Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:10]([Cl:11])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.[F:12][C:13]([F:32])([F:31])[C:14]1([CH2:17][CH:18]([C:21]2[CH:22]=[CH:23][C:24]([C:27]([F:30])([F:29])[F:28])=[N:25][CH:26]=2)[CH2:19][NH2:20])[CH2:16][CH2:15]1>>[Cl:1][C:2]1[C:10]([Cl:11])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([NH:20][CH2:19][CH:18]([C:21]1[CH:22]=[CH:23][C:24]([C:27]([F:30])([F:28])[F:29])=[N:25][CH:26]=1)[CH2:17][C:14]1([C:13]([F:12])([F:31])[F:32])[CH2:16][CH2:15]1)=[O:6]
Reactant: O=C(O)c1cccc(Cl)c1Cl
Reactant: NCC(CC1(C(F)(F)F)CC1)c1ccc(C(F)(F)F)nc1
Product: O=C(NCC(CC1(C(F)(F)F)CC1)c1ccc(C(F)(F)F)nc1)c1cccc(Cl)c1Cl

Procedure:
From 2,3-dichlorobenzoic acid and 3-(1-(trifluoromethyl)cyclopropyl)-2-(2-(trifluoromethyl)pyridin-5-yl)propan-1-amine. LCMS (MH+): m/z=485.1, tR (minutes, Method G)=2.63
Reaction SMILES: [CH3:1][C:2]1([CH2:8][CH2:9][C:10]2[S:11][CH:12]=[C:13]([C:15]#[C:16][CH2:17][CH2:18][CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[CH:14]=2)[CH2:6][O:5][C:4](=[O:7])[NH:3]1>C(O)C.[Pd]>[CH3:1][C:2]1([CH2:8][CH2:9][C:10]2[S:11][CH:12]=[C:13]([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=3)[CH:14]=2)[CH2:6][O:5][C:4](=[O:7])[NH:3]1
Reactant: CC1(CCc2cc(C#CCCCc3ccccc3)cs2)COC(=O)N1
Agent: [Pd]
Solvent: CCO
Product: CC1(CCc2cc(CCCCCc3ccccc3)cs2)COC(=O)N1
Reaction time: 4 h
Yield: 93.6 %

Procedure:
4-Methyl-4-{2-[4-(5-phenylpent-1-ynyl)thiophen-2-yl]}ethyloxazolidin-2-one (174 mg, 0.49 mmol) obtained in Example 25 (h) was dissolved in ethanol (9 ml), and 5% palladium-charcoal (90 mg) was added thereto followed by stirring for 4 hours under a hydrogen atmosphere. After the catalyst was filtered out through Celite, the filtrate was evaporated to dryness under reduced pressure. The residue was purified by chromatography on a silica gel column (elution solvent; hexane:ethyl acetate=1:1) to give the title compound (164 mg, 93% yield).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C@@H:10]([NH2:12])[CH3:11])[CH:5]=[C:6]([O:8][CH3:9])[CH:7]=1.C([O:17][C:18]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[C:26]1[CH:31]=[CH:30][C:29]([CH2:32][N:33]2[C:41]3[C:36](=[CH:37][C:38]([C:42](O)=[O:43])=[CH:39][CH:40]=3)[C:35]([CH3:45])=[C:34]2[CH3:46])=[CH:28][CH:27]=1)=[O:19])(C)(C)C>>[F:1][C:2]1[CH:3]=[C:4]([C@@H:10]([NH:12][C:42]([C:38]2[CH:37]=[C:36]3[C:41](=[CH:40][CH:39]=2)[N:33]([CH2:32][C:29]2[CH:28]=[CH:27][C:26]([C:21]4[C:20]([C:18]([OH:19])=[O:17])=[CH:25][CH:24]=[CH:23][CH:22]=4)=[CH:31][CH:30]=2)[C:34]([CH3:46])=[C:35]3[CH3:45])=[O:43])[CH3:11])[CH:5]=[C:6]([O:8][CH3:9])[CH:7]=1
Reactant: Cc1c(C)n(Cc2ccc(-c3ccccc3C(=O)OC(C)(C)C)cc2)c2ccc(C(=O)O)cc12
Reactant: COc1cc(F)cc([C@H](C)N)c1
Product: COc1cc(F)cc([C@H](C)NC(=O)c2ccc3c(c2)c(C)c(C)n3Cc2ccc(-c3ccccc3C(=O)O)cc2)c1

