Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[N:3]([CH2:29][C:30]([O:32]C)=[O:31])[C:4]([CH3:28])=[C:5]([S:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[S:20]([N:23]2[CH2:27][CH2:26][CH2:25][CH2:24]2)(=[O:22])=[O:21])[C:6]=1[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[OH-].[Na+]>>[CH3:1][C:2]1[N:3]([CH2:29][C:30]([OH:32])=[O:31])[C:4]([CH3:28])=[C:5]([S:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[S:20]([N:23]2[CH2:24][CH2:25][CH2:26][CH2:27]2)(=[O:22])=[O:21])[C:6]=1[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: COC(=O)Cn1c(C)c(Sc2ccccc2S(=O)(=O)N2CCCC2)c(-c2ccccc2)c1C
Agent: [Na+]
Agent: [OH-]
Product: Cc1c(Sc2ccccc2S(=O)(=O)N2CCCC2)c(-c2ccccc2)c(C)n1CC(=O)O
Yield: 62.7 %

Procedure:
was followed using methyl 2-(2,5-dimethyl-3-phenyl-4-(2-(pyrrolidin-1-ylsulfonyl)phenylthio)-1H-pyrrol-1-yl)acetate (24.6 mg, 0.0510 mmol) and 1M sodium hydroxide (0.152 ml, 0.152 mmol) to afford 2-(2,5-dimethyl-3-phenyl-4-(2-(pyrrolidin-1-ylsulfonyl)phenylthio)-1H-pyrrol-1-yl)acetic acid (15.2 mg, 0.0320 mmol, 64% yield) as a tan solid. 1H NMR (400 MHz, CDCl3): δ (ppm) 7.89 (dd, 1H), 7.07-7.22 (m, 7H), 6.93 (dd, 1H), 4.73 (s, 2H), 3.19-3.23 (m, 4H), 2.27 (s, 3H), 2.23 (s, 3H), 1.61-1.64 (m, 4H).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15](=[O:20])[CH2:16][CH2:17][CH2:18]Cl)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[CH2:22][C:23]([O:25][CH3:26])=[O:24].II>C1COCC1.C(OCC)(=O)C.[Zn]>[CH3:26][O:25][C:23](=[O:24])[CH2:22][C:15]1([C:12]2[CH:13]=[CH:14][C:9]([O:8][CH2:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)=[CH:10][CH:11]=2)[CH2:16][CH2:17][CH2:18][O:20]1
Reactant: O=C(CCCCl)c1ccc(OCc2ccccc2)cc1
Reactant: COC(=O)CBr
Agent: II
Agent: [Zn]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: COC(=O)CC1(c2ccc(OCc3ccccc3)cc2)CCCO1
Yield: 88.4 %

Procedure:
1-(4-Benzyloxy-phenyl)-4-chloro-butan-1-one (0.3 g, 1.04 mmol) was combined with methyl bromoacetate (0.24 g, 1.56 mmol) and zinc metal (0.05 g, 2.08 mmol) in THF (15 mL), a catalytic amount of iodine was added, and the reaction was heated to reflux for 18 h. The reaction was taken up in ethyl acetate, washed with water and brine, dried over magnesium sulfate, and concentrated to give [2-(4-benzyloxy-phenyl)-tetrahydro-furan-2-yl]-acetic acid methyl ester (0.3 g, 92%) as an oil. MS found: (M+H)+=327.
Reaction SMILES: [Cl:1][CH2:2][C:3](=[O:11])/[C:4](=[N:8]/[O:9][CH3:10])/[C:5]([OH:7])=O.[NH2:12][CH:13]1[C:43](=[O:44])[N:15]2[C:16]([C:27]([O:29][CH:30]([C:37]3[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=3)[C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)=[O:28])=[C:17]([CH2:20][S:21][C:22]3[S:26][N:25]=[N:24][CH:23]=3)[CH2:18][S:19][C@H:14]12.C(OC(N1C2C(=CC=CC=2)C=CC1OCC)=O)C>C(Cl)Cl>[Cl:1][CH2:2][C:3](=[O:11])/[C:4](=[N:8]/[O:9][CH3:10])/[C:5]([NH:12][C@@H:13]1[C:43](=[O:44])[N:15]2[C:16]([C:27]([O:29][CH:30]([C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)[C:37]3[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=3)=[O:28])=[C:17]([CH2:20][S:21][C:22]3[S:26][N:25]=[N:24][CH:23]=3)[CH2:18][S:19][C@H:14]12)=[O:7]
Reactant: CO/N=C(\C(=O)O)C(=O)CCl
Reactant: NC1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(CSc3cnns3)CS[C@H]12
Agent: CCOC(=O)N1c2ccccc2C=CC1OCC
Solvent: ClCCl
Product: CO/N=C(/C(=O)CCl)C(=O)N[C@@H]1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(CSc3cnns3)CS[C@H]12
Yield: 22.5 %

