C@H:8]([C:12]([NH:14][C@H:15]([C:19]([N:21]([C@@H:23]([C@@H:64]([CH3:67])[CH2:65][CH3:66])[C@H:24]([O:62][CH3:63])[CH2:25][C:26]([N:28]1[CH2:32][CH2:31][CH2:30][C@H:29]1[C@H:33]([O:60][CH3:61])[C@@H:34]([CH3:59])[C:35]([NH:37][C@@H:38]([CH2:52][C:53]1[CH:58]=[CH:57][CH:56]=[CH:55][CH:54]=1)[CH2:39][O:40][CH2:41][C:42]1[CH:43]=[CH:44][C:45]([C:48]([OH:50])=[O:49])=[CH:46][CH:47]=1)=[O:36])=[O:27])[CH3:22])=[O:20])[CH:16]([CH3:18])[CH3:17])=[O:13])[CH:9]([CH3:11])[CH3:10])([OH:3])=[O:2]
Reactant: CC[C@H](C)[C@@H]([C@@H](CC(=O)N1CCC[C@H]1[C@H](OC)[C@@H](C)C(=O)N[C@H](COCc1ccc(C(=O)OC)cc1)Cc1ccccc1)OC)N(C)C(=O)[C@@H](NC(=O)[C@H](C(C)C)N(C)CCCC(=O)O)C(C)C
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CC[C@H](C)[C@@H]([C@@H](CC(=O)N1CCC[C@H]1[C@H](OC)[C@@H](C)C(=O)N[C@H](COCc1ccc(C(=O)O)cc1)Cc1ccccc1)OC)N(C)C(=O)[C@@H](NC(=O)[C@H](C(C)C)N(C)CCCC(=O)O)C(C)C
Temperature: 25 °C
Reaction time: 3 h

Procedure:
7.5 mg (8 μmol) of N-(3-carboxypropyl)-N-methyl-L-valyl-N-[(3R,4S,5S)-3-methoxy-1-{(2S)-2-[(1R,2R)-1-methoxy-3-{[(2S)-1-{[4-(methoxycarbonyl)benzyl]oxy}-3-phenylpropane-2-yl]amino}-2-methyl-3-oxopropyl]pyrrolidin-1-yl}-5-methyl-1-oxoheptan-4-yl]-N-methyl-L-valinamide (example 26) were dissolved in 0.25 ml of THF/water (1:1). 0.8 mg (32 μmol) of lithium hydroxide were added and the batch stirred for 3 hours at RT. Then, the reaction composition was acidized with 1 N hydrochloric acid and extracted three times with 5 ml of ethyl acetate each. The organic phases were dried over magnesium sulphate and evaporated in a vacuum. Following lyophilization from dioxane, the yield was 2.3 mg (71% purity, 22% o. th.) of the title compound in the form of a white solid substance.
Reaction SMILES: Br[C:2]1[C:3]([Cl:9])=[N:4][C:5]([Cl:8])=[N:6][CH:7]=1.C([Mg]Cl)(C)C.[Br:15][C:16]1[CH:17]=[C:18]([CH:21]=[CH:22][CH:23]=1)[CH:19]=[O:20]>C1COCC1>[Br:15][C:16]1[CH:17]=[C:18]([CH:19]([C:2]2[C:3]([Cl:9])=[N:4][C:5]([Cl:8])=[N:6][CH:7]=2)[OH:20])[CH:21]=[CH:22][CH:23]=1
Reactant: Clc1ncc(Br)c(Cl)n1
Reactant: O=Cc1cccc(Br)c1
Agent: CC(C)[Mg]Cl
Solvent: C1CCOC1
Product: OC(c1cccc(Br)c1)c1cnc(Cl)nc1Cl
Reaction time: 1 h

