Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[CH2:7](Br)[C:8]#[C:9][CH3:10].CN(C)C=O.[CH3:17][N:18]1[C:23](=[O:24])[C:22]2[NH:25][C:26]([N:28]3[CH2:33][CH2:32][N:31]([C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35])[CH2:30][CH2:29]3)=[N:27][C:21]=2[CH:20]=[N:19]1>O>[CH2:7]([N:25]1[C:22]2[C:23](=[O:24])[N:18]([CH3:17])[N:19]=[CH:20][C:21]=2[N:27]=[C:26]1[N:28]1[CH2:33][CH2:32][N:31]([C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35])[CH2:30][CH2:29]1)[C:8]#[C:9][CH3:10]
Reactant: CC#CCBr
Reactant: Cn1ncc2nc(N3CCN(C(=O)OC(C)(C)C)CC3)[nH]c2c1=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CC#CCn1c(N2CCN(C(=O)OC(C)(C)C)CC2)nc2cnn(C)c(=O)c21
Temperature: 25 °C
Reaction time: 22 h

Procedure:
43.9 g of potassium carbonate and 27.8 ml of 2-butynyl bromide were successively added to a 5.5-L N,N-dimethylformamide solution of 88.4 g of t-butyl 4-(6-methyl-7-oxo-6,7-dihydro-1H-imidazo[4,5-d]pyridazin-2-yl)piperazine-1-carboxylate at 15° C. under a nitrogen atmosphere. The reaction solution was stirred at room temperature for 22 hours, and then poured into 10 L of water. The mixture was extracted with 5 L of ethyl acetate. The organic layer was successively washed twice with 5 L of water, and with 5 L of a saturated sodium chloride solution. The aqueous layer was extracted twice with 3 L of ethyl acetate. The organic layers were combined together, and then dried over anhydrous magnesium sulfate. The organic layer was concentrated under reduced pressure. The residue was purified by silica gel column chromatography. Thus, 54.3 g of the title compound was obtained from the fraction eluted with hexane-ethyl acetate (3:2 to 3:7).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH:9]([CH2:14][C:15]1[CH:20]=[CH:19][C:18]([N+:21]([O-])=O)=[CH:17][CH:16]=1)[C:10]([O:12][CH3:13])=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2]>CO.[Pd]>[NH2:21][C:18]1[CH:17]=[CH:16][C:15]([CH2:14][CH:9]([NH:8][C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])[C:10]([O:12][CH3:13])=[O:11])=[CH:20][CH:19]=1
Reactant: COC(=O)C(Cc1ccc([N+](=O)[O-])cc1)NC(=O)OC(C)(C)C
Agent: [Pd]
Solvent: CO
Product: COC(=O)C(Cc1ccc(N)cc1)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of methyl 2-[(tert-butoxycarbonyl)amino]-3-(4 nitrophenyl)propanoate 3 (69.4 g) and NH4HCO2 (6.5 equ.) in CH3OH (20 ml/g) is added 5% Pd/C (15% in weight, 10 g). The temperature rises to 40° C. and then decreases. After stirring for 2 h at room temperature, the solution is filtered over celite and the solvent is evaporated. The residue is diluted in AcOEt and washed 3 times with water. The organic phase is dried over MgSO4 and evaporated to dryness. No further purification is needed.
Reaction SMILES: Cl.[F:2][C:3]1[C:8]([F:9])=[CH:7][CH:6]=[CH:5][C:4]=1[C@H:10]1[CH2:16][N:15]2[CH:17]([CH2:20][CH3:21])[CH2:18][N:19]=[C:14]2[C@H:13]([NH:22]C(=O)OC(C)(C)C)[CH2:12][CH2:11]1>O1CCOCC1>[F:2][C:3]1[C:8]([F:9])=[CH:7][CH:6]=[CH:5][C:4]=1[C@H:10]1[CH2:16][N:15]2[CH:17]([CH2:20][CH3:21])[CH2:18][N:19]=[C:14]2[C@H:13]([NH2:22])[CH2:12][CH2:11]1
Reactant: CCC1CN=C2[C@H](NC(=O)OC(C)(C)C)CC[C@@H](c3cccc(F)c3F)CN21
Agent: Cl
Solvent: C1COCCO1
Product: CCC1CN=C2[C@H](N)CC[C@@H](c3cccc(F)c3F)CN21
Reaction time: 1 h

