Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[C:7]([CH:8]2[CH2:12][CH2:11][CH:10]=[CH:9]2)=[CH:6][C:5](Br)=[CH:4][C:3]=1[S:14]([OH:17])(=[O:16])=[O:15].CO.C(O)(=O)C>[Pd].O>[NH2:1][C:2]1[C:7]([CH:8]2[CH2:9][CH2:10][CH2:11][CH2:12]2)=[CH:6][CH:5]=[CH:4][C:3]=1[S:14]([OH:17])(=[O:15])=[O:16]
Reactant: Nc1c(C2C=CCC2)cc(Br)cc1S(=O)(=O)O
Agent: [Pd]
Solvent: CO
Solvent: O
Solvent: CC(=O)O
Product: Nc1c(C2CCCC2)cccc1S(=O)(=O)O
Temperature: 50 °C

Procedure:
9.6 g (30.3 mmol) of 2-amino-5-bromo-3-cyclopent-2-en-1-ylbenzenesulphonic acid are placed in a Parr apparatus and 1 g of 10% palladium-on-charcoal, 80 ml of methanol, 10 ml of acetic acid and 50 ml of water are added. The reaction medium is heated to 50° C. under a pressure of 0.35 MPa (50 psi). It is filtered through Celite, the filtrate is concentrated under reduced pressure and the residue thus obtained is crystallized from a methanol/pentane mixture.
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]2[O:14][CH2:13][CH2:12][C:11]3[CH:10]=[C:9]([C:15]4[N:16]([C:20]5[CH:25]=[CH:24][C:23]([F:26])=[CH:22][C:21]=5[F:27])[N:17]=[CH:18][N:19]=4)[S:8][C:7]=3[C:6]=2[N:28]=1.[CH:29]([NH2:32])([CH3:31])[CH3:30].CC(C1C=C(C(C)C)C(C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)=C(C(C)C)C=1)C.CC(C)([O-])C>O1CCOCC1.CC([O-])=O.CC([O-])=O.[Pd+2]>[F:27][C:21]1[CH:22]=[C:23]([F:26])[CH:24]=[CH:25][C:20]=1[N:16]1[C:15]([C:9]2[S:8][C:7]3[C:6]4[N:28]=[C:2]([NH:32][CH:29]([CH3:31])[CH3:30])[CH:3]=[CH:4][C:5]=4[O:14][CH2:13][CH2:12][C:11]=3[CH:10]=2)=[N:19][CH:18]=[N:17]1
Reactant: Fc1ccc(-n2ncnc2-c2cc3c(s2)-c2nc(Cl)ccc2OCC3)c(F)c1
Reactant: CC(C)N
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)(C)[O-]
Solvent: C1COCCO1
Product: CC(C)Nc1ccc2c(n1)-c1sc(-c3ncnn3-c3ccc(F)cc3F)cc1CCO2
Temperature: 120 °C
Reaction time: 0.08 h
Yield: 25.3 %

Procedure:
A mixture of 9-Chloro-2-[2-(2,4-difluoro-phenyl)-2H-[1,2,4]triazol-3-yl]-4,5-dihydro-6-oxa-1-thia-10-aza-benzo[e]azulene (300 mg, 0.72 mmol), Pd(OAc)2 (20 mg, 0.1 mmol), isopropylamine (80 mg, 1.44 mmol), X-phos (70 mg, 0.144 mmol), tert-butoxide (140 mg, 1.44 mmol) in dioxane (2 mL) was bubbled N2 for 10 min and then stirred at 120° C. for 5 min under the irradition of microwave. The mixture was filtered over celite. The filtrate was concentrated to dryness and purified by pre-HPLC to afford 80 mg of 276 (yield=25%). 1H NMR (CDCl3, 400 MHz) δ: 8.01 (s, 1H), 7.50-7.44 (m, 1H), 7.18-7.15 (m, 1H), 7.09-6.99 (m, 3H), 6.13 (d, J=8.8 Hz, 1H), 4.19-4.14 (m, 2H), 3.96-3.80 (m, 2H), 3.45-3.41 (m, 1H), 3.06-3.04 (m, 2H), 3.18-3.12 (m, 6H). LC-MS (ESI): m/z=439 [M+H]+
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:12][C:11]([CH3:13])=[N:10][C:9]=2[C:14]([N:16]2[CH2:21][CH2:20][CH2:19][CH2:18][CH:17]2[CH2:22][C:23]2[NH:24][C:25]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=3Br)=[CH:26][N:27]=2)=[O:15])=[CH:4][CH:3]=1.[Cu][C:36]#[N:37].C(OCC)(=O)C.O>CN1CCCC1=O.C(OCC)(=O)C>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:12][C:11]([CH3:13])=[N:10][C:9]=2[C:14]([N:16]2[CH2:21][CH2:20][CH2:19][CH2:18][CH:17]2[CH2:22][C:23]2[NH:24][C:25]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=3[C:36]#[N:37])=[CH:26][N:27]=2)=[O:15])=[CH:4][CH:3]=1
Reactant: N#C[Cu]
Reactant: Cc1nc(C(=O)N2CCCCC2Cc2ncc(-c3ccccc3Br)[nH]2)c(-c2ccc(F)cc2)s1
Solvent: CCOC(C)=O
Solvent: O
Solvent: CN1CCCC1=O
Product: Cc1nc(C(=O)N2CCCCC2Cc2ncc(-c3ccccc3C#N)[nH]2)c(-c2ccc(F)cc2)s1
Temperature: 25 °C
Reaction time: 6 h
Yield: 30.3 %

