Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[C:3]([NH:5][C:6]1[CH:11]=[CH:10][C:9]([Cl:12])=[CH:8][CH:7]=1)=O.P([Cl:31])(OC1C=CC=CC=1)(OC1C=CC=CC=1)=O.C(N(CC)CC)C.C(#N)C>C(OCC)(=O)C>[Cl:12][C:9]1[CH:10]=[CH:11][C:6]([N:5]=[C:3]([Cl:31])[C:2]([F:14])([F:13])[F:1])=[CH:7][CH:8]=1
Reactant: O=P(Cl)(Oc1ccccc1)Oc1ccccc1
Reactant: O=C(Nc1ccc(Cl)cc1)C(F)(F)F
Solvent: CCOC(C)=O
Solvent: CC#N
Solvent: CCN(CC)CC
Product: FC(F)(F)C(Cl)=Nc1ccc(Cl)cc1
Temperature: 82 °C
Yield: 78.5 %

Procedure:
Four grams (17.9 mmol) of 2,2,2-trifluoro-N-(4-chlorophenyl)acetamide, 9.61 g (35.8 mmol) of diphenyl chlorophosphate, 3.62 g (35.8 mmol) of triethylamine, and 20 ml of acetonitrile were introduced into a 50 ml flask and reacted for 16 hours while being refluxed (82° C.). After the reaction, the reaction solution was cooled to room temperature, 16 ml of ethyl acetate was added thereto, and the precipitate was then filtered off. The filtrate was subjected to solvent removal by evaporation, and the crude product thus obtained was purified by column chromatography (silica gel, ethyl acetate:hexane=3:7), resulting in 3.40 g of N-(4-chlorophenyl)-2,2,2-trifluoroacetimidoyl chloride as a yellow liquid (yield: 78.6%).
Reaction SMILES: [Br:1][C:2]1[C:6]2[CH:7]=[C:8]([O:11][CH3:12])[CH:9]=[CH:10][C:5]=2[O:4][C:3]=1[CH:13]=[O:14].[CH:15]1([Mg]Br)[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1.[Cl-].[NH4+]>O1CCCC1>[Br:1][C:2]1[C:6]2[CH:7]=[C:8]([O:11][CH3:12])[CH:9]=[CH:10][C:5]=2[O:4][C:3]=1[CH:13]([CH:15]1[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1)[OH:14]
Reactant: COc1ccc2oc(C=O)c(Br)c2c1
Reactant: Br[Mg]C1CCCCC1
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: COc1ccc2oc(C(O)C3CCCCC3)c(Br)c2c1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 67 %

Procedure:
To a solution (50 mL) of 3-bromo-5-methoxy-1-benzofuran-2-carbaldehyde (2.26 g) synthesized above in tetrahydrofuran was added a 1.0M solution (13.3 mL) of cyclohexylmagnesium bromide in tetrahydrofuran at −78° C., and the mixture was stirred at −78° C. for 30 min then at 0° C. for 1 hr. Saturated aqueous ammonium chloride solution was added to quench the reaction, tetrahydrofuran was evaporated in an evaporator, and the residue was extracted with ethyl acetate. The extract was washed with saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (20% ethyl acetate/hexane) to give the title object compound (1.82 g, 67%) as a yellow oil.
Reaction SMILES: Cl.[CH2:2]([N:5]([CH2:37][CH2:38][CH3:39])[CH2:6][CH2:7][CH2:8][CH2:9][N:10]([CH2:33]C(O)=O)[CH2:11][C:12]1[CH:17]=[CH:16][C:15]([CH2:18][N:19]([CH2:27][C:28]2[NH:29][CH:30]=[CH:31][N:32]=2)[CH2:20][C:21]2[N:22]([CH3:26])[CH:23]=[CH:24][N:25]=2)=[CH:14][CH:13]=1)[CH2:3][CH3:4].OCCN1C(=O)CCC1=O.[CH3:50][N:51]([CH:53]=[O:54])[CH3:52]>>[CH2:37]([N:5]([CH2:2][CH2:3][CH3:4])[CH2:6][CH2:7][CH2:8][CH2:9][N:10]([CH2:11][C:12]1[CH:13]=[CH:14][C:15]([CH2:18][N:19]([CH2:27][C:28]2[NH:29][CH:30]=[CH:31][N:32]=2)[CH2:20][C:21]2[N:22]([CH3:26])[CH:23]=[CH:24][N:25]=2)=[CH:16][CH:17]=1)[CH2:33][C:53]([N:51]([CH3:52])[CH3:50])=[O:54])[CH2:38][CH3:39]
Reactant: CN(C)C=O
Reactant: CCCN(CCC)CCCCN(CC(=O)O)Cc1ccc(CN(Cc2ncc[nH]2)Cc2nccn2C)cc1
Agent: Cl
Agent: O=C1CCC(=O)N1CCO
Product: CCCN(CCC)CCCCN(CC(=O)N(C)C)Cc1ccc(CN(Cc2ncc[nH]2)Cc2nccn2C)cc1