Procedure:
The title compound was prepared following the same general protocol as described in Step 8-9, Example 1, using the (S)-1-(3-fluoro-5-methoxyphenyl)ethanamine and the 1-((2′-(tert-butoxycarbonyl)-[1,1′-biphenyl]-4-yl)methyl)-2,3-dimethyl-1H-indole-5-carboxylic acid. ESI-MS (m/z): 551 [M+H]+.
Reaction SMILES: [N+](C1C=CC(C[O:9][C:10](=[O:24])[CH2:11][CH2:12][C:13]2[CH:18]=[CH:17][C:16]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[CH:15][CH:14]=2)=CC=1)([O-])=O.[OH-].[Na+].Cl>O1CCOCC1>[C:20]([O:19][C:16]1[CH:15]=[CH:14][C:13]([CH2:12][CH2:11][C:10]([OH:24])=[O:9])=[CH:18][CH:17]=1)([CH3:23])([CH3:21])[CH3:22]
Reactant: CC(C)(C)Oc1ccc(CCC(=O)OCc2ccc([N+](=O)[O-])cc2)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Product: CC(C)(C)Oc1ccc(CCC(=O)O)cc1

Procedure:
2.86 g (8 mmol) of 3-(4-tert.butoxyphenyl)-propionic acid 4-nitrobenzyl ester in 500 ml of dioxan are saponified while stirring with 8 ml of 2-N sodium hydroxide for 2 hours at 70° C. and for 12 hours at room temperature. After acidifying the solution with an equivalent amount of 1-N hydrochloric acid, the organic solvent is almost completely removed in vacuo and the residue partitioned between 40 ml of 0.5-N potassium hydrogen carbonate solution and diethyl ether. After cooling, the aqueous phase is cautiously acidified with 1-N hydrochloric acid and extracted several times with ethyl acetate. The combined organic phases are washed neutral with water, dried over sodium sulphate and evaporated in vacuo. A solution of the residue in heptane is filtered and evaporated to dryness in vacuo. There is obtained 3-(4-tert.butoxyphenyl)-propionic acid in the form of a crystalline residue of melting point 29°-31° C. The product is chromatographically pure in cyclohexane/chloroform/acetic acid (45:45:10). The yield amounts to 1.3 g (73% of theory).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([C:14]3[O:18][N:17]=[C:16]([C:19]4[CH:31]=[CH:30][C:22]([CH2:23][NH:24][CH2:25][C:26]([O:28][CH3:29])=[O:27])=[CH:21][CH:20]=4)[N:15]=3)=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.[F:32][C:33]1[CH:41]=[C:40]([NH:42][C:43](=[O:57])[CH2:44][C:45]2[CH:50]=[CH:49][C:48]([O:51][CH3:52])=[CH:47][C:46]=2[C:53]([F:56])([F:55])[F:54])[CH:39]=[CH:38][C:34]=1[C:35](O)=[O:36].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C.CC(=O)OCC>[F:32][C:33]1[CH:41]=[C:40]([NH:42][C:43](=[O:57])[CH2:44][C:45]2[CH:50]=[CH:49][C:48]([O:51][CH3:52])=[CH:47][C:46]=2[C:53]([F:55])([F:56])[F:54])[CH:39]=[CH:38][C:34]=1[C:35]([N:24]([CH2:25][C:26]([O:28][CH3:29])=[O:27])[CH2:23][C:22]1[CH:30]=[CH:31][C:19]([C:16]2[N:15]=[C:14]([C:11]3[CH:10]=[CH:9][C:8]([C:5]4[CH:4]=[CH:3][C:2]([CH3:1])=[CH:7][CH:6]=4)=[CH:13][CH:12]=3)[O:18][N:17]=2)=[CH:20][CH:21]=1)=[O:36]
Reactant: COc1ccc(CC(=O)Nc2ccc(C(=O)O)c(F)c2)c(C(F)(F)F)c1
Reactant: COC(=O)CNCc1ccc(-c2noc(-c3ccc(-c4ccc(C)cc4)cc3)n2)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COC(=O)CN(Cc1ccc(-c2noc(-c3ccc(-c4ccc(C)cc4)cc3)n2)cc1)C(=O)c1ccc(NC(=O)Cc2ccc(OC)cc2C(F)(F)F)cc1F
Temperature: 25 °C
Yield: 98 %

