Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([C:7]2[C:8]3[CH:9]=[CH:10][C:11]([C:33]([O:35]C)=[O:34])=[CH:12][C:13]=3[N:14]3[CH2:21][CH2:20][N:19]([CH2:22][CH2:23][N:24]([CH3:26])[CH3:25])[CH2:18][C:17]4[CH:27]=[C:28]([O:31][CH3:32])[CH:29]=[CH:30][C:16]=4[C:15]=23)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1>O1CCOCC1.[OH-].[Na+]>[CH:1]1([C:7]2[C:8]3[CH:9]=[CH:10][C:11]([C:33]([OH:35])=[O:34])=[CH:12][C:13]=3[N:14]3[CH2:21][CH2:20][N:19]([CH2:22][CH2:23][N:24]([CH3:25])[CH3:26])[CH2:18][C:17]4[CH:27]=[C:28]([O:31][CH3:32])[CH:29]=[CH:30][C:16]=4[C:15]=23)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: COC(=O)c1ccc2c(C3CCCCC3)c3n(c2c1)CCN(CCN(C)C)Cc1cc(OC)ccc1-3
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Product: COc1ccc2c(c1)CN(CCN(C)C)CCn1c-2c(C2CCCCC2)c2ccc(C(=O)O)cc21
Temperature: 60 °C
Reaction time: 3 h
Yield: 28 %

Procedure:
The crude methyl 14-cyclohexyl-6-[2-(dimethylamino)ethyl]-3-methoxy-5,6,7,8-tetrahydroindolo[2,1-a][2,5]benzodiazocine-11-carboxylate was dissolved in dioxane (0.06 M) and to that solution 10 eq of an aqueous solution of NaOH (2N) were added. The solution was stirred at 60° C. for 3 h. The solvent was evaporated in vacuo. The crude was then purified by automated RP-MS-HPLC (stationary phase: column Waters XTERRA prep. C18, 5 um, 19×100 mm. Mobile phase: MeCN/H2O buffered with 0.1% TFA). Fractions containing the pure compound were combined and freeze dried to afford the title compound as a white powder (28%).
Reaction SMILES: Br[C:2]1[C:10]2[N:9]3[CH2:11][CH2:12][NH:13][C:14](=[O:15])[C:8]3=[C:7]([CH3:16])[C:6]=2[CH:5]=[C:4]([C:17]#[N:18])[CH:3]=1.[F:19][C:20]1[CH:21]=[C:22](B(O)O)[CH:23]=[CH:24][CH:25]=1>>[F:19][C:20]1[CH:25]=[C:24]([C:2]2[C:10]3[N:9]4[CH2:11][CH2:12][NH:13][C:14](=[O:15])[C:8]4=[C:7]([CH3:16])[C:6]=3[CH:5]=[C:4]([C:17]#[N:18])[CH:3]=2)[CH:23]=[CH:22][CH:21]=1
Reactant: Cc1c2n(c3c(Br)cc(C#N)cc13)CCNC2=O
Reactant: OB(O)c1cccc(F)c1
Product: Cc1c2n(c3c(-c4cccc(F)c4)cc(C#N)cc13)CCNC2=O

Procedure:
The title compound, grey solid (61 mg, 76%), MS (ISP) m/z=320.5 [(M+H)+], mp 226° C., was prepared in accordance with the general method of example 1 from 6-bromo-10-methyl-1-oxo-1,2,3,4-tetrahydro-pyrazino[1,2-a]indole-8-carbonitrile (intermediate 16) (76 mg, 0.25 mmol) and commercially available 3-fluoro-phenylboronic acid (45.5 mg, 0.325 mmol).
Reaction SMILES: [CH2:1]([O:5][C:6]1[N:14]=[C:13]2[C:9]([N:10]=[C:11]([O:21][CH3:22])[N:12]2[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19]Cl)=[C:8]([NH2:23])[N:7]=1)[CH2:2][CH2:3][CH3:4].[NH:24]1[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]1>>[CH2:1]([O:5][C:6]1[N:14]=[C:13]2[C:9]([N:10]=[C:11]([O:21][CH3:22])[N:12]2[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][N:24]2[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]2)=[C:8]([NH2:23])[N:7]=1)[CH2:2][CH2:3][CH3:4]
Reactant: C1CCCNCCC1
Reactant: CCCCOc1nc(N)c2nc(OC)n(CCCCCCl)c2n1
Product: CCCCOc1nc(N)c2nc(OC)n(CCCCCN3CCCCCCC3)c2n1