Procedure:
A solution of 4-chloro-2-(Z)-methoxyimino-3-oxobutanoic acid (4.05 g, 22.6 mmol.), diphenylmethyl 7-amino-3-[(1,2,3-thiadiazol-5-yl)thiomethyl]ceph-3-em-4-carboxylate (11.2 g, 22.6 mmol.) and 1-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline (5.58 g, 22.6 mmol.) in 200 ml of methylene chloride was stirred at room temperature for 3 hours. The solution was evaporated to dryness at reduced pressure and the residue was taken up in 150 ml of ethyl acetate which was extracted with 50 ml aliquots of 1N hydrochloric acid, water, saturated sodium bicarbonate, water and brine. The ethyl acetate was dried over magnesium sulfate, evaporated to dryness and the resulting product was purified by flash chromatography on silica gel 60 using ethyl acetate: hexane (1:2) as the eluent to afford 3.34 g of the desired compound:NMR (CDCl3) δ 3.52 (pair of d, 2H, J=18 Hz, endocyclic --CH2S--), 4.05 (pair of d, 2H, J=13 Hz, exocyclic --CH2S--), 4.15 (S, 3H, --OCH3)j, 4.59 (S, 2H, ClCH2 --), 5.04 (d, 1H, J=4.7 Hz, 6H of 7ACA), 5.88 (dd, 1H, J=4.7 and 8.6 Hz, 7H of 7ACA), 6.89 (S, 1H, --CH--), 7.33 (m, 10H, aromatic H), 8.37 (S, 1H, thiadiazole H).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:9][CH3:10])=[CH:4][CH:3]=1.C([Li])CCC.[CH3:16][C:17]([C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([Br:25])[CH:20]=1)=O.Cl>O1CCCC1>[Br:25][C:21]1[CH:22]=[CH:23][CH:24]=[C:19]([C:17]([C:2]2[CH:7]=[CH:6][C:5]([O:8][CH2:9][CH3:10])=[CH:4][CH:3]=2)=[CH2:16])[CH:20]=1
Reactant: CCOc1ccc(Br)cc1
Reactant: CC(=O)c1cccc(Br)c1
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: C=C(c1ccc(OCC)cc1)c1cccc(Br)c1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 30 %

Procedure:
To a solution of commercially available 1-bromo-4-ethoxy-benzene [588-96-5] (0.1 g, 25 mmol, 1.0 eq) in tetrahydrofuran (20 mL) was added dropwise a solution of n-butyllithium (1.6 M solution in hexane, 14.0 mL, 0.9 eq) at −78° C. After stirring 30 min at −78° C. 3-bromoacetophenone (3.7 mL, 1.1 eq) in tetrahydrofuran (20 mL) was added dropwise. The mixture was allowed to warm up to room temperature and stirred for 2 h, then treated with 1 N HCl (10 mL), extracted with ethyl acetate, dried (sodium sulfate) and concentrated in vacuo. The crude was dissolved in acetic acid (50 mL) and sulfuric acid (10 mL) and the mixture was warmed to 75° C. for 30 min, cooled to room temperature and 1 N NaOH was added up to pH=7. The aqueous phase was extracted with dichloromethane (3×10 mL), dried (sodium sulfate) the solvent was removed and the residue was purified by column chromatography (cyclohexane) to afford the title compound as a colorless oil (2.3 g, 30%);
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1[CH:14]=[CH:13][C:12]([CH:15](C)[CH2:16]C#N)=[CH:11][CH:10]=1.Cl.[C:21]([OH:24])(=[O:23])[CH3:22]>>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1[CH:14]=[CH:13][C:12]([CH:15]([CH3:16])[CH2:22][C:21]([OH:24])=[O:23])=[CH:11][CH:10]=1
Reactant: CC(CC#N)c1ccc(-c2ccc(F)cc2F)cc1
Reactant: CC(=O)O
Agent: Cl
Product: CC(CC(=O)O)c1ccc(-c2ccc(F)cc2F)cc1