Procedure:
The compound of example 95 (0.11 g) and copper(I) cyanide (0.03 g) were combined in N-methylpyrrolidinone (5 ml) and the mixture boiled for 6 h. After cooling to room temperature the reaction mixture was stood overnight, diluted with ethyl acetate, passed through silica gel eluting with ethyl acetate/water. The organic phase was separated washed with water dried (MgSO4) and solvent removed at reduced pressure. The residue was column chromatographed (silica gel, 20→100% ethyl acetate/pentane), the appropriate fractions combined and solvent removed at reduced pressure to give the title compound (0.03 g) as a gum
Reaction SMILES: O=[C:2]1[CH2:7][CH2:6][CH:5]([NH:8][C:9]2[CH:14]=[CH:13][N:12]=[C:11]([CH3:15])[C:10]=2[O:16][CH3:17])[CH2:4][CH2:3]1.[CH2:18]([O:25][NH2:26])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.O.C(OCC)(=O)C.CO>C1(C)C=CC=CC=1>[CH2:18]([O:25][N:26]=[C:2]1[CH2:7][CH2:6][CH:5]([NH:8][C:9]2[CH:14]=[CH:13][N:12]=[C:11]([CH3:15])[C:10]=2[O:16][CH3:17])[CH2:4][CH2:3]1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: COc1c(NC2CCC(=O)CC2)ccnc1C
Reactant: NOCc1ccccc1
Solvent: Cc1ccccc1
Solvent: O
Solvent: CO
Product: COc1c(NC2CCC(=NOCc3ccccc3)CC2)ccnc1C

Procedure:
2 g of 4-(4-oxocyclohexylamino)-3-methoxy-2-methylpyridine and 1.2 g O-benzylhydroxylamine are boiled in toluene in a water separator until liberation of water has ended. The product is isolated by column chromatography (ethyl acetate/methanol 9:1; silica gel). 1.8 g=53%
Reaction SMILES: [CH:1]1([N:7]2[CH2:13][C:12]([F:15])([F:14])[C:11](=[O:16])[N:10]([CH3:17])[C:9]3[CH:18]=[N:19][C:20]([NH:22][C:23]4[CH:31]=[CH:30][C:26]([C:27](O)=[O:28])=[CH:25][C:24]=4[O:32][CH3:33])=[N:21][C:8]2=3)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C([N:36](CC)CC)C.F[P-](F)(F)(F)(F)F.CN(C(N(C)C)=[N+]1C2C(=NC=CC=2)[N+]([O-])=N1)C.[Cl-].[NH4+]>C(OCC)(=O)C.CN(C)C=O>[CH:1]1([N:7]2[CH2:13][C:12]([F:14])([F:15])[C:11](=[O:16])[N:10]([CH3:17])[C:9]3[CH:18]=[N:19][C:20]([NH:22][C:23]4[CH:31]=[CH:30][C:26]([C:27]([NH2:36])=[O:28])=[CH:25][C:24]=4[O:32][CH3:33])=[N:21][C:8]2=3)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CCN(CC)CC
Reactant: COc1cc(C(=O)O)ccc1Nc1ncc2c(n1)N(C1CCCCC1)CC(F)(F)C(=O)N2C
Agent: CN(C)C(N(C)C)=[N+]1N=[N+]([O-])c2ncccc21
Agent: F[P-](F)(F)(F)(F)F
Agent: [Cl-]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COc1cc(C(N)=O)ccc1Nc1ncc2c(n1)N(C1CCCCC1)CC(F)(F)C(=O)N2C
Reaction time: 0.25 h