Procedure:
To the solution of 5-bromo-2,4-dichloropyrimidine (22.8 g, 0.10 mol) in dry THF (150 mL), i-PrMgCl (50 mL, 0.10 mol, 2M in THF) was added dropwise at −35° C. under N2 atmosphere. After addition, the mixture was stirred for another one hour. Then 3-bromobenzaldehyde (18.5 g, 0.10 mol) was added in one portion. The resulting mixture was stirred for another two hours at −35° C. The reaction was quenched by water (10 mL), and filtered. The filtrate was extracted with ethyl acetate (3×300 mL). The combined organic phase was washed with water (300 mL), brine (200 mL) and dried over Na2SO4. The drying agent was removed by filtration and the residue was evaporated to give (3-bromo-phenyl)-(2,4-dichloro-pyrimidin-5-yl)-methanol as yellow oil. (Yield 33 g, 98.8%).
Reaction SMILES: [C:1](Cl)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.S(C1C=CC(C)=CC=1)(O)(=O)=O.[CH2:21]([O:28][C:29](=[O:38])[CH:30]([NH2:37])[CH2:31][S:32][C:33]([CH3:36])([CH3:35])[CH3:34])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>>[CH2:21]([O:28][C:29](=[O:38])[CH:30]([NH:37][C:1](=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[CH2:31][S:32][C:33]([CH3:35])([CH3:34])[CH3:36])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: CC(C)(C)SCC(N)C(=O)OCc1ccccc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Product: CC(C)(C)SCC(NC(=O)c1ccccc1)C(=O)OCc1ccccc1
Yield: 65 %

Procedure:
With General procedure D, starting from 21 (4.2 g, 30.2 mmol) and 15 (9.43 g, 21.45 mmol), 5.18 g (65%) of the title compound was obtained as a yellow solid. 1H NMR (400 MHz, CDCl3) δ 7.82 (d, 2H), 7.50 (m, 8H), 6.98 (br d, 1H), 5.27 (m, 2H), 5.12 (m, 1H), 3.15 (m, 2H), 1.27 (s, 9H). MS m/z 372 (M+1). HPLC: 96.80% (ACQ_PA95_C_BLS; Column: BEH_C18—2−1×50 mm—1-7 μm).
Reaction SMILES: [CH3:1][C:2]12[C:9]([CH3:11])([CH3:10])[CH:6]([CH2:7][CH2:8]1)[CH2:5][CH:4](O)[O:3]2.[I-].[C:14]1([P+](C2C=CC=CC=2)(C2C=CC=CC=2)C(C)C)[CH:19]=CC=C[CH:15]=1>>[CH3:1][C@@:2]1([OH:3])[CH2:8][CH2:7][C@@H:6]([CH2:5][CH:4]=[C:14]([CH3:19])[CH3:15])[C:9]1([CH3:11])[CH3:10]
Reactant: CC(C)[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: CC12CCC(CC(O)O1)C2(C)C
Agent: [I-]
Product: CC(C)=CC[C@@H]1CC[C@@](C)(O)C1(C)C
Yield: 71.1 %

Procedure:
Using the procedure of Example 7, 5 g of 1,8,8-trimethyl-2-oxa bicyclo [3,2,1] octan-3-ol and 15 g of triphenyl isopropyl phosphonium iodide were reacted and the product was chromatographed over silica gel and was eluted with an 8-2 cyclohexane-ethyl acetate mixture to obtain 4.1 g of (1R,S) 1,2,2-trimethyl-3-(3-methyl-2-butenyl)-cyclopentanol.
Reaction SMILES: [OH:1][C:2]1[C:3]([CH3:27])=[C:4]2[C:9](=[C:10]([CH3:13])[C:11]=1[CH3:12])[O:8][C:7]([CH3:26])([C:14]([NH:16][CH2:17][CH2:18][C:19]1[CH:24]=[CH:23][C:22]([OH:25])=[CH:21][CH:20]=1)=[O:15])[CH2:6][CH2:5]2.[O:28]=[N+]([O-])[O-].[O-][N+](=O)[O-].[O-][N+](=O)[O-].[O-][N+](=O)[O-].[O-][N+](=O)[O-].[O-][N+](=O)[O-].[Ce+4].[NH4+].[NH4+]>>[OH:25][C:22]1[CH:23]=[CH:24][C:19]([CH2:18][CH2:17][NH:16][C:14](=[O:15])[C:7]([OH:28])([CH3:26])[CH2:6][CH2:5][C:4]2[C:9](=[O:8])[C:10]([CH3:13])=[C:11]([CH3:12])[C:2](=[O:1])[C:3]=2[CH3:27])=[CH:20][CH:21]=1
Reactant: Cc1c(C)c2c(c(C)c1O)CCC(C)(C(=O)NCCc1ccc(O)cc1)O2
Reactant: O=[N+]([O-])[O-]
Agent: [Ce+4]
Agent: [NH4+]
Product: CC1=C(C)C(=O)C(CCC(C)(O)C(=O)NCCc2ccc(O)cc2)=C(C)C1=O
Yield: 14.4 %