Procedure:
1 g. of 3-(2',4'-difluoro-4-biphenylyl)butyronitrile and 6 ml. of acetic acid and 6 ml. of concentrated hydrochloric acid are heated under reflux for 2 hours under nitrogen. The mixture is evaporated. The residue is dissolved in dilute NaOH and the solution is washed with ether and worked up in the customary manner to give 3-(2',4'-difluoro-4-biphenylyl)butyric acid, m.p. 109°-110°.
Reaction SMILES: [CH2:1]([N:8]1[CH2:15][CH2:14][CH:13]=[CH:12][CH2:11][C@H:10]([NH:16][C:17](=[O:23])[O:18][C:19]([CH3:22])([CH3:21])[CH3:20])[C:9]1=[O:24])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>CCOC(C)=O.[Pd]>[CH2:1]([N:8]1[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][C@H:10]([NH:16][C:17](=[O:23])[O:18][C:19]([CH3:20])([CH3:21])[CH3:22])[C:9]1=[O:24])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)N[C@H]1CC=CCCN(Cc2ccccc2)C1=O
Agent: [Pd]
Agent: CC(C)(C)OC(=O)N[C@H]1C/C=C\CCN(Cc2ccccc2)C1=O
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N[C@H]1CCCCCN(Cc2ccccc2)C1=O
Reaction time: 1 h
Yield: 100 %

Procedure:
A suspension of (S,Z)-tert-butyl 1-benzyl-2-oxo-1,2,3,4,7,8-hexahydroazocin-3-ylcarbamate (86 mg, 0.26 mmol) and 5% Pd/C (15 mg) in EtOAc (1 mL) was stirred under a hydrogen balloon for 1 hr. The reaction mixture was filtered and the filtrate was concentrated and dried under high vacuum to afford (S)-tert-butyl 1-benzyl-2-oxoazocan-3-ylcarbamate (86 mg, 0.26 mmol, 99% yield) as a colorless oil. 1H NMR (400 MHz, CDCl3) δ ppm 7.42-7.14 (m, 5H), 5.71 (d, J=7.5 Hz, 1H), 5.17 (d, J=14.7 Hz, 1H), 4.72 (t, J=9.4 Hz, 1H), 4.02 (d, J=14.7 Hz, 1H), 3.75 (t, J=14.2 Hz, 1H), 3.17 (d, J=15.7 Hz, 1H), 2.18-1.98 (m, 1H), 1.82-1.34 (m, 7H), 1.47 (s, 9H).
Reaction SMILES: [NH:1]1[CH2:4][CH:3]([S:5]([C:8]2[CH:9]=[C:10]([CH:30]=[C:31]([C:33]([F:36])([F:35])[F:34])[CH:32]=2)[C:11]([N:13]([C:15]2[CH:16]=[N:17][CH:18]=[CH:19][C:20]=2[C:21]2[CH:26]=[CH:25][C:24]([F:27])=[CH:23][C:22]=2[O:28][CH3:29])[CH3:14])=[O:12])(=[O:7])=[O:6])[CH2:2]1.[S:37](=[O:41])(=[O:40])(N)[NH2:38]>C(OC(=O)C)(C)C>[F:27][C:24]1[CH:25]=[CH:26][C:21]([C:20]2[CH:19]=[CH:18][N:17]=[CH:16][C:15]=2[N:13]([CH3:14])[C:11](=[O:12])[C:10]2[CH:30]=[C:31]([C:33]([F:34])([F:36])[F:35])[CH:32]=[C:8]([S:5]([CH:3]3[CH2:4][N:1]([S:37](=[O:41])(=[O:40])[NH2:38])[CH2:2]3)(=[O:7])=[O:6])[CH:9]=2)=[C:22]([O:28][CH3:29])[CH:23]=1
Reactant: NS(N)(=O)=O
Reactant: COc1cc(F)ccc1-c1ccncc1N(C)C(=O)c1cc(C(F)(F)F)cc(S(=O)(=O)C2CNC2)c1
Solvent: CC(=O)OC(C)C
Product: COc1cc(F)ccc1-c1ccncc1N(C)C(=O)c1cc(C(F)(F)F)cc(S(=O)(=O)C2CN(S(N)(=O)=O)C2)c1