Procedure:
The hydrochloride (190 mg) of the compound obtained in Example 65-1 was dissolved in DMF (5.0 ml) and added with N-(2-hydroxyethyl)-succinimide (57.8 mg) and the whole was refluxed under heating for 4 hours. After completion of the reaction, the solvent was distilled off. The resultant was dissolved in chloroform and added with a saturated aqueous sodium hydrogen carbonate solution and the whole was stirred for a while. The solution was subjected to extraction with chloroform and washed with a saturated saline solution. The organic layer was dried with anhydrous sodium sulfate. The solvent was distilled off. The residue was purified through silica gel column chromatography (chloroform/methanol) and treated with hydrochloric acid, thereby obtaining a hydrochloride (82.5 mg) of the subject compound as a pale-yellow solid.
Reaction SMILES: C([N:8]1[CH2:12][C@@H:11]([CH2:13][NH:14][CH:15]([CH3:17])[CH3:16])[C@@H:10]([CH2:18][N:19]([CH:36]([CH3:38])[CH3:37])[C:20](=[O:35])[C:21]2[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[C:23]([O:29][CH2:30][CH2:31][CH2:32][O:33][CH3:34])[CH:22]=2)[CH2:9]1)C1C=CC=CC=1.[CH3:39][O:40][CH2:41][CH2:42][CH2:43][O:44][C:45]1[CH:46]=[C:47]([CH:51]=[CH:52][C:53]=1[O:54][CH3:55])[C:48](O)=[O:49].CC#N.O.CC#N>O>[CH:36]([N:19]([CH2:18][C@@H:10]1[C@H:11]([CH2:13][N:14]([CH:15]([CH3:17])[CH3:16])[C:48](=[O:49])[C:47]2[CH:51]=[CH:52][C:53]([O:54][CH3:55])=[C:45]([O:44][CH2:43][CH2:42][CH2:41][O:40][CH3:39])[CH:46]=2)[CH2:12][NH:8][CH2:9]1)[C:20](=[O:35])[C:21]1[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[C:23]([O:29][CH2:30][CH2:31][CH2:32][O:33][CH3:34])[CH:22]=1)([CH3:38])[CH3:37]
Reactant: COCCCOc1cc(C(=O)O)ccc1OC
Reactant: COCCCOc1cc(C(=O)N(C[C@H]2CN(Cc3ccccc3)C[C@H]2CNC(C)C)C(C)C)ccc1OC
Solvent: O
Solvent: CC#N
Product: COCCCOc1cc(C(=O)N(C[C@H]2CNC[C@H]2CN(C(=O)c2ccc(OC)c(OCCCOC)c2)C(C)C)C(C)C)ccc1OC