Procedure:
Prepared similarly to Intermediate 38 from 2-(butyloxy)-9-(5-chloropentyl)-8-(methyloxy)-9H-purin-6-amine and octahydroazocine.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][N:3]=[C:2]1[NH:6][C:7](=[O:9])[CH3:8].C([Li])CCC.[Cl:15][CH:16]([C:19]1[O:24][C:23](=[O:25])[C:22]2[CH:26]=[CH:27][CH:28]=[C:29]([C:30]([F:33])([F:32])[F:31])[C:21]=2[N:20]=1)[CH2:17][CH3:18]>O1CCCC1.CCCCCC>[Cl:15][CH:16]([CH2:17][CH3:18])[C:19]([NH:20][C:21]1[C:29]([C:30]([F:31])([F:32])[F:33])=[CH:28][CH:27]=[CH:26][C:22]=1[C:23](=[O:25])[CH2:8][C:7]([NH:6][C:2]1[S:1][CH:5]=[CH:4][N:3]=1)=[O:9])=[O:24]
Reactant: CC(=O)Nc1nccs1
Reactant: CCC(Cl)c1nc2c(C(F)(F)F)cccc2c(=O)o1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CCC(Cl)C(=O)Nc1c(C(=O)CC(=O)Nc2nccs2)cccc1C(F)(F)F
Yield: 21.7 %

Procedure:
Using the procedure of Step A of Example 6, a solution of 16.58 g of N-(2-thiazolyl)-acetamide in 340 ml of tetrahydrofuran, 155 ml of a solution of butyllithium in hexane and a solution of 17 g of the product of Step A in 170 ml of tetrahydrofuran were reacted to obtain 5.5 g of 2-[(2-chloro-1-oxo-butyl)-amino]-β-oxo-N-(2-thiazolyl)-3-trifluoromethyl-benzenepropanamide melting at 170° C.
Reaction SMILES: [NH:1]1[CH:5]=[N:4][CH:3]=[N:2]1.Cl[C:7]1[N:8]=[C:9]([NH:18][CH2:19][CH2:20][C:21]2[CH:26]=[CH:25][C:24]3[O:27][CH2:28][O:29][C:23]=3[CH:22]=2)[C:10]2[CH:15]=[C:14]([CH2:16][CH3:17])[S:13][C:11]=2[N:12]=1>>[N:1]1([C:7]2[N:8]=[C:9]([NH:18][CH2:19][CH2:20][C:21]3[CH:26]=[CH:25][C:24]4[O:27][CH2:28][O:29][C:23]=4[CH:22]=3)[C:10]3[CH:15]=[C:14]([CH2:16][CH3:17])[S:13][C:11]=3[N:12]=2)[CH:5]=[N:4][CH:3]=[N:2]1
Reactant: CCc1cc2c(NCCc3ccc4c(c3)OCO4)nc(Cl)nc2s1
Reactant: c1nc[nH]n1
Product: CCc1cc2c(NCCc3ccc4c(c3)OCO4)nc(-n3cncn3)nc2s1

Procedure:
Following the procedure of Example 97, the reaction of 1,2,4-triazole with 2-chloro-6-ethyl-4-(3,4-methylenedioxyphenethylamino)-thieno-[2,3-d]-pyrimidine gives 2-(1,2,4-triazol-1-yl)-6-ethyl-4-(3,4-methylenedioxyphenethylamino)-thieno-[2,3-d]-pyrimidine.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[C:4]([F:11])[CH:3]=1.[C:12]1([SiH:18]2[CH2:23][CH2:22][C:21](CCC=CC)([CH:24]3[CH2:29][CH2:28][CH:27](O)[CH2:26][CH2:25]3)[CH2:20][CH2:19]2)C=[CH:16][CH:15]=[CH:14][CH:13]=1>>[Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([O:8][C@H:27]2[CH2:26][CH2:25][C@H:24]([CH:21]3[CH2:20][CH2:19][SiH:18]([CH2:12][CH2:13][CH2:14][CH:15]=[CH2:16])[CH2:23][CH2:22]3)[CH2:29][CH2:28]2)=[O:7])=[C:4]([F:11])[CH:3]=1
Reactant: CC=CCCC1(C2CCC(O)CC2)CC[SiH](c2ccccc2)CC1
Reactant: O=C(O)c1ccc(Cl)cc1F
Product: C=CCCC[SiH]1CCC([C@H]2CC[C@H](OC(=O)c3ccc(Cl)cc3F)CC2)CC1