Procedure:
A suspension of 3-(azetidin-3-ylsulfonyl)-N-(4-(4-fluoro-2-methoxyphenyl)pyridin-3-yl)-N-methyl-5-(trifluoromethyl)benzamide (0.05 g, 95.5 μmol, example 280) and sulfuric diamide (36.7 mg, 382 μmol) in isopropylacetate (1 mL) was heated at reflux for 19 hours. The reaction mixture was evaporated and the product purified by preparative HPLC (Gemini NX column) using a gradient of MeOH:water (containing 0.1% formic acid) (20:80 to 98:2). Light brown solid (0.035 g; 60%). MS (ESI): m/z=603.10 [M+H]+.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([N:10]2[C:15](=[O:16])[NH:14][C:13](=[O:17])[CH:12]=[N:11]2)=[CH:6][CH:5]=1)([O-:3])=[O:2].Br[CH2:19][CH2:20][CH2:21][CH3:22].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[CH2:19]([N:14]1[C:13](=[O:17])[CH:12]=[N:11][N:10]([C:7]2[CH:6]=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:9][CH:8]=2)[C:15]1=[O:16])[CH2:20][CH2:21][CH3:22]
Reactant: CCCCBr
Reactant: O=c1cnn(-c2ccc([N+](=O)[O-])cc2)c(=O)[nH]1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCCCn1c(=O)cnn(-c2ccc([N+](=O)[O-])cc2)c1=O
Temperature: 45 °C
Reaction time: 8 h
Yield: 68.6 %

Procedure:
A mixture of 40 parts of 2-(4-nitrophenyl)-1,2,4-triazine-3,5-(2H,4H)-dione, 25.7 parts of 1-bromobutane, 26.25 parts of potassium carbonate and 720 parts of N,N-dimethylformamide was stirred overnight at 45° C. The reaction mixture was poured into 2000 parts of ice water. The precipitated product was filtered off, washed with water and 2,2'-oxybispropane and stirred in methanol. The product was filtered off and dried in vacuo at 70° C., yielding 33.9 parts (68.6%) of 4-butyl-2-(4-nitrophenyl)-1,2,4-triazine-3,5(2H,4H)-dione (int. 27).
Reaction SMILES: FC1C([O:8][C:9](=O)[C@H:10]([NH:26][C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH2:11][C:12]2[CH:17]=[CH:16][C:15]([C:18]3[CH:23]=[CH:22][C:21]([F:24])=[C:20]([Cl:25])[CH:19]=3)=[CH:14][CH:13]=2)=C(F)C(F)=C(F)C=1F.O[NH:40][C:41](=[NH:43])[CH3:42]>>[C:30]([O:29][C:27](=[O:28])[NH:26][C@@H:10]([C:9]1[O:8][N:43]=[C:41]([CH3:42])[N:40]=1)[CH2:11][C:12]1[CH:13]=[CH:14][C:15]([C:18]2[CH:23]=[CH:22][C:21]([F:24])=[C:20]([Cl:25])[CH:19]=2)=[CH:16][CH:17]=1)([CH3:33])([CH3:31])[CH3:32]
Reactant: CC(=N)NO
Reactant: CC(C)(C)OC(=O)N[C@H](Cc1ccc(-c2ccc(F)c(Cl)c2)cc1)C(=O)Oc1c(F)c(F)c(F)c(F)c1F
Product: Cc1noc([C@@H](Cc2ccc(-c3ccc(F)c(Cl)c3)cc2)NC(=O)OC(C)(C)C)n1
Yield: 88.9 %