Procedure:
A mixture of 0.120 g (0.26 mmole) of 4-(9-cyclohexyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-3-methoxy-benzoic acid (I-246), 0.105 g (1.04 mmole) of triethylamine, 0.148 g (0.39 mmole) of 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium-3-oxide hexafluorophosphate and 5 mL of dimethylformamide was stirred for 15 minutes, then 0.045 g (0.84 mmole) of ammonium chloride was added. The mixture was stirred for 3 hours, then taken up in 100 mL of ethyl acetate and washed twice with 100 mL of water and then 100 mL of brine. The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography, eluting with dichloromethane-methanol-ammonium hydroxide (gradient 100:0:0-92:8:0.3) to give 0.082 of 4-(9-cyclohexyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-3-methoxy-benzamide (I-248).
Reaction SMILES: [OH-].[K+].C([S:6][CH2:7][CH2:8][C:9]([N:11]1[N:15]=[C:14]([C:16]2[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][CH:17]=2)[S:13][CH:12]1[C:26]([O:28]CC1C=CC=CC=1)=[O:27])=[O:10])(=O)C.C(O)(=O)C>CO.O>[SH:6][CH2:7][CH2:8][C:9]([N:11]1[N:15]=[C:14]([C:16]2[CH:17]=[CH:18][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:20][CH:21]=2)[S:13][CH:12]1[C:26]([OH:28])=[O:27])=[O:10]
Reactant: CC(=O)SCCC(=O)N1N=C(c2ccc(C(F)(F)F)cc2)SC1C(=O)OCc1ccccc1
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: CC(=O)O
Solvent: O
Product: O=C(O)C1SC(c2ccc(C(F)(F)F)cc2)=NN1C(=O)CCS
Reaction time: 2 h

Procedure:
Potassium hydroxide in methanol (1M, 4.9 ml) was added to a solution of the product from step c) (0.81 g) in methanol (10 ml) and water (5 ml). The mixture was stirred under an atmosphere of nitrogen for 2 hours. Glacial acetic acid was added and the solvent was removed under reduced pressure The product was purified by flash chromatography using 1% acetic acid/99% ethyl acetate as eluent to yield the title compound (0.23 g) as a fawn solid. mp softens 93°-75°.
Reaction SMILES: CN(C)C=O.[NH2:6][C:7]1[N:12]=[C:11]([N:13]2[C:22]3[C:17](=[CH:18][C:19]([F:25])=[C:20](F)[C:21]=3[Br:23])[C:16](=[O:26])[C:15]([C:27]([OH:29])=[O:28])=[CH:14]2)[C:10]([F:30])=[CH:9][C:8]=1[F:31].Cl.[OH:33][CH:34]1[CH2:37][NH:36][CH2:35]1.CN1CCCC1>C(O)C>[NH2:6][C:7]1[N:12]=[C:11]([N:13]2[C:22]3[C:17](=[CH:18][C:19]([F:25])=[C:20]([N:36]4[CH2:37][CH:34]([OH:33])[CH2:35]4)[C:21]=3[Br:23])[C:16](=[O:26])[C:15]([C:27]([OH:29])=[O:28])=[CH:14]2)[C:10]([F:30])=[CH:9][C:8]=1[F:31]
Reactant: Nc1nc(-n2cc(C(=O)O)c(=O)c3cc(F)c(F)c(Br)c32)c(F)cc1F
Reactant: OC1CNC1
Agent: CN1CCCC1
Agent: Cl
Solvent: CCO
Solvent: CN(C)C=O
Product: Nc1nc(-n2cc(C(=O)O)c(=O)c3cc(F)c(N4CC(O)C4)c(Br)c32)c(F)cc1F
Temperature: 85 °C
Reaction time: 0.42 h
Yield: 81.8 %