Procedure:
The general procedure of Example 31 was repeated using 4-chloro-2-fluorobenzoic acid and 4-(4-phenyl-(3-pentenyl)-4-silacyclohexyl)cyclohexanol, thereby obtaining the intended product.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:40])[CH:4]([C:9]1[CH:10]=[C:11]([C:26]2[CH:31]=[C:30]([C:32]([F:35])([F:34])[F:33])[CH:29]=[C:28]([C:36]([F:39])([F:38])[F:37])[CH:27]=2)[CH:12]=[C:13]([O:15]C2C=CC=C(C(F)(F)F)C=2)[CH:14]=1)[CH2:5][CH:6]([CH3:8])[CH3:7].[F:41][C:42]1[CH:43]=[C:44](B(O)O)[CH:45]=[C:46]([F:48])[CH:47]=1>>[CH3:1][O:2][C:3](=[O:40])[CH:4]([C:9]1[CH:10]=[C:11]([C:26]2[CH:31]=[C:30]([C:32]([F:34])([F:33])[F:35])[CH:29]=[C:28]([C:36]([F:37])([F:38])[F:39])[CH:27]=2)[CH:12]=[C:13]([O:15][C:44]2[CH:43]=[C:42]([F:41])[CH:47]=[C:46]([F:48])[CH:45]=2)[CH:14]=1)[CH2:5][CH:6]([CH3:8])[CH3:7]
Reactant: OB(O)c1cc(F)cc(F)c1
Reactant: COC(=O)C(CC(C)C)c1cc(Oc2cccc(C(F)(F)F)c2)cc(-c2cc(C(F)(F)F)cc(C(F)(F)F)c2)c1
Product: COC(=O)C(CC(C)C)c1cc(Oc2cc(F)cc(F)c2)cc(-c2cc(C(F)(F)F)cc(C(F)(F)F)c2)c1
Yield: 15 %

Procedure:
The title compound was prepared in 15% yield from 2-[3′,5′-bis-trifluoromethyl-5-(3-trifluoromethyl-phenoxy)-biphenyl-3-yl]-4-methyl-pentanoic acid methyl ester (prepared in Example C) and 3,5-difluoro-phenylboronic acid under the conditions described in Example 15, step (g).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][NH:15][C:16]([C:18]2[CH:41]=[CH:40][C:21]3[N:22]([CH2:36][CH2:37][O:38][CH3:39])[C:23]([NH:25][C:26]4[S:27][C:28]5[CH:34]=[C:33]([Cl:35])[CH:32]=[CH:31][C:29]=5[N:30]=4)=[N:24][C:20]=3[CH:19]=2)=[O:17])[CH2:10][CH2:9]1)=O)(C)(C)C>Cl.O1CCOCC1>[ClH:35].[ClH:35].[NH:8]1[CH2:13][CH2:12][CH:11]([CH2:14][NH:15][C:16]([C:18]2[CH:41]=[CH:40][C:21]3[N:22]([CH2:36][CH2:37][O:38][CH3:39])[C:23]([NH:25][C:26]4[S:27][C:28]5[CH:34]=[C:33]([Cl:35])[CH:32]=[CH:31][C:29]=5[N:30]=4)=[N:24][C:20]=3[CH:19]=2)=[O:17])[CH2:10][CH2:9]1
Reactant: COCCn1c(Nc2nc3ccc(Cl)cc3s2)nc2cc(C(=O)NCC3CCN(C(=O)OC(C)(C)C)CC3)ccc21
Agent: Cl
Solvent: C1COCCO1
Product: COCCn1c(Nc2nc3ccc(Cl)cc3s2)nc2cc(C(=O)NCC3CCNCC3)ccc21
Yield: 284.8 %

Procedure:
2-(6-Chloro-benzothiazol-2-ylamino)-1-(2-methoxy-ethyl)-1H-benzoimidazole-5-carboxylic acid (piperidin-4-ylmethyl)-amide dihydrochloride (145 mg) was prepared by following General Procedure L starting from 4-({[2-(6-chloro-benzothiazol-2-ylamino)-1-(2-methoxy-ethyl)-1H-benzoimidazole-5-carbonyl]-amino}-methyl)piperidine-1-carboxylic acid tert-butyl ester (160 mg) in 4M HCl in dioxane (2 mL).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][C:8]([N:10]3[CH2:15][CH2:14][CH2:13][CH2:12][C@H:11]3[C:16]([O:18]CC3C=CC=CC=3)=[O:17])=[N:7][C:6]=2[CH:26]=1.[OH-].[Li+]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][C:8]([N:10]3[CH2:15][CH2:14][CH2:13][CH2:12][C@H:11]3[C:16]([OH:18])=[O:17])=[N:7][C:6]=2[CH:26]=1
Reactant: O=C(OCc1ccccc1)[C@@H]1CCCCN1c1nc2cc(Cl)ccc2o1
Agent: [Li+]
Agent: [OH-]
Product: O=C(O)[C@@H]1CCCCN1c1nc2cc(Cl)ccc2o1