Procedure:
[2-(3′-Chloro-4′-fluoro-biphenyl-4-yl)-1-(R)-(3-methyl-[1,2,4]oxadiazol-5-yl)-ethyl]-carbamic acid tert-butyl ester (96 mg,) was prepared from 2-(R)-tert-butoxycarbonylamino-3-(3′-chloro-4′-fluoro-biphenyl-4-yl)-propionic acid pentafluorophenyl ester (140 mg, 0.25 mmol) and N-hydroxy-acetamidine (37 mg, 0.5 mmol) following the general procedure O.
Reaction SMILES: [OH:1]S([O-])(=O)=O.[K+].[F:7][C:8]([F:26])([C:16]([F:25])([F:24])[C:17]([F:23])([F:22])[C:18]([F:21])([F:20])[F:19])[CH2:9][CH2:10][S:11]([CH2:13][C:14]#[N:15])=[O:12].S([O-])([O-])=O.[Na+].[Na+]>O.CO>[F:26][C:8]([F:7])([C:16]([F:24])([F:25])[C:17]([F:22])([F:23])[C:18]([F:19])([F:20])[F:21])[CH2:9][CH2:10][S:11]([CH2:13][C:14]#[N:15])(=[O:1])=[O:12]
Reactant: O=S(=O)([O-])O
Reactant: N#CCS(=O)CCC(F)(F)C(F)(F)C(F)(F)C(F)(F)F
Agent: O=S([O-])[O-]
Agent: [K+]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: N#CCS(=O)(=O)CCC(F)(F)C(F)(F)C(F)(F)C(F)(F)F
Reaction time: 8 h

Procedure:
To a suspension of 9.21 g of a double salt of 2KHSO5.KHSO4.K2SO4 (Oxone, registered trade mark) in 50 ml of water was added dropwise a solution of 6.80 g of (3,3,4,4,5,5,6,6,6-nonafluorohexylsulfinyl)acetonitrile in 50 ml of methanol at room temperature over 60 minutes under a nitrogen atmosphere, and the mixture was stirred overnight. To the reaction mixture was added 25 ml of an aqueous 10% sodium sulfite solution, followed by extraction with 100 ml of ethyl acetate twice. Organic layers were combined, washed with 25 ml of an aqueous 10% sodium sulfite solution and 50 ml of an aqueous saturated sodium chloride solution, dried over sodium sulfate, filtered, and then concentrated under rescued pressure. The residue was subjected to silica gel column chromatography to obtain 5.4 g of (3,3,4,4,5,5,6,6,6-nonafluorohexylsulfonyl)acetonitrile represented by the formula:
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9][CH:10]([NH:20][C:21]([CH:23]2[CH2:28][CH2:27][N:26]([C:29](=[O:33])[CH2:30][NH:31][CH3:32])[CH2:25][CH2:24]2)=[O:22])[CH2:11][CH2:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[O:34]1[CH2:36][C@@H:35]1[CH2:37][O:38][C:39]1[CH:48]=[CH:47][CH:46]=[C:45]2[C:40]=1[CH:41]=[CH:42][CH:43]=[N:44]2>C(O)C>[C:14]1([CH2:13][CH2:12][CH2:11][CH:10]([NH:20][C:21]([CH:23]2[CH2:28][CH2:27][N:26]([C:29](=[O:33])[CH2:30][N:31]([CH2:36][C@@H:35]([OH:34])[CH2:37][O:38][C:39]3[CH:48]=[CH:47][CH:46]=[C:45]4[C:40]=3[CH:41]=[CH:42][CH:43]=[N:44]4)[CH3:32])[CH2:25][CH2:24]2)=[O:22])[CH2:9][CH2:8][CH2:7][C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: c1cc(OC[C@H]2CO2)c2cccnc2c1
Reactant: CNCC(=O)N1CCC(C(=O)NC(CCCc2ccccc2)CCCc2ccccc2)CC1
Solvent: CCO
Product: CN(CC(=O)N1CCC(C(=O)NC(CCCc2ccccc2)CCCc2ccccc2)CC1)C[C@@H](O)COc1cccc2ncccc12
Temperature: 25 °C