Procedure:
The title compound is prepared analogously as described in Example 361 by coupling N-[(3R*,4R*)-1-benzyl-4-(isopropylamino-methyl)-pyrrolidin-3-ylmethyl]-N-isopropyl4-methoxy-3-(3-methoxy-propoxy)-benzamide and 3-(3-methoxy-propoxy)-4-methoxy-benzoic acid in step J. MS (LC-MS): 658.3 [M+H]+; tR (HPLC, Nucleosil C18 column, 10-100% CH3CN/H2O/5 min, 100% CH3CN/2.5 min, CH3CN and H2O containing 0.1% TFA, flow: 1.5 mL/min): 5.20 min.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:26]#[N:27])=[C:6]([C:8]2[C:13]([O:14][CH3:15])=[CH:12][N:11]([CH:16]([CH2:20][CH:21]3[CH2:24][CH2:23][CH2:22]3)[C:17](O)=[O:18])[C:10](=[O:25])[CH:9]=2)[CH:7]=1.[NH2:28][C:29]1[CH:41]=[CH:40][C:32]([C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])=[CH:31][CH:30]=1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:26]#[N:27])=[C:6]([C:8]2[C:13]([O:14][CH3:15])=[CH:12][N:11]([CH:16]([CH2:20][CH:21]3[CH2:22][CH2:23][CH2:24]3)[C:17]([NH:28][C:29]3[CH:41]=[CH:40][C:32]([C:33]([O:35][C:36]([CH3:37])([CH3:38])[CH3:39])=[O:34])=[CH:31][CH:30]=3)=[O:18])[C:10](=[O:25])[CH:9]=2)[CH:7]=1
Reactant: CC(C)(C)OC(=O)c1ccc(N)cc1
Reactant: COc1cn(C(CC2CCC2)C(=O)O)c(=O)cc1-c1cc(Cl)ccc1C#N
Product: COc1cn(C(CC2CCC2)C(=O)Nc2ccc(C(=O)OC(C)(C)C)cc2)c(=O)cc1-c1cc(Cl)ccc1C#N

Procedure:
104 mg (0.27 mmol) of 2-[4-(5-chloro-2-cyanophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl]-3-cyclobutylpropanoic acid (racemate) and 57 mg (0.30 mmol, 1.1 eq.) of tert-butyl 4-aminobenzoate were reacted according to General Method 5A. Yield: 66 mg (purity 86%, 38% of theory)
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](Cl)=[O:7])=[CH:4][CH:3]=1.[N:11]([CH2:14][C:15]([O:17][CH3:18])=[O:16])=[C:12]=O.C(N(CC)CC)C>C1COCC1>[Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]2[O:7][CH:12]=[N:11][C:14]=2[C:15]([O:17][CH3:18])=[O:16])=[CH:4][CH:3]=1
Reactant: COC(=O)CN=C=O
Reactant: O=C(Cl)c1ccc(Cl)cc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: COC(=O)c1ncoc1-c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
1.40 g (8.00 mmol) of 4-chlorobenzoyl chloride, 1.00 g (10.09 mmol) of methyl isocyanatoacetate and 5.9 ml (42.39 mmol) of triethylamine are dissolved in 15 ml of dry THF and stirred at RT for 48 h. The solvent is then removed on a rotary evaporator. The residue is taken up in 20 ml of ethyl acetate and washed once with 5 ml of water. The organic phase is dried over magnesium sulfate and the solvent is removed on a rotary evaporator. The residue is suspended in 10 ml of cyclohexane and filtered off. It is then recrystallized from about 10 ml of methanol. This gives needle-shaped crystals which are dried in a drying cabinet at 50° C. A further product fraction is obtained by reprecipitation after recrystallization.
Reaction SMILES: [ClH:1].[CH3:2][N:3]([CH3:37])[C:4](=O)[O:5]C1C=C2C(=CC=1)C(CN(CCC(N1CCC3C=C(OC)C(OC)=CC=3CC1)=O)C)C2.[CH3:38][O:39][C:40]1[C:66]([O:67][CH3:68])=[CH:65][C:43]2[CH2:44][CH2:45][N:46]([C:49](=[O:64])[CH2:50][CH2:51][N:52]([CH2:54][CH:55]3[C:62]4[C:57](=[CH:58][CH:59]=[C:60]([OH:63])[CH:61]=4)[CH2:56]3)[CH3:53])[CH2:47][CH2:48][C:42]=2[CH:41]=1>>[ClH:1].[CH3:2][N:3]([CH3:37])[C:4](=[O:5])[O:63][C:60]1[CH:61]=[C:62]2[C:57](=[CH:58][CH:59]=1)[CH2:56][CH:55]2[CH2:54][N:52]([CH2:51][CH2:50][C:49]([N:46]1[CH2:47][CH2:48][C:42]2[CH:41]=[C:40]([O:39][CH3:38])[C:66]([O:67][CH3:68])=[CH:65][C:43]=2[CH2:44][CH2:45]1)=[O:64])[CH3:53]
Reactant: COc1cc2c(cc1OC)CCN(C(=O)CCN(C)CC1Cc3cc(OC(=O)N(C)C)ccc31)CC2
Reactant: COc1cc2c(cc1OC)CCN(C(=O)CCN(C)CC1Cc3ccc(O)cc31)CC2
Agent: Cl
Product: COc1cc2c(cc1OC)CCN(C(=O)CCN(C)CC1Cc3ccc(OC(=O)N(C)C)cc31)CC2