Procedure:
Prepared using General Procedure 6. To a suspension of methyl 2-((4-(5-(4′-methyl-[1,1′-biphenyl]-4-yl)-1,2,4-oxadiazol-3-yl)benzyl)amino)acetate INT-77 (50 mg, 0.121 mmol) and 2-fluoro-4-(2-(4-methoxy-2-(trifluoromethyl)phenyl)acetamido)benzoic acid INT-78 (44.9 mg, 0.121 mmol) in DMF (2 mL) were added HATU (50.6 mg, 0.133 mmol) and TEA (42.1 μL, 0.302 mmol). The reaction mixture was stirred at room temperature. After 60 h the reaction mixture was diluted with EA (20 mL) and washed with NaHCO3 (2×20 mL) and 1 M HCl (2×20 mL). The organics were dried over MgSO4 and concentrated in vacuo to afford 91 mg (98%) of methyl 2-(2-fluoro-4-(2-(4-methoxy-2-(trifluoromethyl)phenyl)acetamido)-N-(4-(5-(4′-methyl-[1,1′-biphenyl]-4-yl)-1,2,4-oxadiazol-3-yl)benzyl)benzamido)acetate INT-79 as a pale yellow solid. LCMS-ESI (m/z) calculated for C42H34F4N4O6: 766; found 767 [M+H]+, tR=3.27 min (Method 10).
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[C:8]([CH2:10][N:11]2[CH2:16][CH2:15][N:14]([CH2:17][C:18]3[S:22][C:21]4[CH:23]=[C:24]([Cl:27])[CH:25]=[CH:26][C:20]=4[CH:19]=3)[CH2:13][C:12]2=[O:28])[CH:7]=[CH:6][C:3]=1[C:4]#[N:5].[N:29]([O-])=O.[Na+].O.O.[Sn](Cl)Cl>Cl.O>[NH2:5][C:4]1[C:3]2[C:2](=[CH:9][C:8]([CH2:10][N:11]3[CH2:16][CH2:15][N:14]([CH2:17][C:18]4[S:22][C:21]5[CH:23]=[C:24]([Cl:27])[CH:25]=[CH:26][C:20]=5[CH:19]=4)[CH2:13][C:12]3=[O:28])=[CH:7][CH:6]=2)[NH:1][N:29]=1
Reactant: O=N[O-]
Reactant: N#Cc1ccc(CN2CCN(Cc3cc4ccc(Cl)cc4s3)CC2=O)cc1N
Agent: Cl
Agent: Cl[Sn]Cl
Agent: [Na+]
Solvent: O
Product: Nc1n[nH]c2cc(CN3CCN(Cc4cc5ccc(Cl)cc5s4)CC3=O)ccc12
Yield: 38.2 %

Procedure:
To a cooled solution (0° C.) of 2-Amino-4-[4-(6-chloro-benzo[b]thiophen-2-ylmethyl)-2-oxo-piperazin-1-ylmethyl]-benzonitrile (0.365 g, 0.89 mmol) in concentrated HCl (2.1 ml) is added dropwise a solution of sodium nitrite (0.068 g, 0.98 mmol) in H2O (0.2 ml). The reaction mixture is added to a cooled solution (0° C.) of tin (II) chloride dihydrate (1.61 g, 7.12 mmol) in concentrated HCl (0.62 ml) and H2O (3 ml). The precipitate is collected by vacuum filtration and dried under high vacuum. The crude solid is purified by column chromatography eluting with 10% 7M NH3 in CH3OH/CH2Cl2 to yield the title compound (0.144 g, 0.34 mmol) as a yellow solid. 1H NMR (DMSO, 300 MHz) δ11.35 (bs, 1H), 8.05 (d, 1H), 7.78 (d, 1H), 7.64 (d, 1H), 7.37 (m, 2H), 7.08 (s, 1H), 6.78 (d, 1H), 5.75 (s, 1H), 5.40 (bs, 1H), 4.58 (s, 2H), 3.88 (s, 2H), 3.20 (m, 4H), 2.70 (bt, 2H). MS (ion spray): m/z 426 (M+H)+. Anal. cald. for C21H20N5OSCl;(H2O)0.25: C, 58.6; H, 4.8; N, 16.3. Found C, 58.6; H, 4.7; N, 15.9. M.P.=246-248° C.
Reaction SMILES: [CH2:1]([N:3]1[CH2:9][CH2:8][C:7]2[CH:10]=[C:11]([NH2:14])[CH:12]=[CH:13][C:6]=2[CH2:5][CH2:4]1)[CH3:2].Cl[C:16]1[N:21]=[C:20]([NH:22][CH2:23][CH2:24][NH:25][S:26]([CH3:29])(=[O:28])=[O:27])[C:19]([Cl:30])=[CH:18][N:17]=1.Cl.O1CCOCC1>CC(O)C>[Cl:30][C:19]1[C:20]([NH:22][CH2:23][CH2:24][NH:25][S:26]([CH3:29])(=[O:28])=[O:27])=[N:21][C:16]([NH:14][C:11]2[CH:12]=[CH:13][C:6]3[CH2:5][CH2:4][N:3]([CH2:1][CH3:2])[CH2:9][CH2:8][C:7]=3[CH:10]=2)=[N:17][CH:18]=1
Reactant: CS(=O)(=O)NCCNc1nc(Cl)ncc1Cl
Reactant: CCN1CCc2ccc(N)cc2CC1
Agent: Cl
Solvent: CC(C)O
Solvent: C1COCCO1
Product: CCN1CCc2ccc(Nc3ncc(Cl)c(NCCNS(C)(=O)=O)n3)cc2CC1
Temperature: 150 °C
Yield: 42.9 %