Procedure:
The title compound was prepared by a similar method to Preparation 3 from benzyl (2S)-1-(5-chloro-1,3-benzoxazol-2-yl)-2-piperidinecarboxylate [see Preparation 28] and 1N aqueous lithium hydroxide solution to afford (2S)-1-(5-chloro-1,3-benzoxazol-2-yl)-2-piperidinecarboxylic acid as an oil.
Reaction SMILES: [OH:1][CH2:2][C:3]1[O:9][C:6]([CH:7]=O)=[CH:5][CH:4]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(Cl)(Cl)(Cl)[Cl:30]>>[Cl:30][CH2:7][C:6]1[O:9][C:3]([CH:2]=[O:1])=[CH:4][CH:5]=1
Reactant: ClC(Cl)(Cl)Cl
Reactant: O=Cc1ccc(CO)o1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: O=Cc1ccc(CCl)o1

Procedure:
A mixture of 5-hydroxymethylfurfuraldehyde (0.5 g, 4 mmol) and triphenylphosphine (1.3 g, 5 mmol) in dry carbon tetrachloride (3 ml) was heated at reflux for 30 min and then filtered to give an unstable 1 M solution of 5-chloromethylfurfuraldehyde.
Reaction SMILES: [N:1]([O-])=O.[Na+].[CH3:5][N:6]([CH2:8][CH2:9][CH:10]([C:16]1[CH:25]=[CH:24][C:19](C(NN)=O)=[CH:18][CH:17]=1)[C:11]1[NH:12][CH:13]=[CH:14][N:15]=1)[CH3:7].C(=O)([O-])[O-].[Na+].[Na+]>O.Cl>[NH2:1][C:19]1[CH:24]=[CH:25][C:16]([CH:10]([C:11]2[NH:12][CH:13]=[CH:14][N:15]=2)[CH2:9][CH2:8][N:6]([CH3:7])[CH3:5])=[CH:17][CH:18]=1
Reactant: O=N[O-]
Reactant: CN(C)CCC(c1ccc(C(=O)NN)cc1)c1ncc[nH]1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Product: CN(C)CCC(c1ccc(N)cc1)c1ncc[nH]1
Reaction time: 0.5 h

Procedure:
A solution of sodium nitrite (0.5 g) in water (5 ml) was added dropwise to a stirred solution of 4-[3-(N,N-dimethylamino)-1-(imidazol-2-yl)propyl]benzoic acid hydrazide (2.0 g) in 2 N hydrochloric acid (10.5 ml) and water (50 ml) at 0° to 5° C. After 30 min. the solution was basified by adding 2 N sodium carbonate (15 ml) and then extracted with ether (3×50 ml). The extracts were dried (Na2SO4) and concentrated to an off white solid (1.7 g). This solid was dissolved in toluene (40 ml) and benzyl alcohol (1.5 ml) and heated on a steam bath for 2 h. Solvent was removed and the residue taken up in ethanol (20 ml) and hydrogenated at atmospheric pressure over 10% palladium oxide on charcoal (0.5 g) for 3 h. The catalyst was filtered off and the filtrate treated with a solution of maleic acid (1.8 g) in ethanol (10 ml). Removal of the solvent and trituration of the residue with dry ether afforded a white solid. Recrystallisation from ethanolether gave the trimaleate salt of the title compound, m.p. 132°-133° (2.6 g).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[CH2:17][CH2:18][N:19]1[CH2:24][CH2:23][N:22]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH2:21][CH2:20]1>CS(C)=O.[OH-].[Na+]>[CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([O:15][CH2:17][CH2:18][N:19]2[CH2:24][CH2:23][N:22]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[CH2:21][CH2:20]2)=[CH:13][CH:14]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: ClCCN1CCN(c2ccccc2)CC1
Reactant: Oc1ccc(OCc2ccccc2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CS(C)=O
Product: c1ccc(COc2ccc(OCCN3CCN(c4ccccc4)CC3)cc2)cc1