Procedure:
Obtained in the same manner as the compound of Example 47 but using the compound of Example 45 instead of the compound of Example 43.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][C:10]2[C:18]3[C:13](=[CH:14][CH:15]=[C:16]([OH:19])[CH:17]=3)[NH:12][C:11]=2[CH3:20])=[CH:4][CH:3]=1.[CH2:21]([O:23][C:24](=[O:29])[C:25](Br)([CH3:27])[CH3:26])[CH3:22]>>[CH2:21]([O:23][C:24](=[O:29])[C:25]([O:19][C:16]1[CH:17]=[C:18]2[C:13](=[CH:14][CH:15]=1)[NH:12][C:11]([CH3:20])=[C:10]2[CH2:9][CH2:8][C:5]1[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=1)([CH3:27])[CH3:26])[CH3:22]
Reactant: CCOC(=O)C(C)(C)Br
Reactant: Cc1[nH]c2ccc(O)cc2c1CCc1ccc(Cl)cc1
Product: CCOC(=O)C(C)(C)Oc1ccc2[nH]c(C)c(CCc3ccc(Cl)cc3)c2c1

Procedure:
The above compound was prepared from 3-[2-(4-chloro-phenyl)-ethyl]-2-methyl-1H-indole-5-ol and 2-bromo-2-methyl-propanoic acid ethylester using a procedure analogous to that of Example 10.
Reaction SMILES: [C:1](Cl)(Cl)=[S:2].[NH:5]([C:7](=[O:24])[S:8][C:9]1[CH:14]=[C:13]([C:15]([CH3:18])([CH3:17])[CH3:16])[C:12]([OH:19])=[C:11]([C:20]([CH3:23])([CH3:22])[CH3:21])[CH:10]=1)[NH2:6].C(OCC)(=O)C.C(=O)(O)[O-].[Na+]>O1CCCC1>[CH3:23][C:20]([C:11]1[CH:10]=[C:9]([S:8][C:7]2[O:24][C:1](=[S:2])[NH:6][N:5]=2)[CH:14]=[C:13]([C:15]([CH3:16])([CH3:17])[CH3:18])[C:12]=1[OH:19])([CH3:21])[CH3:22]
Reactant: CC(C)(C)c1cc(SC(=O)NN)cc(C(C)(C)C)c1O
Reactant: S=C(Cl)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC(C)(C)c1cc(Sc2n[nH]c(=S)o2)cc(C(C)(C)C)c1O
Reaction time: 0.17 h

Procedure:
Thiophosgene (0.39 mL, 5.1 mmol) is added dropwise to a -78° C. solution of S-[3,5-bis(1,1-dimethylethyl)-4-hydroxyphenyl] hydrazinecarbothioate (1.5 g, 5.1 mmol) in tetrahydrofuran (150 mL). The reaction mixture is stirred for 10 minutes then poured into a separatory funnel containing ethyl acetate and aqueous sodium bicarbonate. The organic phase is washed three times with water and once with brine. Drying the organic phase over magnesium sulfate and evaporation gives a solid which is crystallized from dichloromethane/hexane affording 1.1 g (62%) of 5-[[3,5-bis(1,1-dimethylethyl)-4-hydroxyphenyl]thio]-1,3,4-oxadiazole-2(3H)-thione, mp 129.0°-131.0° C.
Reaction SMILES: ClC1C=CC=C(C(OO)=[O:9])C=1.[Cl:12][C:13]1[CH:14]=[N:15][CH:16]=[CH:17][C:18]=1[CH:19]([S:28][C:29]1[CH:34]=[CH:33][C:32]([Cl:35])=[CH:31][CH:30]=1)[C:20]1[CH:25]=[C:24]([F:26])[CH:23]=[CH:22][C:21]=1[F:27]>C(Cl)Cl.CCOCC>[Cl:12][C:13]1[CH:14]=[N:15][CH:16]=[CH:17][C:18]=1[CH:19]([S:28]([C:29]1[CH:34]=[CH:33][C:32]([Cl:35])=[CH:31][CH:30]=1)=[O:9])[C:20]1[CH:25]=[C:24]([F:26])[CH:23]=[CH:22][C:21]=1[F:27]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: Fc1ccc(F)c(C(Sc2ccc(Cl)cc2)c2ccncc2Cl)c1
Solvent: CCOCC
Solvent: ClCCl
Product: O=S(c1ccc(Cl)cc1)C(c1cc(F)ccc1F)c1ccncc1Cl
Reaction time: 3 h