Procedure:
1-[(N-methyl)-2-aminoacetyl]-piperidine-4-carboxylic acid [4-phenyl-1-(3-phenyl-propyl)-butyl]-amide (63) (223.5 mg; 0.497 mmol]) is dissolved in ethanol (10 mL) at ambient temperature. (R)-5-Oxiranylmethoxy-quinoline (2) (100.0 mg; 0.497 mmol) is added, then the mixture is refluxed for 17.5 hours. After cooling to ambient temperature, the solution is concentrated in vacuo at 40° C. The residue is purified via silica gel chromatography with gradient elution (50%→100% acetone in hexanes, then 5%→20% ethanol in acetone) affording the desired product (110 mg) as a white solid. ESMS: MH+ 651.6.
Reaction SMILES: S(Cl)([Cl:3])=O.[NH2:5][C:6]1[N:11]=[C:10]([CH3:12])[C:9]([CH2:13][C:14]2[CH:19]=[CH:18][C:17]([CH2:20]O)=[CH:16][C:15]=2[F:22])=[C:8]([NH:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])[N:7]=1>C(Cl)Cl>[Cl:3][CH2:20][C:17]1[CH:18]=[CH:19][C:14]([CH2:13][C:9]2[C:8]([NH:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])=[N:7][C:6]([NH2:5])=[N:11][C:10]=2[CH3:12])=[C:15]([F:22])[CH:16]=1
Reactant: O=S(Cl)Cl
Reactant: CCCCCNc1nc(N)nc(C)c1Cc1ccc(CO)cc1F
Solvent: ClCCl
Product: CCCCCNc1nc(N)nc(C)c1Cc1ccc(CCl)cc1F
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Thionyl chloride (0.224 mL) was added to a solution of the product from step (v) (0.85 g) in DCM (15 mL) under nitrogen. The resulting mixture was stirred at rt for 2 h. The reaction mixture was evaporated to dryness under reduced pressure to give the subtitle compound as a yellow solid 0.85 g that was used without purification.
Reaction SMILES: CN([CH:9]=[O:10])C1C=CC=CC=1.P(Cl)(Cl)(Cl)=O.[Cl:16][C:17]1[CH:30]=[CH:29][C:28]2[C:19](=[CH:20][C:21]3[C:26]([CH:27]=2)=[CH:25][CH:24]=[CH:23][CH:22]=3)[CH:18]=1>ClC1C=CC=CC=1Cl>[Cl:16][C:17]1[CH:30]=[CH:29][C:28]2[C:19](=[C:20]([CH:9]=[O:10])[C:21]3[C:26]([CH:27]=2)=[CH:25][CH:24]=[CH:23][CH:22]=3)[CH:18]=1
Reactant: CN(C=O)c1ccccc1
Reactant: Clc1ccc2cc3ccccc3cc2c1
Solvent: Clc1ccccc1Cl
Solvent: O=P(Cl)(Cl)Cl
Product: O=Cc1c2ccccc2cc2ccc(Cl)cc12
Temperature: 25 °C
Reaction time: 2 h
Yield: 56.8 %

Procedure:
N-methylformanilide (2.45 kg, 18.12 mol) was treated with phosphorus oxychloride (2.66 kg, 17.35 mol) over a 40 min period at ambient temperature. The intermediate Vilsmeier complex was stirred for 2 h at room temperature, then treated with 2-chloroanthracene (described in example 1a) (963 g, 4.53 mol), and o-dichlorobenzene (1.0 L). The resulting bright yellow mixture was heated gradually over 1.5 h to 9° C. at which point an exotherm ensued raising the reaction temperature to 115° C. The heat was removed until the exotherm subsided (45 min), after which time the mixture was heated for 9 h at 90° C., then cooled. TLC analysis (silica gel; ethyl acetate:hexane 1:4) showed a small amount of unreacted anthracene (Rf 0.90), a small amount of the 3-chloro isomer (Rf 0.65), and the 2-chloro isomer (Rf 0.58) as the major component. The cooled reaction mixture was poured into ice/water (27 L) precipitating a dark brown tar. The aqueous layer was decanted away from the tar and extracted with methylene chloride (5×2 L). The combined extracts were used to redissolve the tar. The methylene chloride solution was washed with 3N hydrochloric acid (4×1.5 L), followed by water (2 L), then dried over magnesium sulfate. The extracts were filtered, then pressure-filtered through a bed of silica gel, eluting with methylene chloride until all of the desired compound had been recovered. The eluent was concentrated on the rotary evaporator to give a slurry of bright yellow crystals (in o-dichlorobenzene). The crystals were collected by filtration, washed with diethyl ether (2×500 ml), then vacuum dried to afford 619.7 g (56.9%) of the desired 2-chloro-9-formylanthracene (mp 148°-150° C.). 1H NMR (CDCl3) 11.35 (s, 1H), 9.02 (d, J=0.9 Hz, 1H), 8.81 (d, J=8.9 Hz, 1H), 8.56 (s, 1H), 7.98 (m, 1H), 7.90 (d, J=8.9 Hz, 1H), 7.66 (m, 1H), 7.53 (m, 1H), 7.42 (m, 1H).
Reaction SMILES: C(N(CC)CC)C.[NH2:8][C@@H:9]1[CH2:13][CH2:12][N:11]([C:14]2[C:23]3[C:18](=[CH:19][C:20]([CH3:24])=[CH:21][CH:22]=3)[N:17]=[C:16]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=3[OH:31])[N:15]=2)[CH2:10]1.Cl[C:33]([O:35][CH2:36][CH:37]([CH3:39])[CH3:38])=[O:34]>CN(C=O)C>[OH:31][C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][C:25]=1[C:16]1[N:15]=[C:14]([N:11]2[CH2:12][CH2:13][C@@H:9]([NH:8][C:33](=[O:34])[O:35][CH2:36][CH:37]([CH3:39])[CH3:38])[CH2:10]2)[C:23]2[C:18](=[CH:19][C:20]([CH3:24])=[CH:21][CH:22]=2)[N:17]=1
Reactant: CC(C)COC(=O)Cl
Reactant: Cc1ccc2c(N3CC[C@@H](N)C3)nc(-c3ccccc3O)nc2c1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: Cc1ccc2c(N3CC[C@@H](NC(=O)OCC(C)C)C3)nc(-c3ccccc3O)nc2c1
Temperature: -20 °C
Reaction time: 0.25 h
Yield: 58.2 %