Procedure:
26.25 ml 4 N NaOH (0.105 mol) was added to a stirred mixture of 21.0 g (0.105 mol) 4-benzyloxyphenol and 22.5 g (0.1 mol) of 1-(2-chloroethyl)-4-phenylpiperazine in 250 ml DMSO and the reaction was heated at 60° for 60 min. After cooling, the stirred mixture was diluted with 50 ml 1 N NaOH solution and the resulting crystalline precipitate was collected by filtration and washed with water to give, after drying in vacuo, essentially pure end product, mp 116°-119°.
Reaction SMILES: C([O:14][C:15]1[C:16]2[C:44](=[O:45])[N:43]([CH2:46][C:47]3[CH:52]=[CH:51][C:50]([F:53])=[CH:49][CH:48]=3)[CH2:42][C:17]=2[C:18]([O:25][S:26]([CH2:29][CH2:30][N:31]2[C:39](=[O:40])[C:38]3[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=3)[C:32]2=[O:41])(=[O:28])=[O:27])=[C:19]2[C:24]=1[N:23]=[CH:22][CH:21]=[CH:20]2)(C1C=CC=CC=1)C1C=CC=CC=1.[F:54][C:55]([F:60])([F:59])[C:56]([OH:58])=[O:57].C([SiH](CC)CC)C>ClCCl>[F:53][C:50]1[CH:49]=[CH:48][C:47]([CH2:46][N:43]2[C:44](=[O:45])[C:16]3[C:15]([OH:14])=[C:24]4[C:19]([CH:20]=[CH:21][CH:22]=[N:23]4)=[C:18]([O:25][S:26]([CH2:29][CH2:30][N:31]4[C:39](=[O:40])[C:38]5[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=5)[C:32]4=[O:41])(=[O:28])=[O:27])[C:17]=3[CH2:42]2)=[CH:52][CH:51]=1.[C:56]([OH:58])([C:55]([F:60])([F:59])[F:54])=[O:57]
Reactant: O=C1c2c(c(OS(=O)(=O)CCN3C(=O)c4ccccc4C3=O)c3cccnc3c2OC(c2ccccc2)c2ccccc2)CN1Cc1ccc(F)cc1
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C1c2c(c(OS(=O)(=O)CCN3C(=O)c4ccccc4C3=O)c3cccnc3c2O)CN1Cc1ccc(F)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 268 (12.2 mg, 0.017 mmol) dissolved in dichloromethane (1 mL) was added trifluoroacetic acid (100 μl) and triethylsilane (200 μl). The reaction mixture was stirred at room temperature for ½ hours under an inert atmosphere then concentrated in vacuo. The residue was triturated with diethyl ether/hexane (1/1) to afford 2-(1,3-dioxo-1,3-dihydro-isoindol-2-yl)-ethanesulfonic acid 7-(4-fluoro-benzyl)-9-hydroxy-8-oxo-7,8-dihydro-6H-pyrrolo[3,4-g]quinolin-5-yl ester 269, TFA salt, (9.0 mg, 76%) as a yellow solid: 1H NMR (CDCl3) δ 9.0 (d, 1H), 8.5 (dd, 1H), 7.9 (m, 2H), 7.8 (m, 2H), 7.7 (m, 1H), 7.3 (m, 2H), 7.0 (t, 2H), 4.8 (s, 2H), 4.6 (s, 2H), 4.4 (q, 2H), 3.9 (q, 2H); MS: 562 (M+1).
Reaction SMILES: [CH2:1]([SH:5])[CH2:2][CH2:3][SH:4].C(=O)([O-])[O-].[K+].[K+].F[C:13]1[CH:18]=[CH:17][C:16]([C:19](=[O:33])[C:20]([N:30]([CH3:32])[CH3:31])([CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH2:21][CH3:22])=[CH:15][CH:14]=1>CC(N(C)C)=O>[SH:4][CH2:3][CH2:2][CH2:1][S:5][C:13]1[CH:14]=[CH:15][C:16]([C:19](=[O:33])[C:20]([N:30]([CH3:32])[CH3:31])([CH2:23][C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=2)[CH2:21][CH3:22])=[CH:17][CH:18]=1
Reactant: CCC(Cc1ccccc1)(C(=O)c1ccc(F)cc1)N(C)C
Reactant: SCCCS
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Product: CCC(Cc1ccccc1)(C(=O)c1ccc(SCCCS)cc1)N(C)C
Temperature: 50 °C
Reaction time: 12 h