Procedure:
After 3-chloroperbenzoic acid (33 mg, 0.20 mmol) was added to a solution of the 3-chloro-4-[(4-chlorophenylthio)-(2,5-difluorophenyl)methyl]pyridine (75 mg, 0.20 mmol), which had been obtained in Example 341, in methylene chloride (10 ml), the mixture was stirred for 3 hours under ice cooling. The reaction mixture was diluted with ether (80 ml). The solution was washed with water and brine, and then concentrated under reduced pressure. The residue was purified by silica gel chromatography (hexane:ethyl acetate=3:1), whereby the title compound (48 mg, 60%) was obtained as a diastereomeric mixture (1:1).
Reaction SMILES: C([NH:4][C:5]1[CH:10]=[CH:9][C:8]([S:11][C:12]2[C:20]([S:21](=[O:24])(=[O:23])[NH2:22])=[CH:19][C:15]([C:16]([OH:18])=[O:17])=[CH:14][C:13]=2[NH2:25])=[CH:7][CH:6]=1)(=O)C.[CH:26](=O)[CH2:27][CH2:28][CH3:29].C([BH3-])#N.[Na+].Cl>CN(C)C=O.O>[NH2:4][C:5]1[CH:6]=[CH:7][C:8]([S:11][C:12]2[C:20]([S:21](=[O:23])(=[O:24])[NH2:22])=[CH:19][C:15]([C:16]([OH:18])=[O:17])=[CH:14][C:13]=2[NH:25][CH2:26][CH2:27][CH2:28][CH3:29])=[CH:9][CH:10]=1
Reactant: CCCC=O
Reactant: CC(=O)Nc1ccc(Sc2c(N)cc(C(=O)O)cc2S(N)(=O)=O)cc1
Agent: Cl
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCCCNc1cc(C(=O)O)cc(S(N)(=O)=O)c1Sc1ccc(N)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To the solution of 1.52 g of 4-(4-acetamidophenylmercapto)-3-amino-5-sulfamoylbenzoic acid in 600 ml of dimethylformamide, 40 g of butyraldehyde and 1.60 g of molecular sieves [Na12 (AlSiO4)12. 27 H2O], 36 g of sodium cyanoborohydride are added while stirring under nitrogen and keeping the temperature between about 20° and 30° for 1 hour. After stirring the mixture for 68 hours at room temperature, 6 lt of water are added, followed by 110 ml of concentrated hydrochloric acid and stirring is continued for 1 hour. The precipitate formed is filtered off, washed with water, dissolved in 1.2 lt of 2N aqueous sodium hydroxide and the solution refluxed for 2 hours under nitrogen. After cooling to room temperature it is filtered and the filtrate combined with 250 ml of glacial acetic acid. The precipitate formed is collected, 333 g thereof are dissolved in 2.8 lt of hot, 80% aqueous acetonitrile, the solution filtered, the filter washed with 500 ml more of said acetonitrile and the filtrate diluted with 3.3 lt of hot water. The precipitate formed at 14° is filtered off, taken up in 2.15 lt of hot, 90% aqueous ethanol and the solution diluted with 2.5 lt of hot water. The solids separated after cooling are collected and washed with water, to yield the 4-(4-aminophenylmercapto)-3-n-butylamino-5-sulfamoylbenzoic acid melting at 232°-234°, it is identical with that obtained according to Example 3.
Reaction SMILES: CO.C([O:5][C:6]([C:8]1[C:9]([C:14]([C:16]2[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=2)=[O:15])=[N:10][CH:11]=[N:12][CH:13]=1)=[O:7])C.[OH-].[Na+]>O>[CH3:23][O:22][C:19]1[CH:20]=[CH:21][C:16]([C:14]([C:9]2[C:8]([C:6]([OH:7])=[O:5])=[CH:13][N:12]=[CH:11][N:10]=2)=[O:15])=[CH:17][CH:18]=1
Reactant: CCOC(=O)c1cncnc1C(=O)c1ccc(OC)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: COc1ccc(C(=O)c2ncncc2C(=O)O)cc1
Temperature: 25 °C
Reaction time: 15 h