Procedure:
Hydrochloric acid (4.0 M in dioxane; 3 mL, 12.0 mmol) was added to a solution of tert-butyl [(6S,9R)-6-(2,3-difluorophenyl)-3-ethyl-2,5,6,7,8,9-hexahydro-3H-imidazo[1,2-a]azepin-9-yl]carbamate (122 mg, 0.310 mmol) in 1,4-dioxane (3 mL). After 1 h, the reaction was concentrated to give the title compound as a bis hydrochloride salt (136 mg). MS 294.1 (M+1).
Reaction SMILES: [C:1]([O:5][C:6]12[CH2:15][CH:10]3[CH2:11][CH:12]([CH2:14][C:8]([C:16]([OH:18])=[O:17])([CH2:9]3)[CH2:7]1)[CH2:13]2)(=[O:4])[CH:2]=[CH2:3].[CH2:19]=[C:20]([CH3:22])[CH3:21].S(=O)(=O)(O)O>ClCCl>[C:1]([O:5][C:6]12[CH2:15][CH:10]3[CH2:11][CH:12]([CH2:14][C:8]([C:16]([O:18][C:20]([CH3:22])([CH3:21])[CH3:19])=[O:17])([CH2:9]3)[CH2:7]1)[CH2:13]2)(=[O:4])[CH:2]=[CH2:3]
Reactant: C=C(C)C
Reactant: C=CC(=O)OC12CC3CC(C1)CC(C(=O)O)(C3)C2
Agent: O=S(=O)(O)O
Solvent: ClCCl
Product: C=CC(=O)OC12CC3CC(C1)CC(C(=O)OC(C)(C)C)(C3)C2
Yield: 81 %

Procedure:
A mixture of 5 mmole of 1-acryloyloxy-3-carboxyadamantane thus obtained, 50 mmole of isobutene, 0.5 mmole of sulfuric acid and 50 ml of dichloromethane was stirred at 0° C. for 24 hours. After concentrating the reaction mixture, the concentrate was subjected to column chromatography on a silica gel to thereby yield the title compound in a yield of 81%.
Reaction SMILES: [OH-].[K+].[NH2:3][C:4]1[CH:9]=[C:8]([Cl:10])[N:7]=[C:6]([S:11][CH3:12])[N:5]=1.Cl[C:14]1[C:19]([N+:20]([O-:22])=[O:21])=[CH:18][C:17]([C:23]([F:26])([F:25])[F:24])=[C:16]([Cl:27])[C:15]=1[N+:28]([O-:30])=[O:29]>CS(C)=O>[Cl:27][C:16]1[C:15]([N+:28]([O-:30])=[O:29])=[C:14]([N:7]2[C:8]([Cl:10])=[CH:9][C:4]([NH2:3])=[N:5][CH:6]2[S:11][CH3:12])[C:19]([N+:20]([O-:22])=[O:21])=[CH:18][C:17]=1[C:23]([F:25])([F:26])[F:24]
Reactant: O=[N+]([O-])c1cc(C(F)(F)F)c(Cl)c([N+](=O)[O-])c1Cl
Reactant: CSc1nc(N)cc(Cl)n1
Agent: [K+]
Agent: [OH-]
Solvent: CS(C)=O
Product: CSC1N=C(N)C=C(Cl)N1c1c([N+](=O)[O-])cc(C(F)(F)F)c(Cl)c1[N+](=O)[O-]
Temperature: 25 °C