Procedure:
32.5 g (0.3 mol) of 1,3-propanedithiol are dissolved in 50 ml of dry dimethylacetamide, and the solution is heated to about 50° C. together with 13.8 g (0.1 mol) of potassium carbonate. 15.0 g (0.05 mol) of 1-(4-fluorophenyl)-2-dimethylamino-2-benzyl-butan-1-one in 30 ml of dry dimethylacetamide are added dropwise. The suspension is stirred at 50° C. overnight (about 12 hours), then the solid is filtered off. The excess 1,3-propanedithiol and dimethylacetamide are distilled off. To the residue is added toluene, then the precipitate is filtered off. After distilling off the toluene, the residue is purified by means of column chromatography on silica gel with ethyl acetate-hexane (1:7) as an eluent, and an oily product is obtained. The structure is confirmed by the 1H-NMR spectrum (CDCl3): δ [ppm]: 0.68 (t, 3H), 1.39 (t, 1H), 1.79-1.88 (m, 1H), 1.97-2.11 (m, 3H), 2.36 (s, 6H), 2.69 (q, 2H), 3.12 (t, 2H), 3.19 (s, 2H), 7.15-7.27 (m, 7H), 8.28 (d, 2H).
Reaction SMILES: [F:1][C:2]([F:28])([F:27])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[S:10][C:11]([CH2:25][OH:26])=[C:12]([CH2:14][N:15]3[CH2:20][CH2:19][CH:18]([C:21]([F:24])([F:23])[F:22])[CH2:17][CH2:16]3)[N:13]=2)=[CH:5][CH:4]=1.[H-].[Na+].[F:31][CH:32]([F:43])[O:33][C:34]1[CH:41]=[C:40](F)[CH:39]=[CH:38][C:35]=1[C:36]#[N:37].O>CN(C)C=O>[F:31][CH:32]([F:43])[O:33][C:34]1[CH:41]=[C:40]([O:26][CH2:25][C:11]2[S:10][C:9]([C:6]3[CH:7]=[CH:8][C:3]([C:2]([F:1])([F:27])[F:28])=[CH:4][CH:5]=3)=[N:13][C:12]=2[CH2:14][N:15]2[CH2:20][CH2:19][CH:18]([C:21]([F:22])([F:24])[F:23])[CH2:17][CH2:16]2)[CH:39]=[CH:38][C:35]=1[C:36]#[N:37]
Reactant: OCc1sc(-c2ccc(C(F)(F)F)cc2)nc1CN1CCC(C(F)(F)F)CC1
Reactant: N#Cc1ccc(F)cc1OC(F)F
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: N#Cc1ccc(OCc2sc(-c3ccc(C(F)(F)F)cc3)nc2CN2CCC(C(F)(F)F)CC2)cc1OC(F)F
Temperature: 5 °C
Reaction time: 0.5 h
Yield: 82.3 %

Procedure:
To a solution of 3 g of [2-(4-trifluoromethyl-phenyl)-4-(4-trifluoromethyl-piperidin-1-ylmethyl)-thiazol-5-yl]-methanol in 12 mL of dimethylformamide at 5° C. was added 319 mg of a 55% suspension of sodium hydride in mineral oil. The resulting mixture was stirred for 30 minutes at 5° C. 4.7 mL of the resulting solution was slowly added to a solution 319 mg of 2-difluoromethoxy-4-fluoro-benzonitrile in 1.2 mL of dimethylformamide at 5° C. The resulting mixture was stirred at 5° C. allowing the temperature to warm up to room temperature. It was then heated in a sealed tube to 60° C. under microwave irradiation for 15 minutes. After allowing it to cool down to room temperature, the mixture was poured into water and extracted with dichloromethane. The organic extracts were dried over magnesium sulfate, filtered and concentrated under reduced pressure. The crude product was purified by column chromatography on silica gel (gradient from heptane 100 to heptane 50/ethyl acetate 50) to give 0.83 g of 2-difluoromethoxy-4-[2-(4-trifluoromethyl-phenyl)-4-(4-trifluoromethyl-piperidin-1-ylmethyl)-thiazol-5-ylmethoxy]-benzonitrile.
Reaction SMILES: C([N:4]1[C:46]2[C:41](=[CH:42][CH:43]=[C:44]([Cl:47])[CH:45]=2)[C:6]2([CH:11]([C:12]3[CH:17]=[C:16]([Cl:18])[CH:15]=[CH:14][C:13]=3[O:19][C:20]([CH2:30][CH3:31])([CH2:28][CH3:29])[C:21]([NH:23][S:24]([CH3:27])(=[O:26])=[O:25])=[O:22])[CH2:10][C:9](=[S:32])[NH:8][CH:7]2[C:33]2[CH:38]=[C:37]([F:39])[CH:36]=[CH:35][C:34]=2[CH3:40])[C:5]1=[O:48])(=O)C.C([O-])([O-])=O.[K+].[K+]>CO>[Cl:47][C:44]1[CH:45]=[C:46]2[NH:4][C:5](=[O:48])[C:6]3([CH:11]([C:12]4[CH:17]=[C:16]([Cl:18])[CH:15]=[CH:14][C:13]=4[O:19][C:20]([CH2:30][CH3:31])([CH2:28][CH3:29])[C:21]([NH:23][S:24]([CH3:27])(=[O:25])=[O:26])=[O:22])[CH2:10][C:9](=[S:32])[NH:8][CH:7]3[C:33]3[CH:38]=[C:37]([F:39])[CH:36]=[CH:35][C:34]=3[CH3:40])[C:41]2=[CH:42][CH:43]=1
Reactant: CCC(CC)(Oc1ccc(Cl)cc1C1CC(=S)NC(c2cc(F)ccc2C)C12C(=O)N(C(C)=O)c1cc(Cl)ccc12)C(=O)NS(C)(=O)=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: CCC(CC)(Oc1ccc(Cl)cc1C1CC(=S)NC(c2cc(F)ccc2C)C12C(=O)Nc1cc(Cl)ccc12)C(=O)NS(C)(=O)=O
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 82.5 %