Procedure:
To a methanol solution(15 ml) of 4-(4-methoxyphenylcarbonyl)pyrimidine-5-carboxylic acid ethyl ester was added 4N NaOH(4 ml). The solution was stirred at room temperature for 15 h. Water was added to the reaction solution to dissolve the resulting solid. After removal of methanol the aqueous layer was washed with AcOEt, made pH2 with 2N HCl and extracted with AcOEt. The organic layer was washed with brine and dried over Na2SO4. After removal of the solvent the residue was recrystallized from AcOEt and hexane(1:1) to give 4-(4-methoxyphenylcarbonyl)pyrimidine-5-carboxylic acid(1.06 g) as a yellow solid.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22]CC)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Cl:25][S:26](O)(=[O:28])=[O:27]>C(Cl)(Cl)Cl>[CH2:7]([C:1]1[CH:6]=[CH:5][C:4]([S:26]([Cl:25])(=[O:28])=[O:27])=[CH:3][CH:2]=1)[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22]
Reactant: CCCCCCCCCCCCCCCCCCc1ccccc1
Reactant: O=S(=O)(O)Cl
Solvent: ClC(Cl)Cl
Product: CCCCCCCCCCCCCCCCc1ccc(S(=O)(=O)Cl)cc1
Temperature: 25 °C
Reaction time: 22 h
Yield: 72 %

Procedure:
To a solution of 1-phenyloctadecane (0.76 g, 2.5 mmol) in CHCl3 (5 mL) was added chlorosulfonic acid (0.5 mL, 7.5 mmol) and the mixture was stirred at rt for 22 h. The mixture was poured on ice and extracted with CH2Cl2. The combined extracts were washed with water, a solution of NaHCO3, and water, dried (Na2SO4), and concentrated in vacuo. The residue was chromatographed on silica gel (70-230 mesh) with hexane/ethyl acetate (49:1) to give the product as a white solid (0.71 g, 1.8 mmol, 72%), mp 35-36° C.; 1H NMR (300 MHz, CDCl3) δ 0.88 (t, 3H, J=7.2 Hz), 1.25 (m, 26H), 1.62 (m, 2H), 2.72 (t, 2H, J=7.8 Hz), 7.42 (d, 2H, J=8.4 Hz), 7.95 (d, 2H, J=8.4 Hz); 13C NMR (75 MHz, CDCl3) 14.4, 22.9, 29.4, 29.64, 29.8, 29.9, 31.2, 32.2, 36.3, 127.3, 129.8, 142.0, 151.9.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([CH3:13])([C:11]#[CH:12])[CH3:10])=[CH:4][CH:3]=1.C1(C)C=CC=CC=1.O>[Cu]Cl.CCOC(C)=O>[Br:1][C:2]1[CH:7]=[C:6]2[C:5](=[CH:4][CH:3]=1)[NH:8][C:9]([CH3:13])([CH3:10])[CH:11]=[CH:12]2
Reactant: C#CC(C)(C)Nc1ccc(Br)cc1
Agent: Cl[Cu]
Solvent: O
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: CC1(C)C=Cc2cc(Br)ccc2N1
Reaction time: 8 h

Procedure:
To a solution of 4-bromo-N-(2-methylbut-3-yn-2-yl)benzenamine (3.30 g, 14 mmol) in toluene (14 ml, 14 mmol) was added copper(I) chloride (0.300 g, 3.0 mmol) in one portion. The reaction vessel was sealed and the resulting mixture was heated to 90 deg C. After stirring overnight, the mixture was transferred to a separatory funnel containing water and EtOAc. The aqueous layer was washed 1× with EtOAc and 3× with DCM. The organic layers were combined, dried with MgSO4, filtered and concentrated. The crude oil was purified with an MPLC (100% DCM to 10% (91/10/1 DCM:MeOH:NH4OH)) to provide the product. MS m/z: 238.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[CH:2]1.I[C:7]1[CH:12]=[CH:11][C:10]([C:13]2([OH:23])[CH2:22][CH2:21][C:16]3(OCC[O:17]3)[CH2:15][CH2:14]2)=[CH:9][CH:8]=1.C([O-])([O-])=O.[Cs+].[Cs+]>CN(C=O)C.C(OCC)(=O)C.O.[Cu]I>[OH:23][C:13]1([C:10]2[CH:11]=[CH:12][C:7]([N:1]3[CH:5]=[CH:4][N:3]=[CH:2]3)=[CH:8][CH:9]=2)[CH2:14][CH2:15][C:16](=[O:17])[CH2:21][CH2:22]1
Reactant: c1c[nH]cn1
Reactant: OC1(c2ccc(I)cc2)CCC2(CC1)OCCO2
Agent: [Cu]I
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: O
Product: O=C1CCC(O)(c2ccc(-n3ccnc3)cc2)CC1
Temperature: 190 °C
Reaction time: 0.17 h