Procedure:
7.9 parts of finely powdered 85% potassium hydroxide are dissolved in 70 ml of dimethylsulfoxide. To this solution is added dropwise a solution of 17.6 parts of 4-amino-6-chloro-2-methylmercaptopyrimidine in 80 ml of dimethylsulfoxide at about 15° C., and the reaction mixture is subsequently stirred for half an hour at room temperature. Then 30.5 parts of 1,3-dichloro-2,6-dinitro-4-trifluoromethylbenzene in 100 ml of dimethylsulfoxide are added dropwise at about 115° C. The reaction mixture is stirred overnight at room temperature, then poured into 2 liters of ice-water and extracted with ethyl acetate. The combined extracts are washed repeatedly with water, dried over sodium sulfate, filtered and concentrated. The crude product is purified by column chromatography over silica gel with dichloromethane as eluant. Yield: 22.3 parts of the title compound with a melting point of 171°-175° C.
Reaction SMILES: [OH:1][C@@H:2]1[CH2:25][CH2:24][C@@:23]2([CH3:26])[C@H:4](/[C:5](=[CH:29]\[CH3:30])/[C:6](=[O:28])[C@@H:7]3[C@@H:22]2[CH2:21][CH2:20][C@@:19]2([CH3:27])[C@H:8]3[CH2:9][CH2:10][C@@H:11]2[C@H:12]([CH3:18])[CH2:13][CH2:14][C:15]([OH:17])=[O:16])[CH2:3]1.[OH-].[Na+]>[Pd].O>[OH:1][C@@H:2]1[CH2:25][CH2:24][C@@:23]2([CH3:26])[C@H:4]([C@@H:5]([CH2:29][CH3:30])[C:6](=[O:28])[C@@H:7]3[C@@H:22]2[CH2:21][CH2:20][C@@:19]2([CH3:27])[C@H:8]3[CH2:9][CH2:10][C@@H:11]2[C@H:12]([CH3:18])[CH2:13][CH2:14][C:15]([OH:17])=[O:16])[CH2:3]1
Reactant: C/C=C1/C(=O)[C@@H]2[C@H](CC[C@]3(C)[C@@H]([C@H](C)CCC(=O)O)CC[C@@H]23)[C@@]2(C)CC[C@@H](O)C[C@@H]12
Agent: [Pd]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CC[C@H]1C(=O)[C@@H]2[C@H](CC[C@]3(C)[C@@H]([C@H](C)CCC(=O)O)CC[C@@H]23)[C@@]2(C)CC[C@@H](O)C[C@@H]12

Procedure:
In one embodiment in Step 5, E-3α-hydroxy-6-ethylidene-7-keto-5β-cholan-24-oic acid (5), water, NaOH solution (e.g. 50% wt.), and Pd/C are mixed at about 5 bar of H2 gas and at a temperature at about 100° C. to about 105° C. until H2 uptake has ceased. The reaction mixture is cooled to about 40° C. to about 50° C. and Pd/C is filtered off. Then n-butyl acetate and HCl are added to the solution containing compound 6. In one embodiment, the aqueous phase is separated and discarded. The organic phase containing compound 6 is treated with activated carbon. The carbon is filtered off and the filtrate is moved to another reactor where it is reduced down by distillation, and then the suspension is cooled to about 5° C. to about 20° C. In one embodiment, compound 6 is isolated via filtration and the filtrate is dried on the pressure filter under vacuum at about 80° C.
Reaction SMILES: [CH3:1][Si:2]([CH3:11])([CH3:10])[C:3]#[C:4][C:5]1[S:6][CH:7]=[CH:8][N:9]=1.[O:12]1[C:16]2([CH2:21][CH2:20][C:19](=[O:22])[CH2:18][CH2:17]2)[O:15][CH2:14][CH2:13]1>>[CH3:11][Si:2]([CH3:10])([CH3:1])[C:3]#[C:4][C:5]1[S:6][C:7]([C:19]2([OH:22])[CH2:20][CH2:21][C:16]3([O:15][CH2:14][CH2:13][O:12]3)[CH2:17][CH2:18]2)=[CH:8][N:9]=1
Reactant: C[Si](C)(C)C#Cc1nccs1
Reactant: O=C1CCC2(CC1)OCCO2
Product: C[Si](C)(C)C#Cc1ncc(C2(O)CCC3(CC2)OCCO3)s1

Procedure:
The title compound was prepared as a white solid from 2-trimethylsilanylethynyl-thiazole, as prepared in the previous step, and 1,4-dioxa-spiro[4.5]decan-8-one using the procedure described in Step A of Example 33.
Reaction SMILES: [Cl:1][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[C:5]([O:15][CH3:16])[CH:4]=1.[F:17]C1C=CC(C2C=CC(CO)=CC=2OC)=CC=1>>[Cl:1][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:14]=[CH:13][C:12]([F:17])=[CH:11][CH:10]=2)=[C:5]([O:15][CH3:16])[CH:4]=1
Reactant: COc1cc(CO)ccc1-c1ccc(F)cc1
Reactant: COc1cc(CCl)ccc1-c1ccccc1
Product: COc1cc(CCl)ccc1-c1ccc(F)cc1