Procedure:
3-Ethyl-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-ylamine (90.9 mg, 0.478 mmol) and N-[2-(2,5-dichloro-pyrimidin-4-ylamino)-ethyl]-methanesulfonamide (150 mg, 0.526 mmol, 1.1 eq) were dissolved in IPA (3 mL). 4.0 M HCl in dioxane (132 μL, 0.526 mmol, 1.1 eq) was added and the reaction was heated at 150° C. in a microwave for 6 hours. The reaction was then concentrated under reduced pressure and the residue was taken up in CH2Cl2 (20 mL) and washed with sat. NaHCO3 (20 mL). The organic layer was dried (sodium sulfate), filtered, and concentrated under reduced pressure. Purification by basic alumina chromatography using a gradient of 0-10% MeOH/CH2Cl2 as the eluting solvent to obtain N-{2-[5-chloro-2-(3-ethyl-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-ylamino)-pyrimidin-4-ylamino]-ethyl}-methanesulfonamide as a white solid (90 mg, 43%). m.p.=146° C.; LCMS (m/e) 439 (M+1); 1H-NMR (d6-DMSO, 400 MHz) δ 9.06 (s, 1H), 7.93 (s, 1H), 7.45-7.40 (m, 2H), 7.18-7.08 (m, 2H), 6.97 (d, 1H, J=8.3 Hz), 3.58-3.50 (m, 2H), 3.25-3.14 (m, 2H), 2.89 (s, 3H), 2.82-2.73 (m, 4H), 2.57-2.40 (m, 6H) 1.00 (t, 3H, J=7.2 Hz).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:41]=[CH:42][CH:43]=1)[CH2:5][N:6]1[CH:10]=[C:9]([C:11]2[C:19]3[C:14](=[N:15][CH:16]=[C:17]([C:20]4[CH:21]=[C:22]([NH:26][S:27]([CH3:30])(=[O:29])=[O:28])[CH:23]=[CH:24][CH:25]=4)[CH:18]=3)[N:13](S(C3C=CC(C)=CC=3)(=O)=O)[CH:12]=2)[CH:8]=[N:7]1.[OH-].[Li+]>C1COCC1.O.CO>[F:1][C:2]1[CH:3]=[C:4]([CH:41]=[CH:42][CH:43]=1)[CH2:5][N:6]1[CH:10]=[C:9]([C:11]2[C:19]3[C:14](=[N:15][CH:16]=[C:17]([C:20]4[CH:21]=[C:22]([NH:26][S:27]([CH3:30])(=[O:28])=[O:29])[CH:23]=[CH:24][CH:25]=4)[CH:18]=3)[NH:13][CH:12]=2)[CH:8]=[N:7]1
Reactant: Cc1ccc(S(=O)(=O)n2cc(-c3cnn(Cc4cccc(F)c4)c3)c3cc(-c4cccc(NS(C)(=O)=O)c4)cnc32)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: CS(=O)(=O)Nc1cccc(-c2cnc3[nH]cc(-c4cnn(Cc5cccc(F)c5)c4)c3c2)c1
Yield: 12.7 %