Procedure:
Under an N2 atmosphere, triethylamine (0.35 mL, 2.5 mmol) was added to a solution of (R)-2-(4-(3-aminopyrrolidin-1-yl)-7-methylquinazolin-2-yl)phenol (0.40 g, 1.25 mmol) in DMF (6.0 mL). The reaction mixture was cooled to −20° C. external temperature, and isobutyl chloroformate (180 μL, 1.38 mmol) was added dropwise. The reaction was stirred for 10 minutes at −20° C. and 15 minutes at RT. The mixture was quenched with H2O, and partitioned between CH2Cl2 and H2O, and the aqueous layer was extracted once more with CH2Cl2. The organic phase was dried over Na2SO4, filtered and purified via silica gel chromatography using 6% EtOAc in a 1:1 mixture of hexanes and CH2Cl2 to yield (R)-isobutyl 1-(2-(2-hydroxyphenyl)-7-methylquinazolin-4-yl)pyrrolidin-3-ylcarbamate (compound 5) (306 mg, 58%). 1H NMR (400 MHz, DMSO-d6) δ 8.43 (m, 1H), 8.18 (d, J=8.6 Hz, 1H), 7.59 (s, 2H), 7.35 (m, 2H), 6.92 (m, 2H), 4.06 (m, 5H), 3.75 (d, J=4.4 Hz, 2H), 2.49 (s, 3H), 2.23 (m, 1H), 2.03 (m, 1H), 1.83 (m, 1H), 0.87 (d, J=6.5 Hz, 6H) ppm. LC/MS: m/z 421.3 (M+H)+ at 2.54 min (10%-99% CH3CN (0.035% TFA)/H2O (0.05% TFA)).
Reaction SMILES: [CH3:1][C:2]1[S:3][C:4]([C:8]([OH:10])=O)=[C:5]([CH3:7])[N:6]=1.C(N(CC)CC)C.ClC(OCCCC)=O.Cl.[O:27]1[CH:31]=[CH:30][CH:29]=[C:28]1[CH:32]([NH2:35])[C:33]#[N:34]>O1CCCC1>[C:33]([CH:32]([NH:35][C:8]([C:4]1[S:3][C:2]([CH3:1])=[N:6][C:5]=1[CH3:7])=[O:10])[C:28]1[O:27][CH:31]=[CH:30][CH:29]=1)#[N:34]
Reactant: Cc1nc(C)c(C(=O)O)s1
Reactant: N#CC(N)c1ccco1
Agent: CCCCOC(=O)Cl
Agent: Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: Cc1nc(C)c(C(=O)NC(C#N)c2ccco2)s1
Reaction time: 8 h
Yield: 63.3 %