Procedure:
Oxidation as described in protocol B, using 100 mg 6-hydroxy-N-(4-hydroxyphenethyl)-2,5,7,8-tetramethylchroman-2-carboxamide (0.271 mmol) and 325 mg CAN (0.595 mmol) yielded 15 mg of N-(4-hydroxyphenethyl)-2-hydroxy-2-methyl-4-(2,4,5-trimethyl-3,6-dioxocyclohexa-1,4-dienyl)butanamide as a yellow solid.
Reaction SMILES: F[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[N+:12]([O-:14])=[O:13])[NH:8][C:7](=[O:15])[N:6]([NH:16][S:17]([CH3:20])(=[O:19])=[O:18])[C:5]2=[O:21].[NH:22]1[CH2:26][CH2:25][CH:24]([OH:27])[CH2:23]1>>[OH:27][CH:24]1[CH2:25][CH2:26][N:22]([C:2]2[CH:3]=[C:4]3[C:9](=[CH:10][C:11]=2[N+:12]([O-:14])=[O:13])[NH:8][C:7](=[O:15])[N:6]([NH:16][S:17]([CH3:20])(=[O:19])=[O:18])[C:5]3=[O:21])[CH2:23]1
Reactant: OC1CCNC1
Reactant: CS(=O)(=O)Nn1c(=O)[nH]c2cc([N+](=O)[O-])c(F)cc2c1=O
Product: CS(=O)(=O)Nn1c(=O)[nH]c2cc([N+](=O)[O-])c(N3CCC(O)C3)cc2c1=O
Yield: 58 %

Procedure:
N-(6-Fluoro-7-nitro-2,4-dioxo-1,4-dihydro-2H-quinazolin-3-yl)-methanesulfonamide (30 mg, 0.0943 mmol) is reacted with pyrrolidin-3-ol according to the GPA affording 21 mg (58%) of a red powder. Rt=4.22 min.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([Br:8])[CH:5]=[C:4]([CH3:9])[C:3]=1[NH:10][C:11](=[O:17])[CH2:12][C:13]([CH3:16])([CH3:15])[CH3:14].C(N(CC)C(C)C)(C)C.Br[CH2:28][CH2:29][O:30][CH2:31][CH2:32]Br.C(=O)(O)[O-].[Na+]>CN(C)C=O>[Br:8][C:6]1[CH:7]=[C:2]([N:1]2[CH2:32][CH2:31][O:30][CH2:29][CH2:28]2)[C:3]([NH:10][C:11](=[O:17])[CH2:12][C:13]([CH3:14])([CH3:16])[CH3:15])=[C:4]([CH3:9])[CH:5]=1
Reactant: Cc1cc(Br)cc(N)c1NC(=O)CC(C)(C)C
Reactant: BrCCOCCBr
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1cc(Br)cc(N2CCOCC2)c1NC(=O)CC(C)(C)C
Temperature: 180 °C
Yield: 60 %