Procedure:
To 270 mg of N,N-dimethylformamide were added 110 mg of 1-(6-amino-3,5-difluoropyridine-2-yl)-8-bromo-6,7-difluoro-4-oxo-1,4-dihydroquinoline-3-carboxylic acid, 50 mg of 3-hydroxyazetidine hydrochloride, and 100 mg of N-methy-lpyrrolidine together with 3 drops of ethanol, and the mixture was stirred at 85° C. for 25 minutes. After adding 0.5 ml of ethanol, the solution was allowed to cool, and the precipitate was collected by filtration and washed with ethanol and diisopropylether successively to obtain 101 mg of the title compound as a pale yellow powder.
Reaction SMILES: Cl.Cl.[NH2:3][CH2:4][CH2:5][N:6]1[C:14]2[C:13]([NH:15][C:16]3[CH:21]=[CH:20][C:19]([O:22][C:23]4[CH:28]=[CH:27][CH:26]=[C:25]([Cl:29])[CH:24]=4)=[C:18]([Cl:30])[CH:17]=3)=[N:12][CH:11]=[N:10][C:9]=2[CH:8]=[CH:7]1.[CH3:31][S:32]([CH2:35][C:36](O)=[O:37])(=[O:34])=[O:33].ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C>CN(C)C=O.O.C(N(CC)CC)C>[Cl:30][C:18]1[CH:17]=[C:16]([NH:15][C:13]2[C:14]3[N:6]([CH2:5][CH2:4][NH:3][C:36](=[O:37])[CH2:35][S:32]([CH3:31])(=[O:34])=[O:33])[CH:7]=[CH:8][C:9]=3[N:10]=[CH:11][N:12]=2)[CH:21]=[CH:20][C:19]=1[O:22][C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([Cl:29])[CH:24]=1
Reactant: NCCn1ccc2ncnc(Nc3ccc(Oc4cccc(Cl)c4)c(Cl)c3)c21
Reactant: CS(=O)(=O)CC(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: O
Solvent: CN(C)C=O
Product: CS(=O)(=O)CC(=O)NCCn1ccc2ncnc(Nc3ccc(Oc4cccc(Cl)c4)c(Cl)c3)c21
Temperature: 25 °C
Reaction time: 16 h
Yield: 68.8 %

Procedure:
To a solution of 5-(2-aminoethyl)-N-[3-chloro-4-(3-chlorophenoxy)phenyl]-5H-pyrrolo[3,2-d]pyrimidin-4-amine dihydrochloride (200 mg), 2-(methylsulfonyl)acetic acid (113 mg) and 1-hydroxybenzotriazole (122 mg) in N,N-dimethylformamide (5.0 mL) were added a solution of triethylamine (419 mg) in N,N-dimethylformamide (1.25 mL) and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (173 mg) under ice-cooling. After stirring the reaction mixture at room temperature for 16 hrs, water was added under ice-cooling, and the mixture was extracted twice with ethyl acetate. The organic layers were collected, dried over anhydrous magnesium sulfate and concentrated. The residue was purified by silica gel column chromatography (eluent:ethyl acetate/methanol=100/0→80/20), and recrystallized from ethanol-ethyl acetate-diisopropyl ether to give the title compound (151 mg) as crystals.
Reaction SMILES: [CH:1]1([C:7]2[NH:11][C:10](=[O:12])[C:9]3([CH2:17][CH2:16][N:15]([S:18](/[CH:21]=[CH:22]/[C:23]4[C:31]5[O:30][C:29](=[O:32])[NH:28][C:27]=5[CH:26]=[CH:25][CH:24]=4)(=[O:20])=[O:19])[CH2:14][CH2:13]3)[N:8]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[H][H]>CO.CN(C=O)C.[Pd]>[CH:1]1([C:7]2[NH:11][C:10](=[O:12])[C:9]3([CH2:17][CH2:16][N:15]([S:18]([CH2:21][CH2:22][C:23]4[C:31]5[O:30][C:29](=[O:32])[NH:28][C:27]=5[CH:26]=[CH:25][CH:24]=4)(=[O:20])=[O:19])[CH2:14][CH2:13]3)[N:8]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: [H][H]
Reactant: O=C1NC(C2CCCCC2)=NC12CCN(S(=O)(=O)/C=C/c1cccc3[nH]c(=O)oc13)CC2
Agent: [Pd]
Solvent: CO
Solvent: CN(C)C=O
Product: O=C1NC(C2CCCCC2)=NC12CCN(S(=O)(=O)CCc1cccc3[nH]c(=O)oc13)CC2
Yield: 82.8 %