Procedure:
4.71 g of 2,4-dimethylthiazole-5-carboxylic acid was suspended in 70 ml of tetrahydrofuran, and 6.67 g of triethylamine was added. The mixture was stirred. While it was cooled to -10° to -5° C., 4.10 g of n-butyl chloroformate was added, and the mixture was stirred at this temperature for 30 minutes, and then 4.03 g of alpha-(2-furyl)-alpha-aminoacetonitrile hydrochloride was added. The mixture was stirred at room temperature for 5 hours, and then left to stand overnight. The precipitate was separated by filtration and distilled under reduced pressure to remove the solvent. The residue was purified by silica gel column chromatography. Elution with hexane/ethyl acetate gave 4.20 g (yield 53.6%) of the desired N-(alpha-cyanofurfuryl)-2,4-dimethylthiazole-5-carboxylic acid amide.
Reaction SMILES: [NH2:1][C:2]1[C:11]2[N:12]=[C:13]([CH2:19][CH2:20][CH2:21][CH3:22])[N:14]([CH2:15][CH2:16][CH2:17]O)[C:10]=2[C:9]2[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=2[N:3]=1.S(Cl)(Cl)=O>C(Cl)Cl>[NH2:1][C:2]1[C:11]2[N:12]=[C:13]([CH2:19][CH2:20][CH2:21][CH3:22])[N:14]([CH2:15][CH2:16][CH2:17][NH:12][CH2:11][CH2:10][N:14]([CH3:15])[CH3:13])[C:10]=2[C:9]2[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=2[N:3]=1
Reactant: CCCCc1nc2c(N)nc3ccccc3c2n1CCCO
Solvent: ClCCl
Solvent: O=S(Cl)Cl
Product: CCCCc1nc2c(N)nc3ccccc3c2n1CCCNCCN(C)C

Procedure:
A mixture of the product from step (v) (0.96 g) and thionyl chloride (10 mL) in DCM (20 mL) was heated under reflux for 6 h then evaporated under reduced pressure. The residue was dissolved in acetonitrile (20 mL) then N,N-dimethylethylenediamine (10 mL) added and the mixture heated under reflux for 24 h. The solvent was removed under reduced pressure and the residue purified by RPHPLC, yield 0.512 g.
Reaction SMILES: C(OC(N1CCC2N(C)C3C(C(F)(F)F)=CC(NC4C=CC=CN=4)=CC=3C2C1)=O)(C)(C)C.C(OC([N:40]1[CH2:56][CH2:55][C@@H:43]2[N:44]([CH3:54])[C:45]3[C:46]([C:52]#[N:53])=[CH:47][C:48](Br)=[CH:49][C:50]=3[C@@H:42]2[CH2:41]1)=O)(C)(C)C.[Cl:57][C:58]1[C:63]([NH2:64])=[CH:62][CH:61]=[C:60]([C:65]([F:68])([F:67])[F:66])[N:59]=1.CC([O-])(C)C.[Na+]>>[Cl:57][C:58]1[C:63]([NH:64][C:48]2[CH:49]=[C:50]3[C:45](=[C:46]([C:52]#[N:53])[CH:47]=2)[N:44]([CH3:54])[C@H:43]2[CH2:55][CH2:56][NH:40][CH2:41][C@@H:42]32)=[CH:62][CH:61]=[C:60]([C:65]([F:66])([F:67])[F:68])[N:59]=1
Reactant: CN1c2c(C#N)cc(Br)cc2[C@@H]2CN(C(=O)OC(C)(C)C)CC[C@@H]21
Reactant: Nc1ccc(C(F)(F)F)nc1Cl
Agent: CC(C)(C)[O-]
Agent: CN1c2c(cc(Nc3ccccn3)cc2C(F)(F)F)C2CN(C(=O)OC(C)(C)C)CCC21
Agent: [Na+]
Product: CN1c2c(C#N)cc(Nc3ccc(C(F)(F)F)nc3Cl)cc2[C@@H]2CNCC[C@@H]21

Procedure:
The title compound was prepared by following the general method for (5-methyl-6-trifluoromethyl-2,3,4,4a,5,9b-hexahydro-1H-pyrido[4,3-b]indol-8-yl)-pyridin-3-yl-amine (Method A) as an oil (40 mg, 20%) from (4aS,9bR)-8-bromo-6-cyano-5-methyl-1,3,4,4a,5,9b-hexahydro-pyrido[4,3-b]indole-2-carboxylic acid tert-butyl ester (Example 158, 196 mg, 0.5 mmol), 2-chloro-6-trifluoromethyl-pyridin-3-ylamine(186 mg, 1.5 mmol) and NaOt-Bu (144 mg, 1.5 mmol). MS (ESI): 408 (base, M+H).