Procedure:
N-(2-Amino-4-bromo-6-methyl-phenyl)-3,3-dimethyl-butyramide (1v, 1.01 g), N,N-diisopropyl-ethylamine (1.80 mL) and bis(2-bromoethyl)ether (0.50 mL) were dissolved in dry N,N-dimethylformamide (5 mL) and heated to 180° C. for 50 minutes in a sealed microwave process vial. Saturated aqueous sodium bicarbonate (20 mL) was added and the mixture was extracted with ethyl acetate (3×20 mL), the combined organic phases were dried over sodium sulfate and concentrated in vacuo. The crude product was purified by flash chromatography to furnish 0.740 g (60% yield) of the title compound as a white solid. LC-MS (m/z) 370 (MH+); tR=3.05, (UV, ELSD) 95%, 99%. 1H NMR (500 MHz, DMSO-d6): 1.05 (s, 9H), 2.09 (s, 3H), 2.23 (s, 2H), 2.80 (t, 4H), 3.69 (t, 4H), 7.03 (d, 1H), 7.15 (d, 1H), 8.99 (s, 1H).
Reaction SMILES: [N:1]1([C:6]2[CH:7]=[C:8]([CH:12]=[CH:13][CH:14]=2)[C:9]([OH:11])=O)[CH:5]=[N:4][N:3]=[N:2]1.Cl.[CH2:16]([O:18][CH2:19][CH2:20][N:21]1[C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=2[N:23]=[C:22]1[N:30]1[CH2:36][CH2:35][CH2:34][N:33]([CH2:37][CH2:38][C:39]2([C:44]3[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=3)[CH2:43][CH2:42][NH:41][CH2:40]2)[CH2:32][CH2:31]1)[CH3:17]>>[N:1]1([C:6]2[CH:7]=[C:8]([CH:12]=[CH:13][CH:14]=2)[C:9]([N:41]2[CH2:42][CH2:43][C:39]([CH2:38][CH2:37][N:33]3[CH2:34][CH2:35][CH2:36][N:30]([C:22]4[N:21]([CH2:20][CH2:19][O:18][CH2:16][CH3:17])[C:25]5[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=5[N:23]=4)[CH2:31][CH2:32]3)([C:44]3[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=3)[CH2:40]2)=[O:11])[CH:5]=[N:4][N:3]=[N:2]1
Reactant: O=C(O)c1cccc(-n2cnnn2)c1
Reactant: CCOCCn1c(N2CCCN(CCC3(c4ccccc4)CCNC3)CC2)nc2ccccc21
Agent: Cl
Product: CCOCCn1c(N2CCCN(CCC3(c4ccccc4)CCN(C(=O)c4cccc(-n5cnnn5)c4)C3)CC2)nc2ccccc21

Procedure:
Prepare by the method of Example 56.1 using 3-(1H-tetrazol-1-yl)benzoic acid and 3-(2-(4-(1-(2-ethoxyethyl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-phenylpyrrolidine hydrochloric acid salt (prepared from (−)-3-phenyl-3-(2-hydroxyethyl)pyrrolidine(R,R)-di-p-anisoyltartaric acid salt) to give the title compound.
Reaction SMILES: C([NH:4][C:5]1(C(OCC)=O)[C:22](=[O:23])[N:8]2[C:9]3[CH:21]=[CH:20][CH:19]=[CH:18][C:10]=3[CH2:11][C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[CH:7]2[CH2:6]1)(=O)C.OS(O)(=O)=O.[OH-].[K+]>O>[NH2:4][CH:5]1[C:22](=[O:23])[N:8]2[C:9]3[CH:21]=[CH:20][CH:19]=[CH:18][C:10]=3[CH2:11][C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[CH:7]2[CH2:6]1
Reactant: CCOC(=O)C1(NC(C)=O)CC2c3ccccc3Cc3ccccc3N2C1=O
Agent: O=S(=O)(O)O
Agent: [K+]
Agent: [OH-]
Solvent: O
Product: NC1CC2c3ccccc3Cc3ccccc3N2C1=O
Temperature: 130 °C
Yield: 97 %

Procedure:
To 34,5 g of 2-acetylamino-2-ethoxycarbonyl-3-oxo-1,2,3,13b-tetrahydro-9H-pyrrolo[1,2-a]-dibenzo[c,f] azepine (oil, Rf in toluene: ethanol (9:2) = 0.5) are added 170 ml water and 10 ml concentrated H2SO4. The mixture is refluxed at 130° C. for 18 hours, then cooled down and made alcaline with KOH. The mixture is extracted wtih methylenechloride and the extracts washed with water, dried and evaporated. Melting point 186°-188° C. Yield 97%.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([N:15]2[C:19]([CH3:20])=[CH:18][CH:17]=[C:16]2[C:21]2[CH:26]=[CH:25][C:24]([OH:27])=[CH:23][CH:22]=2)=[CH:11][CH:10]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7].O[C@@H:29]([CH2:35][C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)[C:30]([O:32][CH2:33][CH3:34])=[O:31].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O>C1(C)C=CC=CC=1.O>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([N:15]2[C:19]([CH3:20])=[CH:18][CH:17]=[C:16]2[C:21]2[CH:22]=[CH:23][C:24]([O:27][C@H:29]([CH2:35][C:36]3[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=3)[C:30]([O:32][CH2:33][CH3:34])=[O:31])=[CH:25][CH:26]=2)=[CH:11][CH:10]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7]
Reactant: CCOC(=O)[C@@H](O)Cc1ccccc1
Reactant: CCCCCCCOc1ccc(-n2c(C)ccc2-c2ccc(O)cc2)cc1
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Solvent: O
Product: CCCCCCCOc1ccc(-n2c(C)ccc2-c2ccc(O[C@H](Cc3ccccc3)C(=O)OCC)cc2)cc1
Temperature: 80 °C
Reaction time: 12 h
Yield: 25.2 %