Procedure:
Following the same procedure for the preparation of 4-Chloromethyl-2-methoxy-biphenyl, the title compound is prepared from (4′-Fluoro-2-methoxy-biphenyl-4-yl)-methanol (crude material from the previous step). The crude material is used directly in the next step.
Reaction SMILES: Br[C:2]1[C:10]2[N:9]3[CH2:11][CH2:12][CH2:13][NH:14][C:15](=[O:16])[C:8]3=[C:7]([CH3:17])[C:6]=2[CH:5]=[C:4]([C:18]#[N:19])[CH:3]=1.[N:20]1[CH:25]=[CH:24][C:23](B(O)O)=[CH:22][CH:21]=1>>[CH3:17][C:7]1[C:6]2[CH:5]=[C:4]([C:18]#[N:19])[CH:3]=[C:2]([C:23]3[CH:24]=[CH:25][N:20]=[CH:21][CH:22]=3)[C:10]=2[N:9]2[CH2:11][CH2:12][CH2:13][NH:14][C:15](=[O:16])[C:8]=12
Reactant: Cc1c2n(c3c(Br)cc(C#N)cc13)CCCNC2=O
Reactant: OB(O)c1ccncc1
Product: Cc1c2n(c3c(-c4ccncc4)cc(C#N)cc13)CCCNC2=O

Procedure:
The title compound, white solid (64 mg, 81%), MS (ISP) m/z=317.5 [(M+H)+], mp 285° C., was prepared in accordance with the general method of example 1 from 7-bromo-11-methyl-1-oxo-2,3,4,5-tetrahydro-[1,4]diazepino[1,2-a]indole-9-carbonitrile (intermediate 17) (79.5 mg, 0.25 mmol) and commercially available pyridin-4-ylboronic acid (39.9 mg, 0.325 mmol).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([C:17]([NH2:19])=O)[CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].COC1C=CC(P2(=S)SP(C3C=CC(OC)=CC=3)(=S)[S:29]2)=CC=1>O1CCCC1>[NH2:19][C:17](=[S:29])[C@@H:9]([NH:8][C:6](=[O:7])[O:5][C:1]([CH3:4])([CH3:3])[CH3:2])[CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)C(N)=O
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)C(N)=S
Temperature: 25 °C
Yield: 130.6 %

Procedure:
To a solution of #12 (14.060 g, 53.192 mmol, 1 eq.) in tetrahydrofuran (180 mL, 0.296 M), was added 2,4-bis(4-methoxyphenyl)-1,3,2,4-dithiadiphosphetane-2,4-dithione (Lawesson's reagent) (12.70 g, 31.40 mmol, 0.59 eq.) and the reaction was refluxed for 90 minutes. The reaction was cooled to room temperature and quenched by addition of saturated aqueous sodium bicarbonate solution. The mixture was extracted twice with ethyl acetate and the combined organic layers were dried over sodium sulfate, filtered, and concentrated in vacuo. The residue was dissolved in ethyl acetate, concentrated in vacuo onto silica and purified by silica gel chromatography (Gradient: 0% to 100% ethyl acetate in heptane), affording #13 (11.50 g, 77%) as a white solid. LC-MS: m/z 279.4 [M−H+], 225.2 [(M−2-methylprop-1-ene)+H+], 181.2 [(M−Boc)+H+]; 1H NMR (400 MHz, DMSO-d6), presumed to be a mixture of rotamers, major rotamer: δ 9.60 (br s, 1H), 9.19 (br s, 1H), 7.23-7.32 (m, 5H), 6.82 (d, J=8.8 Hz, 1H), 4.44 (ddd, J=9.4, 9.1, 4.4 Hz, 1H), 3.00 (dd, J=13.7, 4.5 Hz, 1H), 2.79 (dd, J=13.6, 9.9 Hz, 1H), 1.29 (s, 9H).
Reaction SMILES: [NH2:1][C:2]1[C:10]([N+:11]([O-:13])=[O:12])=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][C:3]=1[Br:14].[CH3:15][Si](C=[N+]=[N-])(C)C>ClCCl.CO>[NH2:1][C:2]1[C:10]([N+:11]([O-:13])=[O:12])=[CH:9][C:5]([C:6]([O:8][CH3:15])=[O:7])=[CH:4][C:3]=1[Br:14]
Reactant: C[Si](C)(C)C=[N+]=[N-]
Reactant: Nc1c(Br)cc(C(=O)O)cc1[N+](=O)[O-]
Solvent: CO
Solvent: ClCCl
Product: COC(=O)c1cc(Br)c(N)c([N+](=O)[O-])c1
Temperature: 25 °C
Yield: 40 %