Procedure:
To a solution of imidazole (102 mg, 1.5 mmol) and 8-(4-iodo-phenyl)-1,4-dioxa-spiro[4.5]decan-8-ol (316 mg, 1 mmol) in DMF (1 mL) was added CuI (19 mg, 0.1 mmol) and Cs2CO3 (488 mg, 1.5 mmol) and the mixture was stirred at 190° C. under microwave for 10 min. The mixture was diluted with ethyl acetate (50 mL) and water (10 mL). The organic layer was filtered through celite and the filtrate was washed with saline solution (2×10 mL), dried over sodium sulfate, and concentrated in vacuo. The residue was dissolve in THF (1 mL) and was treated with 5% HCl (9 mL) at rt for 14 h. The mixture was neutralized with 1N NaOH to pH 7, concentrated on rotovap, and then extracted with EtOAc (2×50 mL). The organic extracts were combined, washed with saline solution (2×50 mL), dried over sodium sulfate, concentrated in vacuo. The resulting residue was chromatographed on silica gel, eluting with hexane/ethyl acetate (100/0 to 0/100), to provide the desired compound (180 mg, 70% for the two steps). LCMS: 257.2 (M+H+, 100%); 1H NMR: (CDCl3) δ 7.82 (s, 1H), 7.64 (d, 2H), 7.40 (s, 1H), 7.28 (s, 1H), 7.21 (s, 1H), 2.99-2.91 (m, 2H), 2.43-2.28 (m 4H), 2.23-2.18 (m, 2H).
Reaction SMILES: Cl[C:2]1[C:7]([C:8]#[N:9])=[C:6]([C:10]2[CH:15]=[CH:14][C:13]([NH:16][C:17]([NH:19][C:20]3[CH:21]=[C:22]([CH3:26])[CH:23]=[CH:24][CH:25]=3)=[O:18])=[CH:12][CH:11]=2)[CH:5]=[CH:4][N:3]=1.O.[NH2:28][NH2:29]>C(O)CCC>[NH2:9][C:8]1[C:7]2[C:2](=[N:3][CH:4]=[CH:5][C:6]=2[C:10]2[CH:15]=[CH:14][C:13]([NH:16][C:17]([NH:19][C:20]3[CH:25]=[CH:24][CH:23]=[C:22]([CH3:26])[CH:21]=3)=[O:18])=[CH:12][CH:11]=2)[NH:29][N:28]=1
Reactant: Cc1cccc(NC(=O)Nc2ccc(-c3ccnc(Cl)c3C#N)cc2)c1
Reactant: NN
Solvent: O
Solvent: CCCCO
Product: Cc1cccc(NC(=O)Nc2ccc(-c3ccnc4[nH]nc(N)c34)cc2)c1

Procedure:
A mixture of Example 35D (0.08 g, 0.22 mmol) and hydrazine hydrate (0.11 mL, 2.2 mmol) in n-butanol (5 mL) was heated at 110° C. for 2 h, then concentrated. The residue was purified via HPLC on an Agilent Zorbax Stablebond C-18 (7 micron particle size) preparative column using a solvent gradient of 20% to 100% acetonitrile in 0.1% aqueous TFA at a flow rate of 15 ml/min over 50 min, to give the title compound. 1H NMR (500 MHz, DMSO-D6) δ ppm 2.29 (s, 3H) 6.81 (d, J=7.32 Hz, 1H) 6.93 (d, J=4.58 Hz, 1H) 7.17 (t, J=7.63 Hz, 1H) 7.26 (d, J=7.63 Hz, 1H) 7.33 (s, 1H) 7.54 (d, J=8.24 Hz, 2H) 7.66 (d, J=7.93 Hz, 2H) 8.38 (d, J=4.27 Hz, 1H) 8.80 (s, 1H) 9.04 (s, 1H); MS (ESI(+)) m/e 359 (M+H)+.
Reaction SMILES: [CH2:1]1[C@@H:5]([C:6]([OH:8])=[O:7])[NH:4][CH2:3][C@@H:2]1[OH:9].[CH:10](N)=O.[H][H]>[Pd].O.C(O)C>[OH:9][C@H:2]1[CH2:3][N:4]([CH3:10])[C@H:5]([C:6]([OH:8])=[O:7])[CH2:1]1
Reactant: [H][H]
Reactant: O=C(O)[C@@H]1C[C@@H](O)CN1
Reactant: NC=O
Agent: [Pd]
Solvent: CCO
Solvent: O
Product: CN1C[C@H](O)C[C@H]1C(=O)O
Yield: 92.1 %