Procedure:
Using similar reaction conditions as described in step-iii of example-1, N-(3-(3-(1-(3-fluorobenzyl)-1H-pyrazol-4-yl)-1-tosyl-1H-pyrrolo[2,3-b]pyridin-5-yl)phenyl)methane sulfonamide (106 mg, 0.17 mmol) was hydrolyzed with lithium hydroxide (36 mg, 0.861 mmol) in THF/water/methanol (12/6/2 ml) mixture to afford 10 mg (12.6% yield) of the pure product. 1H NMR (CD3OD, 300 MHz): δ 8.464-8.458 (d, 1H), 8.352-8.347 (d, 1H), 8.185 (s, 1H), 7.923 (s, 1H), 7.64 (s, 1H), 7.544-7.538 (m, 1H), 7.514-7.431 (m, 2H), 7.37-7.26 (m, 2H), 7.115-6.997 (m, 2H), 5.426 (s, 2H), 3.002 (s, 3H). MS: m/z=461.8 (M+1), HPLC: 96.947% in method A.
Reaction SMILES: [O:1]([CH3:11])[CH:2]1[O:8][C@@H:7]([CH2:9][OH:10])[C@@H:5]([OH:6])[C@@H:3]1[OH:4].[H-].[Na+].[Cl:14][C:15]1[CH:22]=[C:21]([Cl:23])[CH:20]=[CH:19][C:16]=1[CH2:17]Cl>CO>[Cl:14][C:15]1[CH:22]=[C:21]([Cl:23])[CH:20]=[CH:19][C:16]=1[CH2:17][O:4][C@H:3]1[C@H:5]([O:6][CH2:17][C:16]2[CH:19]=[CH:20][C:21]([Cl:23])=[CH:22][C:15]=2[Cl:14])[C@H:7]([CH2:9][O:10][CH2:17][C:16]2[CH:19]=[CH:20][C:21]([Cl:23])=[CH:22][C:15]=2[Cl:14])[O:8][CH:2]1[O:1][CH3:11]
Reactant: ClCc1ccc(Cl)cc1Cl
Reactant: COC1O[C@@H](CO)[C@@H](O)[C@@H]1O
Agent: [H-]
Agent: [Na+]
Solvent: CO
Product: COC1O[C@@H](COCc2ccc(Cl)cc2Cl)[C@@H](OCc2ccc(Cl)cc2Cl)[C@@H]1OCc1ccc(Cl)cc1Cl
Reaction time: 0.67 h

Procedure:
Compound 1-1 from Step A is dissolved in anhydrous TBF and the solution is cooled in an ice bath. To the cold solution is added sodium hydride (60% dispersion in mineral oil) and the reaction mixture is stirred for 35 to 45 min under an argon atmosphere. To this mixture is added 2,4-dichlorobenzyl chloride slowly over 20 min. The reaction mixture is stirred for 72 h, then cooled in an ice bath. MeOH is added slowly to decompose excess NaH. The mixture is concentrated under reduced pressure and the residue is taken up in ethyl acetate and washed several times with water. The organic layer is dried over anhydrous Na2SO4, filtered, and evaporated. The residue is purified by silica gel chromatography using a mixture of hexane and ethyl acetate as the eluent. The appropriate fractions are combined and evaporated to afford compound 1-2.
Reaction SMILES: CC([O-])(C)C.[Na+].Br[C:8]1[CH:13]=[CH:12][C:11]([C:14]([CH3:17])([CH3:16])[CH3:15])=[CH:10][CH:9]=1.[CH3:18][N:19]([CH3:25])[CH2:20][CH2:21][CH2:22][NH:23][CH3:24]>CC([O-])=O.CC([O-])=O.[Pd+2].C1(C)C=CC=CC=1>[C:14]([C:11]1[CH:12]=[CH:13][C:8]([N:23]([CH3:24])[CH2:22][CH2:21][CH2:20][N:19]([CH3:25])[CH3:18])=[CH:9][CH:10]=1)([CH3:17])([CH3:16])[CH3:15]
Reactant: CNCCCN(C)C
Reactant: CC(C)(C)c1ccc(Br)cc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)(C)[O-]
Solvent: Cc1ccccc1
Product: CN(C)CCCN(C)c1ccc(C(C)(C)C)cc1
Temperature: 80 °C
Yield: 85.8 %