Procedure:
To a solution of 4-amino-3-bromo-5-nitrobenzoic acid (3.65 g, 14.0 mmol) in dichloromethane (35 mL) and methanol (35 mL) at 0° C. was slowly added trimethylsilyl-diazomethane (8.74 mL, 17.5 mmol). The mixture was allowed to warm to ambient temperature and concentrated. Purification by silica gel chromatography (100% hexanes→50% hexanes/ethyl acetate) gave the title compound (1.54 g). LC-MS [M]=275.1.
Reaction SMILES: O[Li].O.[C:4]1([N:10]2[C:18]3[CH2:17][CH2:16][CH2:15][CH:14]([CH2:19][C:20]([O:22]CC)=[O:21])[C:13]=3[CH:12]=[N:11]2)[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1>O.CO>[C:4]1([N:10]2[C:18]3[CH2:17][CH2:16][CH2:15][CH:14]([CH2:19][C:20]([OH:22])=[O:21])[C:13]=3[CH:12]=[N:11]2)[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: CCOC(=O)CC1CCCc2c1cnn2-c1ccccc1
Agent: [Li]O
Solvent: CO
Solvent: O
Product: O=C(O)CC1CCCc2c1cnn2-c1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 55.8 %

Procedure:
LiOH.H2O (120 mg, 2.85 mmol), dissolved in 1 ml of water, is added to a solution of ethyl 2-(4,5,6,7-tetrahydro-1-phenyl-1H-indazol-4-yl)acetate (808 mg, 2.85 mmol) in methanol (20 mL) and is stirred at room temperature for 1 hour following the reaction by means of TLC. The methanol is evaporated under reduced pressure, the residue is suspended in water and acidified with diluted HCl forming a pulp that is extracted with ethyl acetate. The organic phase is washed with water, dried and evaporated at reduced pressure, giving 2-(4,5,6,7-tetrahydro-1-phenyl-1H-indazol-4-yl)acetic acid (410 mg, 1.59 mmol, 53%, solid).
Reaction SMILES: CN1[CH2:7][CH:6]=[C:5]([C:8]2[C:16]3[C:11](=[N:12][CH:13]=[CH:14][CH:15]=3)[NH:10][CH:9]=2)CC1.[C:17](Cl)(=[O:24])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>>[C:17]([N:10]1[C:11]2[C:16](=[CH:15][CH:14]=[CH:13][N:12]=2)[C:8]([CH:5]2[CH2:6][CH:7]=[CH:8][CH2:9][N:10]2[CH3:11])=[CH:9]1)(=[O:24])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: CN1CC=C(c2c[nH]c3ncccc23)CC1
Reactant: O=C(Cl)c1ccccc1
Product: CN1CC=CCC1c1cn(C(=O)c2ccccc2)c2ncccc12

Procedure:
(6.7 mg, 18%); from 3-(1-methyl-1,2,3,6-tetrahydro-4-pyridinyl)-1H-7-azaindole (25.0 mg, 0.12 mmol) and benzoyl chloride (28 μL, 0.24 mmol); HRMS-FAB+for C20H19N3O: calculated MH+:318.16064; found:318.16191.
Reaction SMILES: Cl.Cl.[F:3][C:4]([F:24])([F:23])[C:5]([C:11]1[CH:16]=[CH:15][C:14]([N:17]2[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]2)=[CH:13][CH:12]=1)([OH:10])[C:6]([F:9])([F:8])[F:7].C(N(CC)CC)C.[N+:32]([C:35]1[CH:40]=[CH:39][C:38]([S:41](Cl)(=[O:43])=[O:42])=[CH:37][CH:36]=1)([O-:34])=[O:33]>C(Cl)Cl>[N+:32]([C:35]1[CH:36]=[CH:37][C:38]([S:41]([N:20]2[CH2:21][CH2:22][N:17]([C:14]3[CH:13]=[CH:12][C:11]([C:5]([OH:10])([C:6]([F:9])([F:8])[F:7])[C:4]([F:3])([F:23])[F:24])=[CH:16][CH:15]=3)[CH2:18][CH2:19]2)(=[O:43])=[O:42])=[CH:39][CH:40]=1)([O-:34])=[O:33]
Reactant: OC(c1ccc(N2CCNCC2)cc1)(C(F)(F)F)C(F)(F)F
Reactant: O=[N+]([O-])c1ccc(S(=O)(=O)Cl)cc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=[N+]([O-])c1ccc(S(=O)(=O)N2CCN(c3ccc(C(O)(C(F)(F)F)C(F)(F)F)cc3)CC2)cc1
Temperature: 0 °C
Yield: 56.5 %