Procedure:
10% Pd—C (28 mg) was added to a solution of 2-cyclohexyl-8-[(E)-2-(2-oxo-2,3-dihydro-benzoxazol-7-yl)-ethenesulfonyl]-1,3,8-triaza-spiro[4.5]dec-1-en-4-one (56.6 mg, 0.123 mmol) in MeOH-DMF (4 ml, 1:1). The mixture was stirred at room temperature overnight in a hydrogen atmosphere. The reaction mixture was filtered through celite, and the filtrate was then concentrated under reduced pressure. The resulting residue was diluted with ethyl acetate, and the organic layer was then washed with water (×2), dried over anhydrous Na2SO4 and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, AcOEt-hexane) to give 2-cyclohexyl-8-[2-(2-oxo-2,3-dihydro-benzoxazol-7-yl)-ethanesulfonyl]-1,3,8-triaza-spiro[4.5]dec-1-en-4-one as a colorless foam (46.9 mg, 83%).
Reaction SMILES: C(=O)([O-])[O-].[Cs+].[Cs+].C1(P(C2CCCCC2)C2C=CC=CC=2C2C(C(C)C)=CC(C(C)C)=CC=2C(C)C)CCCCC1.Br[C:42]1[C:50]2[O:49][C:48]([C:51]([O:53][CH2:54][CH3:55])=[O:52])=[CH:47][C:46]=2[CH:45]=[CH:44][CH:43]=1.[N:56]1([CH2:62][CH2:63][C:64]2[CH:65]=[C:66]3[C:70](=[CH:71][CH:72]=2)[N:69]([C:73](=[O:75])[CH3:74])[CH2:68][CH2:67]3)[CH2:61][CH2:60][NH:59][CH2:58][CH2:57]1>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[C:73]([N:69]1[C:70]2[C:66](=[CH:65][C:64]([CH2:63][CH2:62][N:56]3[CH2:61][CH2:60][N:59]([C:42]4[C:50]5[O:49][C:48]([C:51]([O:53][CH2:54][CH3:55])=[O:52])=[CH:47][C:46]=5[CH:45]=[CH:44][CH:43]=4)[CH2:58][CH2:57]3)=[CH:72][CH:71]=2)[CH2:67][CH2:68]1)(=[O:75])[CH3:74]
Reactant: CCOC(=O)c1cc2cccc(Br)c2o1
Reactant: CC(=O)N1CCc2cc(CCN3CCNCC3)ccc21
Agent: [Pd]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Product: CCOC(=O)c1cc2cccc(N3CCN(CCc4ccc5c(c4)CCN5C(C)=O)CC3)c2o1
Temperature: 95 °C
Yield: 61.5 %

Procedure:
Cesium carbonate (0.724 g, 2.22 mmol), 2-dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl (0.081 g, 0.17 mmol) and tris(dibenzylideneacetone)dipalladium(0) (0.078 g, 0.09 mmol) were added under argon to a mixture of ethyl 7-bromobenzofuran-2-carboxylate (0.460 g, 1.71 mmol) and 1-(5-(2-(piperazin-1-yl)ethyl)indolin-1-yl)ethanone (0.491 g, 1.79 mmol) (example 38c) in dry degassed dioxane (8 mL) and the reaction was heated at 95° C. over night. After cooling to room temperature, water and DCM were added and the layers separated. The aq phase was extracted with DCM (3×). The combined organic phases were washed with water, dried (MgSO4), filtered and evaporated. The crude product was purified by flash chromatography (DCM/MeOH 95/5) to give 0.485 g (61%) of the product.
Reaction SMILES: [N:1]1([C:8]2[N:12]3[CH:13]=[C:14]([O:17][C@H:18]4[C:27]5[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=5)[C@@H:21]([NH2:28])[CH2:20][CH2:19]4)[CH:15]=[CH:16][C:11]3=[N:10][N:9]=2)[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.ClC(Cl)(Cl)C[O:32][C:33](=O)[NH:34][C:35]1[N:36]([C:44]2[CH:49]=[CH:48][C:47]([CH3:50])=[CH:46][CH:45]=2)[N:37]=[C:38]([C:40]([CH3:43])([CH3:42])[CH3:41])[CH:39]=1.CCN(C(C)C)C(C)C>O1CCOCC1>[N:1]1([C:8]2[N:12]3[CH:13]=[C:14]([O:17][C@H:18]4[C:27]5[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=5)[C@@H:21]([NH:28][C:33]([NH:34][C:35]5[N:36]([C:44]6[CH:49]=[CH:48][C:47]([CH3:50])=[CH:46][CH:45]=6)[N:37]=[C:38]([C:40]([CH3:43])([CH3:42])[CH3:41])[CH:39]=5)=[O:32])[CH2:20][CH2:19]4)[CH:15]=[CH:16][C:11]3=[N:10][N:9]=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7]1
Reactant: Cc1ccc(-n2nc(C(C)(C)C)cc2NC(=O)OCC(Cl)(Cl)Cl)cc1
Reactant: N[C@H]1CC[C@@H](Oc2ccc3nnc(N4CCCCCC4)n3c2)c2ccccc21
Solvent: C1COCCO1
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccc(-n2nc(C(C)(C)C)cc2NC(=O)N[C@H]2CC[C@@H](Oc3ccc4nnc(N5CCCCCC5)n4c3)c3ccccc32)cc1
Yield: 10 %