Procedure:
To a solution of 4-[1-(4-heptyloxyphenyl)-5-methyl-1H-pyrrol-2-yl]phenol (640 mg, 1.76 mmol), ethyl (S)-2-hydroxy-3-phenylpropanoate (513 mg, 2.64 mmol) and triphenylphosphine (692 mg, 2.64 mmol) in toluene (2 ml) was added 1,1′-(azodicarbonyl)dipiperidine (666 mg, 2.64 mmol) and the mixture was stirred at 80° C. for 12 hours. The reaction solution was poured into water and the mixture was extracted with ethyl acetate. The extract was dried over magnesium sulfate anhydride and the solvent was removed under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=30:1) to give the object compound as an oily substance. 240 mg (yield: 25.2%)
Reaction SMILES: [C:1]([C:3]1[C:4]([CH3:16])=[CH:5][C:6]([CH:13]([CH3:15])[CH3:14])=[C:7]([CH:12]=1)[C:8]([O:10][CH3:11])=[O:9])#[N:2].P(OCC)(OCC)([S-])=[S:18]>O1CCCC1.O>[C:1]([C:3]1[C:4]([CH3:16])=[CH:5][C:6]([CH:13]([CH3:14])[CH3:15])=[C:7]([CH:12]=1)[C:8]([O:10][CH3:11])=[O:9])(=[S:18])[NH2:2]
Reactant: CCOP(=S)([S-])OCC
Reactant: COC(=O)c1cc(C#N)c(C)cc1C(C)C
Solvent: O
Solvent: C1CCOC1
Product: COC(=O)c1cc(C(N)=S)c(C)cc1C(C)C
Temperature: 85 °C
Reaction time: 15 h
Yield: 86.5 %

Procedure:
To a round-bottom flask was added a solution of methyl 5-cyano-2-isopropyl-4-methylbenzoate (compound 196.3, 800 mg, 3.68 mmol, 1.00 equiv) in tetrahydrofuran/H2O (10/5 mL). O,O′-diethyl dithiophosphate (2.05 g, 11.0 mmol, 3.00 equiv) was added to the reaction mixture. The resulting solution was stirred for 15 h at 85° C. in an oil bath (CAUTION: significant gas evolution occurs—this and all other reactions described herein should be carried out in well ventilated fume hoods). After cooling to ambient temperature, the mixture was extracted with 2×100 mL of ethyl acetate. The combined organic layers were dried (Na2SO4) and concentrated in vacuo. The residue was purified using silica gel column chromatography with ethyl acetate/petroleum ether (1:100-1:50-1:0) as eluent to furnish 0.800 g (86%) of methyl 5-carbamothioyl-2-isopropyl-4-methylbenzoate as a yellow oil.
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[C:7]([C:16]3[C:25]4[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=4)[C:19](=[O:26])[N:18]([CH3:27])[CH:17]=3)=[N:8][C:9](S(C)(=O)=O)=[N:10][CH:11]=2)[CH2:3][CH2:2]1.[O:28]=[S:29]1(=[O:34])[CH2:33][CH2:32][CH2:31][NH:30]1>>[CH:1]1([CH2:4][O:5][C:6]2[C:7]([C:16]3[C:25]4[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=4)[C:19](=[O:26])[N:18]([CH3:27])[CH:17]=3)=[N:8][C:9]([N:30]3[CH2:31][CH2:32][CH2:33][S:29]3(=[O:34])=[O:28])=[N:10][CH:11]=2)[CH2:2][CH2:3]1
Reactant: Cn1cc(-c2nc(S(C)(=O)=O)ncc2OCC2CC2)c2ccccc2c1=O
Reactant: O=S1(=O)CCCN1
Product: Cn1cc(-c2nc(N3CCCS3(=O)=O)ncc2OCC2CC2)c2ccccc2c1=O