Procedure:
To a sealed tube was added Pd(OAc)2 (105 mg 0.469 mmol), NaOtBu (1.35 g, 14.07 mmol), 1-Bromo-4-tert-butylbenzene (2.0 g, 9.38 mmol), N,N, N′-Trimethyl-propane-1,3-diamine (1.65 mL, 11.26 mmol), P(iBuNCH2CH2)3N (133 μL, 0.375 mmol), and 5 mL toluene. The solution was heated to 80° C. for 1 h, cooled to RT, filtered through a pad of silica gel (rinsing with 10% MeOH/CH2Cl2), and concentrated in vacuo to yield the title compound (2.0 g, 86%) as a dark brown oil. MS (M+H)+=249; Calc'd 248.41 for C16H28N2.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9](=[O:16])[CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:4][CH:3]=1.CO[CH:19](OC)[N:20]([CH3:22])[CH3:21].C1(C)C=CC=CC=1>CO>[CH3:19][N:20]([CH3:22])[CH:21]=[C:8]([C:5]1[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=1)[C:9](=[O:16])[C:10](=[CH:19][N:20]([CH3:22])[CH3:21])[C:11]([O:13][CH2:14][CH3:15])=[O:12]
Reactant: CCOC(=O)CC(=O)Cc1ccc(F)cc1
Reactant: COC(OC)N(C)C
Solvent: CO
Solvent: Cc1ccccc1
Product: CCOC(=O)C(=CN(C)C)C(=O)C(=CN(C)C)c1ccc(F)cc1
Temperature: 25 °C

Procedure:
A mixed solution of ethyl 4-(4-fluorophenyl)-3-oxobutanoate (0.95 g), N,N-dimethylformamide dimethylacetal (1.59 g) and toluene (7 ml) was stirred at 100° C. to 105° C. for 14 hours while methanol was distilled off. After cooling to room temperature, the residue was concentrated under reduced pressure. Further, 7 ml of toluene was added and the residue was concentrated to one-third of its volume under reduced pressure. Toluene (3.5 ml) was added to give a solution of ethyl 5-(dimethylamino)-2-[(dimethylamino)methylene]-4-(4-fluorophenyl)-3-oxopent-4-enoate. This solution was cooled to 0° C. to 5° C., trifluoroethyl amine (0.43 ml) and a 4.3 M solution of hydrogen chloride in ethyl acetate (1.57 ml) were added, and the mixture was stirred at 100° C. to 105° C. for three hours. After cooling to room temperature, the layers were separated by adding water, and the organic layer was concentrated to 3.5 ml. Toluene (1.4 ml) was added, followed by stirring at room temperature. The resulting solid was collected by filtration to give 1.07 g of the title compound as a solid.
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[C:7]([C:10]([O:12]CC)=[O:11])[CH:8]=[CH:9][C:4]=2[N:3]=[CH:2]1.[OH-].[Na+].Br>C(O)C>[S:1]1[C:5]2[CH:6]=[C:7]([C:10]([OH:12])=[O:11])[CH:8]=[CH:9][C:4]=2[N:3]=[CH:2]1
Reactant: CCOC(=O)c1ccc2ncsc2c1
Agent: Br
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: O=C(O)c1ccc2ncsc2c1
Yield: 97.7 %

Procedure:
Ethyl benzothiazole-6-carboxylate (1.30 g, 6.28 mmol) prepared in the Step 36-1-2 was suspended in ethanol (10 ml) and a 1 mol/L sodium hydroxide aqueous solution (10 ml), and the mixture was heated under reflux for 40 minutes. After the mixture was allowed to cool, concentrated hydrobromic acid was added to the mixture, and the resulting mixture was adjusted to pH 4. The precipitate was separated by filtration, washed with water, and then subjected to through circulation drying to give the title compound (1.10 g, 98%) as a light-brown powder.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[O:7]([CH2:14][C:15]1[S:16][C:17]2[C:18](=O)[N:19]([CH2:25][C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[CH2:20][CH2:21][CH2:22][C:23]=2[N:24]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1>C1COCC1>[O:7]([CH2:14][C:15]1[S:16][C:17]2[CH2:18][N:19]([CH2:25][C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[CH2:20][CH2:21][CH2:22][C:23]=2[N:24]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: O=C1c2sc(COc3ccccc3)nc2CCCN1Cc1ccccc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: c1ccc(CN2CCCc3nc(COc4ccccc4)sc3C2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 68.2 %