Procedure:
A solution of Intermediate 67b (173 mg, 0.458 mmol) and (5-tert-butyl-2-p-tolyl-2H-pyrazol-3-yl)-carbamic acid 2,2,2-trichloro-ethyl ester (Synthetic Communications, 2009, 39, 3999-4009, which is incorporated herein by reference in its entirety; 186 mg, 0.458 mmol) in 1,4-dioxane (3 mL) and DIPEA (122 μl, 0.700 mmol) was stirred at 95° C. for 3.5 h. The cooled mixture was concentrated in vacuo. The residue was purified by FCC, using 0-14% [2M NH3 in MeOH] in DCM. Further purification by FCC, using 0-10% MeOH in DCM, gave impure product. This was further purified by HPLC (C18 X-select column, 30-98% MeCN in H2O, 0.1% HCO2H) to give impure product. Further purified by HPLC (XBridge column, 35-98% MeCN in H2O, 0.1% NH4OH) to give an off-white powder after freeze-drying (50 mg). This material was further purified by MDAP (Method 7) to give the title compound as a white solid (28 mg, 10%). LCMS (Method 5): Rt 4.77 min, m/z 633.2 [MH+]. 1H NMR (400 MHz, d6-DMSO): 1.27 (9H, s), 1.64-1.71 (4H, m), 1.74-1.97 (6H, m), 1.99-2.18 (2H, m), 2.36 (3H, s), 3.38-3.43 (4H, m, under water signal), 4.77-4.85 (1H, m), 5.47 (1H, t, J 4.3), 6.32 (1H, s), 7.07-7.14 (2H, m), 7.25-7.40 (8H, m), 7.55-7.59 (2H, m), 8.06 (1H, s).
Reaction SMILES: [CH:1]1[C:11]2[CH:10]=[CH:9][C:8]3[CH:12]=[CH:13][CH:14]=[CH:15][C:7]=3[NH:6][C:5]=2[CH:4]=[CH:3][CH:2]=1.[I:16][C:17]1[CH:22]=[CH:21][C:20]([C:23]2[CH:28]=[CH:27][C:26](I)=[CH:25][CH:24]=2)=[CH:19][CH:18]=1.[OH-].[K+].C1C2C(CCCC2)CCC1>[Cu].C(Cl)(Cl)Cl>[I:16][C:17]1[CH:18]=[CH:19][C:20]([C:23]2[CH:28]=[CH:27][C:26]([N:6]3[C:7]4[CH:15]=[CH:14][CH:13]=[CH:12][C:8]=4[CH:9]=[CH:10][C:11]4[CH:1]=[CH:2][CH:3]=[CH:4][C:5]3=4)=[CH:25][CH:24]=2)=[CH:21][CH:22]=1
Reactant: Ic1ccc(-c2ccc(I)cc2)cc1
Reactant: C1=Cc2ccccc2Nc2ccccc21
Agent: [Cu]
Agent: [K+]
Agent: [OH-]
Solvent: C1CCC2CCCCC2C1
Solvent: ClC(Cl)Cl
Product: Ic1ccc(-c2ccc(N3c4ccccc4C=Cc4ccccc43)cc2)cc1
Temperature: 200 °C
Reaction time: 36 h
Yield: 50 %