Procedure:
The title compound of Example 152, step 5 was treated with 1,1-dioxidoisothiazolidine instead of MeSO2NH2 in a manner similar to Example 152, step 6 to give the title compound. 1H NMR (DMSO-d6, 400 MHz) δ 8.56 (s, 1H), 8.30 (d, J=8.0 Hz, 1H), 7.86 (s, 1H), 7.77 (d, J=8.0 Hz, 1H), 7.67 (t, J=7.6 Hz, 1H), 7.55 (t, J=7.6 Hz, 1H), 3.93-3.91 (m, 4H), 3.59 (s, 3H), 2.38-2.31 (m, 2H), 1.06-1.01 (m, 1H), 0.44-0.39 (m, 2H), 0.20-0.16 (m, 2H). LCMS: 427.1 (M+H)+
Reaction SMILES: [N:1]1([C:7]2[N:12]=[C:11]([NH2:13])[CH:10]=[CH:9][N:8]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[CH3:14][O:15][C:16](=[O:30])[C:17]([C:19]1[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[C:22](Br)=[CH:21][CH:20]=1)=[O:18].C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1>C1(C)C=CC=CC=1.CC([O-])=O.CC([O-])=O.[Pd+2]>[CH3:14][O:15][C:16](=[O:30])[C:17]([C:19]1[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[C:22]([NH:13][C:11]2[CH:10]=[CH:9][N:8]=[C:7]([N:1]3[CH2:6][CH2:5][O:4][CH2:3][CH2:2]3)[N:12]=2)=[CH:21][CH:20]=1)=[O:18]
Reactant: Nc1ccnc(N2CCOCC2)n1
Reactant: COC(=O)C(=O)c1ccc(Br)c2ccccc12
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: c1ccc(P(c2ccccc2)c2ccc3ccccc3c2-c2c(P(c3ccccc3)c3ccccc3)ccc3ccccc23)cc1
Solvent: Cc1ccccc1
Product: COC(=O)C(=O)c1ccc(Nc2ccnc(N3CCOCC3)n2)c2ccccc12
Temperature: 100 °C
Reaction time: 24 h

Procedure:
2-Morpholin-4-yl-pyrimidin-4-ylamine (140 mg, 0.77 mmol) and (4-bromo-naphthalen-1-yl)-oxo-acetic acid methyl ester (18) (228 mg, 0.77 mmol) were suspended in 5 mL toluene and Pd(OAc)2 (5 mg, 3 mol %), BINAP (24 mg, 5 mol5) and CS2CO3 (753 mg, 2031 mmol) were added. The reaction mixture was stirred at 100° C. for 24 hrs. The cooled mixture was purified by column chromatography (0-100% EtOAc/Hex) to yield 169 mg of target product.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([C:8]2[N:9]=[C:10]3[C:19]4[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=4)[CH:13]=[CH:12][N:11]3[CH:20]=2)[CH:5]=[CH:6][CH:7]=1.[OH-].[K+].S(OCC)(O[CH2:27][CH3:28])(=O)=O>C(O)C>[CH2:27]([O:1][C:2]1[CH:3]=[C:4]([C:8]2[N:9]=[C:10]3[C:19]4[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=4)[CH:13]=[CH:12][N:11]3[CH:20]=2)[CH:5]=[CH:6][CH:7]=1)[CH3:28]
Reactant: Oc1cccc(-c2cn3ccc4ccccc4c3n2)c1
Reactant: CCOS(=O)(=O)OCC
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: CCOc1cccc(-c2cn3ccc4ccccc4c3n2)c1
Temperature: 25 °C

Procedure:
2-(3-Hydroxyphenyl)imidazo[2,1-a]isoquinoline (2.07 g.) is added to 0.63 g. of 85 percent potassium hydroxide in 25 ml. of ethanol. To this mixture, 1.56 ml. of diethyl sulfate in 5 ml. of ethanol is added at 0° to 5° C. The mixture is maintained for 16 hours at room temperature, then is refluxed for 30 minutes. After cooling, the solution is evaporated to dryness and the residue is washed thoroughly with water. Crystallization of the solid from ethanol yields 1 g. of the title product, melting at 102°-3° C.