Procedure:
A 1 M solution of lithium aluminium hydride in THF (0.28 mL, 0.28 mmol) was added dropwise to a stirred solution of 5,6,7,8-tetrahydro-2-(phenoxymethyl)-5-(phenylmethyl)-4H-thiazolo[5,4-c]azepin-4-one (0.084 g, 0.23 mmol) in THF (1.8 mL) under N2 at 0° C. The mixture was stirred at room temperature for 1 hour and then quenched with a saturated solution of NH4Cl, diluted with DCM and filtered through a pad of diatomaceous earth. The solvents were evaporated in vacuo to yield 5,6,7,8-tetrahydro-2-(phenoxymethyl)-5-(phenylmethyl)-4H-thiazolo[5,4-c]azepine (0.055 g, 68% yield) as a yellow oil that was used in the next step without further purification. C21H20N2O2S LCMS: Rt 3.02, m/z 365 [M+H]+ (using method, LC-MS Method 6).
Reaction SMILES: FC(F)(F)C(O)=O.[F:8][C:9]([F:15])([F:14])[S:10]([OH:13])(=[O:12])=[O:11].COC1C=CC(C[S:23][C@@H:24]2[CH2:28][N:27]([CH3:29])[C@H:26]([C:30]([N:32]3[CH2:37][CH2:36][N:35]([CH3:38])[CH2:34][CH2:33]3)=[O:31])[CH2:25]2)=CC=1>C1(OC)C=CC=CC=1>[F:8][C:9]([F:15])([F:14])[S:10]([OH:13])(=[O:12])=[O:11].[F:8][C:9]([F:15])([F:14])[S:10]([OH:13])(=[O:12])=[O:11].[SH:23][C@@H:24]1[CH2:28][N:27]([CH3:29])[C@H:26]([C:30]([N:32]2[CH2:33][CH2:34][N:35]([CH3:38])[CH2:36][CH2:37]2)=[O:31])[CH2:25]1
Reactant: COc1ccc(CS[C@H]2C[C@@H](C(=O)N3CCN(C)CC3)N(C)C2)cc1
Agent: O=S(=O)(O)C(F)(F)F
Solvent: O=C(O)C(F)(F)F
Solvent: COc1ccccc1
Product: CN1CCN(C(=O)[C@@H]2C[C@H](S)CN2C)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
10 ml of trifluoroacetic acid, followed by liters of trifluoromethanesulfonic acid were added, whilst ice-cooling, to a solution of 1050 mg of (2S,4S)-4-(4-methoxybenzylthio)-2-(4-methyl-1-piperazinylcarbonyl)-1-methylpyrrolidine [prepared as described in step (i) above] in 3 ml of anisole, and the resulting mixture was stirred at room temperature for 1 hour. At the end of this time, the reaction mixture was concentrated by evaporation under reduced pressure, and the residue was triturated with diethyl ether to cause solidification. The solid was washed with diethyl ether five times and dried, to give 1350 mg of the title compound as a powder.
Reaction SMILES: [CH:1]1[C:13]2[CH:12]([CH2:14][O:15][C:16]([NH:18][C@H:19]([CH2:26][O:27][C@@H:28]3[O:37][CH:36]4[C@@H:31]([O:32][CH:33]([C:38]5[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=5)[O:34][CH2:35]4)[C@H:30]([OH:44])[C@@H:29]3[NH:45][C:46](=[O:48])[CH3:47])[C:20]([O:22][CH2:23][CH:24]=[CH2:25])=[O:21])=[O:17])[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.[C:49]([S:68][CH2:69][C:70](O)=[O:71])([C:62]1[CH:67]=[CH:66][CH:65]=[CH:64][CH:63]=1)([C:56]1[CH:61]=[CH:60][CH:59]=[CH:58][CH:57]=1)[C:50]1[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=1.CC(C)N=C=NC(C)C>ClCCl.CN(C1C=CN=CC=1)C>[CH:10]1[C:11]2[CH:12]([CH2:14][O:15][C:16]([NH:18][C@H:19]([CH2:26][O:27][C@@H:28]3[O:37][CH:36]4[C@@H:31]([O:32][CH:33]([C:38]5[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=5)[O:34][CH2:35]4)[C@H:30]([O:44][C:70](=[O:71])[CH2:69][S:68][C:49]([C:50]4[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=4)([C:56]4[CH:57]=[CH:58][CH:59]=[CH:60][CH:61]=4)[C:62]4[CH:67]=[CH:66][CH:65]=[CH:64][CH:63]=4)[C@@H:29]3[NH:45][C:46](=[O:48])[CH3:47])[C:20]([O:22][CH2:23][CH:24]=[CH2:25])=[O:21])=[O:17])[C:13]3[C:5](=[CH:4][CH:3]=[CH:2][CH:1]=3)[C:6]=2[CH:7]=[CH:8][CH:9]=1
Reactant: C=CCOC(=O)[C@@H](CO[C@@H]1OC2COC(c3ccccc3)O[C@H]2[C@H](O)[C@@H]1NC(C)=O)NC(=O)OCC1c2ccccc2-c2ccccc21
Reactant: O=C(O)CSC(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: CC(C)N=C=NC(C)C
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: C=CCOC(=O)[C@@H](CO[C@@H]1OC2COC(c3ccccc3)O[C@H]2[C@H](OC(=O)CSC(c2ccccc2)(c2ccccc2)c2ccccc2)[C@@H]1NC(C)=O)NC(=O)OCC1c2ccccc2-c2ccccc21
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 88.6 %