Procedure:
5H-Dibenz[b,f]azepine in an amount of 20.0 g (0.10 mol), 4,4'-diiodobiphenyl in an amount of 60.9 g (0.15 mol), potassium hydroxide in an amount of 6.7 g (0.12 mol) and a copper powder in an amount of 1.3 g (0.02 mol) were mixed with 20 ml of decalin, and heated with stirring in a stream of nitrogen for 36 hours at the external temperature of 200° C. After cooling to room temperature or its vicinity, the reaction solution was admixed with chloroform, and subjected to Celite filtration to remove the insoluble matter. The filtrate was concentrated, and the concentrated solution was purified by column chromatography on silica gel. Thus, 23.6 g of 5-(4'-iodobiphenyl-4-yl)dibenz[b,f]azepine was obtained (in a 50% yield).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:9]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[C:12](=[N:19][CH3:20])[CH2:11][CH2:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8].ClC1C=CC=CC=1C.[H][H]>[Ni].CO>[CH3:20][NH:19][C@@H:12]1[C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][C:18]=2[C@H:9]([C:4]2[CH:5]=[CH:6][C:7]([Cl:8])=[C:2]([Cl:1])[CH:3]=2)[CH2:10][CH2:11]1
Reactant: CN=C1CCC(c2ccc(Cl)c(Cl)c2)c2ccccc21
Reactant: [H][H]
Agent: [Ni]
Solvent: Cc1ccccc1Cl
Solvent: CO
Product: CN[C@H]1CC[C@@H](c2ccc(Cl)c(Cl)c2)c2ccccc21
Yield: 0.76 %

Procedure:
N-[4-(3,4-dichlorophenyl)-3,4-dihydro-1(2H)naphthalenylidene]methanamine (Ketimine) (50 g), methanol (300 ml), Raney Nickel (0.15 g wet basis) and o-chlorotoluene (50 ml) are charged into a reaction vessel. The mixture is hydrogenated at 5 to 6 kg/cm2 over pressure of hydrogen for 6 to 7 hrs at about 28 to 30° C. The catalyst is removed by filtration and the cake is washed with 50 ml methanol. The amount of dehalogenated by product is <0.1%. Sertraline racemate free base thus formed is treated with hydrochloric acid (24 ml, 33%) and predominantly isomer of sertraline HCl racemate is filtered [Cis>95%, trans<5%, dehalogenation product<0.1%, yield 0.76%].
Reaction SMILES: O=[C:2]1[CH2:6][CH2:5][C:4](=[O:7])[N:3]1[CH2:8][C:9]([O:20]C)(OC)[CH2:10][CH2:11][CH2:12][CH2:13][C:14]([O:16][CH3:17])=[O:15].[BH4-].[Na+].[SH:24][CH2:25][C:26]([OH:33])([CH3:32])[CH2:27][CH2:28][CH2:29][CH2:30][CH3:31].CC1C=CC(S(O)(=O)=O)=CC=1>C(O)C.Cl.[Cl-].[Na+].C(Cl)Cl>[OH:33][C:26]([CH3:32])([CH2:27][CH2:28][CH2:29][CH2:30][CH3:31])[CH2:25][S:24][CH:2]1[CH2:6][CH2:5][C:4](=[O:7])[N:3]1[CH2:8][C:9](=[O:20])[CH2:10][CH2:11][CH2:12][CH2:13][C:14]([O:16][CH3:17])=[O:15]
Reactant: COC(=O)CCCCC(CN1C(=O)CCC1=O)(OC)OC
Reactant: CCCCCC(C)(O)CS
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: Cl
Agent: [BH4-]
Solvent: ClCCl
Solvent: CCO
Product: CCCCCC(C)(O)CSC1CCC(=O)N1CC(=O)CCCCC(=O)OC
Reaction time: 1 h
Yield: 11.5 %