Procedure:
A suspension of (2S,4R)-trans-4-hydroxyproline (5 g), 37% aqueous formamide solution (4.6 g) and 7.5% palladium on charcoal (53% water content, 3.2 g) in water (15 mL) was stirred at room temperature in an atmosphere of high-pressure hydrogen for 10 hours. After removing the palladium on charcoal by filtration, the water of the filtrate was removed by distillation under reduced pressure. The solid residue thus obtained was suspended and stirred in ethanol (25 mL). The crystals which precipitated were collected by filtration to give the title compound (5.1 g, yield 92%).
Reaction SMILES: ClC1C=CC=C(C(OO)=[O:9])C=1.[CH3:12][C:13]1[CH2:22][CH2:21][C:16]2([O:20][CH2:19][CH2:18][CH2:17]2)[O:15][CH:14]=1.C(=O)([O-])[O-].[K+].[K+]>C(Cl)Cl>[CH3:12][C:13]1([CH:14]=[O:9])[CH2:22][CH2:21][C:16]2([CH2:17][CH2:18][CH2:19][O:20]2)[O:15]1
Reactant: CC1=COC2(CCCO2)CC1
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Product: CC1(C=O)CCC2(CCCO2)O1
Reaction time: 0.25 h
Yield: 64.3 %

Procedure:
To a cooled and stirred solution of 8.80 g of 85% m-chloroperbenzoic acid in 120 ml of methylene chloride was added 6.16 g of 8-methyl-1,6-dioxaspiro[4.5]dec-7-ene in 20 ml of methylene chloride. The exothermic reaction was kept below 15° C. After 15 minutes, the mixture was poured into 600 ml of saturated potassium carbonate. The resulting organic layer was then washed with aqueous base, dried and distilled to yield 4.37 g of the desired product as a colorless liquid, b.p. 65°-70° C. (1 torr.).
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][N:5]2[C:10]([C:11]=1[CH3:12])=[C:9]([CH:13]1[CH2:15][CH2:14]1)[CH:8]=[C:7]([C:16]([O:18][CH3:19])=[O:17])[C:6]2=[O:20].[NH2:21][C:22]1[CH:23]=[C:24](B(O)O)[CH:25]=[C:26]([F:28])[CH:27]=1>>[NH2:21][C:22]1[CH:23]=[C:24]([C:2]2[CH:3]=[CH:4][N:5]3[C:10]([C:11]=2[CH3:12])=[C:9]([CH:13]2[CH2:15][CH2:14]2)[CH:8]=[C:7]([C:16]([O:18][CH3:19])=[O:17])[C:6]3=[O:20])[CH:25]=[C:26]([F:28])[CH:27]=1
Reactant: Nc1cc(F)cc(B(O)O)c1
Reactant: COC(=O)c1cc(C2CC2)c2c(C)c(Cl)ccn2c1=O
Product: COC(=O)c1cc(C2CC2)c2c(C)c(-c3cc(N)cc(F)c3)ccn2c1=O
Yield: 86.7 %

Procedure:
Methyl 8-(3-amino-5-fluoro-phenyl)-1-cyclopropyl-9-methyl-4-oxo-4H-quinolizine-3-carboxylate was prepared according to General Procedure A using methyl 8-chloro-1-cyclopropyl-9-methyl-4-oxo-4H-quinolizine-3-carboxylate (100 mg, 0.34 mmol) and 3-amino-5-fluoro-phenyl-boronic acid (80 mg, 0.51 mmol). Purification by flash silica column chromatography (CH2Cl2:MeOH) (1:0 to 94:6) afforded the title compound as a yellow solid (108 mg, 81%). ESI-MS m/z: 367 (M+H)+.