Procedure:
A mixture of chiral (2′S, 3S, 4′R)-1-acetyl-6-chloro-4′-[5-chloro-2-(2-methanesulfonylamino-1,1-diethyl-2-oxo-ethoxy)-phenyl]-2′-(5-fluoro-2-methyl-phenyl)-6′-thioxo spiro[3H-indole-3,3′-piperidine]-2(1H)-one (45 mg) and K2CO3 (30 mg) in methanol (2 mL) was stirred at room temperature for 15 min, and then the mixture was partitioned between ethyl acetate and diluted aqueous HCl solution. The organic layer was washed with brine, dried over anhydrous Na2SO4, concentrated to give the title compound as white solid (35 mg).
Reaction SMILES: O.[OH-].[Li+].Cl.[CH3:5][O:6][C:7](=[O:11])[CH2:8][CH2:9][NH2:10].Br[CH2:13][C:14]1[CH:19]=[C:18]([Cl:20])[CH:17]=[CH:16][C:15]=1[N+:21]([O-:23])=[O:22]>CN(C)C=O>[CH3:5][O:6][C:7](=[O:11])[CH2:8][CH2:9][NH:10][CH2:13][C:14]1[CH:19]=[C:18]([Cl:20])[CH:17]=[CH:16][C:15]=1[N+:21]([O-:23])=[O:22]
Reactant: O=[N+]([O-])c1ccc(Cl)cc1CBr
Reactant: COC(=O)CCN
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)CCNCc1cc(Cl)ccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
A mixture of 4 Å molecular sieve powder (16.9 g) and lithium hydroxide monohydrate (1.80 g, 43 mmol) in N,N-dimethylformamide (100 ml) was stirred at room temperature for 20 minutes. β-Alanine methyl ester hydrochloride (5.0 g, 35.8 mmol) was added and the mixture stirred for a further 45 minutes. 2-(Bromomethyl)-4-chloro-1-nitrobenzene (J. Het. Chem. 1972; 9(1), 119-22) (8.98 g, 35.8 mmol) was added and the reaction stirred at room temperature for 16 hours. The mixture was filtered, the filtrate diluted with ethyl acetate (150 ml), then washed with brine (3×150 ml) and extracted with 2N hydrochloric acid (2×75 ml). The combined acidic extracts were basified using sodium carbonate, then extracted with ethyl acetate. The combined organic extracts were dried over magnesium sulphate and evaporated under reduced pressure to afford the title compound, 1.29 g.
Reaction SMILES: Cl.[F:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[NH:9][C:10]1[O:14][C:13]([C:15]([NH:17][C:18]2[CH:23]=[CH:22][C:21]([C@H:24]3[CH2:29][CH2:28][C@H:27]([CH2:30][NH:31]C(=O)OC(C)(C)C)[CH2:26][CH2:25]3)=[CH:20][CH:19]=2)=[O:16])=[N:12][N:11]=1>O1CCOCC1>[NH2:31][CH2:30][C@H:27]1[CH2:28][CH2:29][C@H:24]([C:21]2[CH:20]=[CH:19][C:18]([NH:17][C:15]([C:13]3[O:14][C:10]([NH:9][C:4]4[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=4[F:2])=[N:11][N:12]=3)=[O:16])=[CH:23][CH:22]=2)[CH2:25][CH2:26]1
Reactant: CC(C)(C)OC(=O)NC[C@H]1CC[C@H](c2ccc(NC(=O)c3nnc(Nc4ccccc4F)o3)cc2)CC1
Agent: Cl
Solvent: C1COCCO1
Product: NC[C@H]1CC[C@H](c2ccc(NC(=O)c3nnc(Nc4ccccc4F)o3)cc2)CC1
Reaction time: 18 h