Procedure:
To a solution of 15 (50 mg, 0.16 mmol) in ethanol (2 mL) at 0° was added sodium borohydride (10 mg, 0.25 mmol). Two drops of 2N hydrochloric acid (in ethanol) were added at fifteen minute intervals for 1.5 hours. After continued stirring at 0° for one hour, the reaction was diluted with saturated aqueous sodium chloride and extracted three times with chloroform. The combined chloroform layer was dried over sodium sulfate. Removal of the solvent afforded 57 mg of the crude product which was dissolved in 2 mL of methylene chloride and treated with 20 mg of 1-mercapto-2-hydroxy-2-methylheptane in the presence of 15 mg of PTSA at room temperature overnight. It was then diluted with methylene chloride and washed with saturated sodium chloride solution. The separated aqueous layer was extracted twice with methylene chloride and the combined organic layer was dried over magnesium sulfate. The crude product was purified by preparative TLC to give 5.7 mg of methyl 7-[2-(2-hydroxy-2-methylheptylthio)-5-oxopyrrolidin-1-yl]-6-oxoheptanoate (16). IR (CH2Cl2): 1740, 1705 cm-1 ; PMR (CDCl3): δ 4.87 (t, 1H), 4.23 (AB, q, 2H), 3.67 (s, 3H), 2.70-1.20 (m, 22H), 1.20 (s, 3H), and 0.90 (t, 3H); MS: m/z 240.1227 (M+ -lower side chain), calcd. for C12H18NO4, 240.1236.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([NH:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]([N:19]3[C@@H:24]([CH3:25])[CH2:23][O:22][CH2:21][C@H:20]3[CH3:26])=[O:18])=[CH:13][N:12]=2)[C:5](=[O:9])[N:6]([CH3:8])[CH:7]=1.[C:27]([O:30][CH2:31][C:32]1[C:33]([N:47]2[CH2:58][CH2:57][N:56]3[C:49](=[CH:50][C:51]4[CH2:52][C:53]([CH3:60])([CH3:59])[CH2:54][C:55]=43)[C:48]2=[O:61])=[N:34][CH:35]=[CH:36][C:37]=1B1OC(C)(C)C(C)(C)O1)(=[O:29])[CH3:28].[O-]P([O-])([O-])=O.[K+].[K+].[K+].C([O-])(=O)C.[Na+]>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].O.C(#N)C>[C:27]([O:30][CH2:31][C:32]1[C:33]([N:47]2[CH2:58][CH2:57][N:56]3[C:49](=[CH:50][C:51]4[CH2:52][C:53]([CH3:60])([CH3:59])[CH2:54][C:55]=43)[C:48]2=[O:61])=[N:34][CH:35]=[CH:36][C:37]=1[C:2]1[CH:3]=[C:4]([NH:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]([N:19]3[C@@H:24]([CH3:25])[CH2:23][O:22][CH2:21][C@H:20]3[CH3:26])=[O:18])=[CH:13][N:12]=2)[C:5](=[O:9])[N:6]([CH3:8])[CH:7]=1)(=[O:29])[CH3:28]
Reactant: C[C@@H]1COC[C@H](C)N1C(=O)c1ccc(Nc2cc(Br)cn(C)c2=O)nc1
Reactant: CC(=O)OCc1c(B2OC(C)(C)C(C)(C)O2)ccnc1N1CCn2c(cc3c2CC(C)(C)C3)C1=O
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: CC(=O)[O-]
Solvent: CC#N
Solvent: O
Product: CC(=O)OCc1c(-c2cc(Nc3ccc(C(=O)N4[C@H](C)COC[C@@H]4C)cn3)c(=O)n(C)c2)ccnc1N1CCn2c(cc3c2CC(C)(C)C3)C1=O
Temperature: 90 °C
Yield: 64.5 %

Procedure:
A 50-mL single-neck round-bottomed flask equipped with a magnetic stirrer and a reflux condenser was charged with 320b (150 mg, 1.0 eq., 0.36 mmol), {3-[(acetoxy)methyl]-2-{4,4-dimethyl-9-oxo-1,10-diazatricyclo[6.4.0.02,6]dodeca-2(6),7-dien-10-yl}pyridin-4-yl}boronic acid 199e (286 mg, 2.0 eq., 0.72 mmol), PdCl2(dppf) (29 mg, 0.10 eq., 0.040 mmol), K3PO4 (153 mg, 2.0 eq., 0.72 mmol), sodium acetate (59 mg, 2.0 eq., 0.72 mmol), acetonitrile (10 mL), and water (0.2 mL). After three cycles of vacuum/nitrogen flush, the mixture was heated at 90° C. for 2 h. It was then cooled to room temperature and filtered. The filtrate was evaporated under reduced pressure and the resulting residue was purified by silica-gel column chromatography eluting with 50:1 dichloromethane/methanol to afford 320c (161 mg, 64%) as brown solid. MS-ESI: [M+H]+ 693.8