Procedure:
Alcohol 33 (142 mg, 0.22 mmol) was dissolved in dry dichloromethane (7.5 ml). S-Trityl-mercaptoacetic acid (110 mg, 0.32 mmol) was added and the reaction cooled to 0° C. DIC (50 μl, 0.32 mmol) and DMAP (1.3 mg, 0.01 mmol) was added and the reaction stirred at 0° C. for 15 min. The solvent was removed in vacuo and the product purified by column chromatography (eluent: 2:1 hexane/ethyl acaetate—1:1 v/v hexane/ethyl acetate) to afford 34 as a white solid (190 mg, 91%).
Reaction SMILES: O[CH:2]=[C:3]1[C:11]2[C:6](=[CH:7][C:8]([C:12]([C:14]3[CH:15]=[C:16]([NH:20][C:21]([C:23]4[CH:24]=[N:25][N:26]([CH3:29])[C:27]=4[Cl:28])=[O:22])[CH:17]=[CH:18][CH:19]=3)=[O:13])=[CH:9][CH:10]=2)[NH:5][C:4]1=[O:30].C1COCC1.[N:36]1([CH2:41][CH2:42][C:43]2[CH:48]=[CH:47][C:46]([NH2:49])=[CH:45][CH:44]=2)[CH2:40][CH2:39][CH2:38][CH2:37]1>CCOC(C)=O.CCCCCC>[O:30]=[C:4]1[C:3](=[CH:2][NH:49][C:46]2[CH:47]=[CH:48][C:43]([CH2:42][CH2:41][N:36]3[CH2:40][CH2:39][CH2:38][CH2:37]3)=[CH:44][CH:45]=2)[C:11]2[C:6](=[CH:7][C:8]([C:12]([C:14]3[CH:15]=[C:16]([NH:20][C:21]([C:23]4[CH:24]=[N:25][N:26]([CH3:29])[C:27]=4[Cl:28])=[O:22])[CH:17]=[CH:18][CH:19]=3)=[O:13])=[CH:9][CH:10]=2)[NH:5]1
Reactant: Nc1ccc(CCN2CCCC2)cc1
Reactant: Cn1ncc(C(=O)Nc2cccc(C(=O)c3ccc4c(c3)NC(=O)C4=CO)c2)c1Cl
Solvent: CCCCCC
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: Cn1ncc(C(=O)Nc2cccc(C(=O)c3ccc4c(c3)NC(=O)C4=CNc3ccc(CCN4CCCC4)cc3)c2)c1Cl
Temperature: 65 °C
Reaction time: 24 h
Yield: 29 %

Procedure:
A small screw cap test tube was charged with 5-Chloro-1-methyl-1H-pyrazole-4-carboxylic acid [3-(3-hydroxymethylene-2-oxo-2,3-dihydro-1H-indole-6-carbonyl)-phenyl]-amide (as prepared in Example 328, 100 mg, 0.2365 mmol) and THF (2.5 mL). To the resulting solution was added 4-(2-Pyrrolidin-1-yl-ethyl)-phenylamine (45 mg, 0.236 mmol), and the mixture was stirred for 24 h at 65° C. Subsequently, the reaction mixture was cooled to room temperature and diluted with EtOAc (˜5 mL) and Hexane (˜50 mL). The precipitate that formed was collected by filtration and washed with acetone (˜15 mL) to afford the title compound in 29% yield (0.041 g, 0.0689 mmol).