Procedure:
4M HCl in 1,4-dioxane (1 mL) was added to tert-butyl [(trans-4-{4-[({5-[(2-fluorophenyl)amino]-1,3,4-oxadiazol-2-yl}carbonyl)amino]phenyl}cyclohexyl)-methyl]carbamate (Example 618) (50 mg, 0.10 mmol) and the suspension stirred for 18 hours. All volatiles were removed in vacuo and the residue triturated with Et2O (3 mL), the solid filtered, washed with Et2O (2×5 mL), isohexane (2×5 mL) to give the title compound (as a hydrochloride salt) (44 mg, 99%) as a white solid; 1H NMR δ 1.07-1.16 (2H, m), 1.39-1.47 (2H, m), 1.57-1.69 (1H, m), 1.87 (4H, t), 2.41-2.52 (1H, m), 2.71 (2H, d), 7.14-7.20 (1H, m), 7.23 (1H, s), 7.25-7.27 (2H, m), 7.29-7.34 (1H, m), 7.70 (2H, d), 7.87 (3H, s), 8.01-8.06 (1H, m), 10.76 (1H, s), 10.94 (1H, s); MS m/e (MH)+ 410.
Reaction SMILES: [N:1]1([C:7](=[O:15])[CH2:8][N:9]2[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.C(=O)(O)[O-].[Na+].[C:21](Cl)([Cl:23])=[O:22]>ClCCl>[N:1]1([C:7](=[O:15])[CH2:8][N:9]2[CH2:10][CH2:11][N:12]([C:21]([Cl:23])=[O:22])[CH2:13][CH2:14]2)[CH2:2][CH2:3][O:4][CH2:5][CH2:6]1
Reactant: O=C(Cl)Cl
Reactant: O=C(CN1CCNCC1)N1CCOCC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: O=C(Cl)N1CCN(CC(=O)N2CCOCC2)CC1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To the solution of 1-morpholin-4-yl-2-piperazin-1-yl-ethanone (0.5 g, 2.34 mmol) (Oakwood) in dichloromethane (15 mL) was added saturated sodium bicarbonate solution (15 mL). The reaction mixture was cooled to 0° C. and then followed by the dropwise addition of phosgene (20% in toluene, 2.22 mL, 4.21 mmol). The reaction mixture was allowed to warm up to room temperature. After stirring at room temperature for 30 minutes, the reaction mixture was extracted with dichloromethane three times. The combined organic layer was washed with water and brine, dried (Na2SO4), filtered and concentrated to give crude 4-(2-morpholin-4-yl-2-oxo-ethyl)-piperazine-1-carbonyl chloride as yellow oil and used for the next step without further purification.
Reaction SMILES: [CH2:1]([C:3]1[CH:4]=[C:5]([CH2:11][C@@H:12]([NH:16][C:17]([N:19]2[CH2:24][CH2:23][CH:22]([N:25]3[CH2:31][CH2:30][C:29]4[CH:32]=[CH:33][CH:34]=[CH:35][C:28]=4[NH:27][C:26]3=[O:36])[CH2:21][CH2:20]2)=[O:18])[C:13](O)=[O:14])[CH:6]=[CH:7][C:8]=1[CH2:9][CH3:10])[CH3:2].[CH3:37][N:38]1[CH2:44][CH2:43][CH2:42][N:41]([CH:45]2[CH2:50][CH2:49][NH:48][CH2:47][CH2:46]2)[CH2:40][CH2:39]1>>[CH2:1]([C:3]1[CH:4]=[C:5]([CH:6]=[CH:7][C:8]=1[CH2:9][CH3:10])[CH2:11][C@@H:12]([NH:16][C:17]([N:19]1[CH2:24][CH2:23][CH:22]([N:25]2[CH2:31][CH2:30][C:29]3[CH:32]=[CH:33][CH:34]=[CH:35][C:28]=3[NH:27][C:26]2=[O:36])[CH2:21][CH2:20]1)=[O:18])[C:13]([N:48]1[CH2:49][CH2:50][CH:45]([N:41]2[CH2:42][CH2:43][CH2:44][N:38]([CH3:37])[CH2:39][CH2:40]2)[CH2:46][CH2:47]1)=[O:14])[CH3:2]
Reactant: CCc1ccc(C[C@@H](NC(=O)N2CCC(N3CCc4ccccc4NC3=O)CC2)C(=O)O)cc1CC
Reactant: CN1CCCN(C2CCNCC2)CC1
Product: CCc1ccc(C[C@@H](NC(=O)N2CCC(N3CCc4ccccc4NC3=O)CC2)C(=O)N2CCC(N3CCCN(C)CC3)CC2)cc1CC

Procedure:
Prepared analogously to Example 9i) from 400 mg (0.81 mmol) (R)-3-(3,4-diethyl-phenyl)-2-{[4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carbonyl]-amino}-propionic acid and 200 mg (1.01 mmol) 1-methyl-4-piperidin-4-yl-[1,4]diazepan.