Procedure:
A 25-mL round-bottomed flask was cooled to 0° C. and charged with 1,1,1,3,3,3-hexafluoro-2-(4-(1-piperazinyl)phenyl)-2-propanol dihydrochloride (250 mg, 0.62 mmol, Example 91, Step 1), CH2Cl2 (5 mL) and triethylamine (0.26 mL, 1.87 mmol). 4-Nitrobenzenesulfonyl chloride (166 mg, 0.75 mmol, Sigma-Aldrich, St. Louis, Mo.) was added. After 10 min at 0° C. the reaction was concentrated onto silica gel and purified via column chromatography (40 g silica gel, 0 to 10% MeOH in CH2Cl2) to give 2-(4-(4-((4-nitrophenyl)sulfonyl)-1-piperazinyl)phenyl)-1,1,1,3,3,3-hexafluoro-2-propanol (180 mg).
Reaction SMILES: [CH3:1][C:2]1([CH3:19])[C:10]2[C:5](=[CH:6][C:7]([N+:15]([O-:17])=[O:16])=[C:8]([NH:11]C(=O)C)[CH:9]=2)[NH:4][C:3]1=[O:18].Cl[CH2:21][C:22]1[S:26][C:25]([CH3:27])=[N:24][C:23]=1[CH3:28].C([O-])([O-])=O.[K+].[K+].C1CCN2C(=NCCC2)CC1>CO>[NH2:11][C:8]1[CH:9]=[C:10]2[C:5](=[CH:6][C:7]=1[N+:15]([O-:17])=[O:16])[N:4]([CH2:21][C:22]1[S:26][C:25]([CH3:27])=[N:24][C:23]=1[CH3:28])[C:3](=[O:18])[C:2]2([CH3:1])[CH3:19]
Reactant: Cc1nc(C)c(CCl)s1
Reactant: CC(=O)Nc1cc2c(cc1[N+](=O)[O-])NC(=O)C2(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCC2=NCCCN2CC1
Solvent: CO
Product: Cc1nc(C)c(CN2C(=O)C(C)(C)c3cc(N)c([N+](=O)[O-])cc32)s1
Yield: 61.8 %

Procedure:
Analogously to general procedure (I) N-(3,3-dimethyl-6-nitro-2-oxo-2,3-dihydro-1H-indol-5-yl)-acetamide (1.77 g) is alkylated using 5-chloromethyl-2,4-dimethyl-thiazole (1.09 g; 6.74 mmol) (Zh. Obshch. Khim. 1956, engl. transl. 3835) and K2CO3 (1.05 g; 7.41 mmol) at 60° C. for 3 days. After aqueous work-up the crude material is de-acetylated in MeOH (70 ml) using DBU (2.2 ml) at reflux. After aqueous work-up 5-amino-1-(2,4-dimethyl-thiazol-5-ylmethyl)-3,3-dimethyl-6-nitro-1,3-dihydro-indol-2-one (1.44 g) is obtained and used without further purification.
Reaction SMILES: [CH2:1]1[C:6]2([CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]2)[CH2:5][CH2:4][CH:3]([O:12][C:13]2[CH:14]=[C:15]3[C:20](=[CH:21][CH:22]=2)[CH:19]=[C:18]([CH:23]=O)[CH:17]=[CH:16]3)[CH2:2]1.[NH2:25][CH2:26][C:27]([F:32])([F:31])[C:28]([OH:30])=[O:29].C(O)C.C([BH3-])#N.[Na+].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>>[F:31][C:27]([F:32])([CH2:26][NH:25][CH2:23][C:18]1[CH:17]=[CH:16][C:15]2[C:20](=[CH:21][CH:22]=[C:13]([O:12][CH:3]3[CH2:2][CH2:1][C:6]4([CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]4)[CH2:5][CH2:4]3)[CH:14]=2)[CH:19]=1)[C:28]([OH:30])=[O:29]
Reactant: NCC(F)(F)C(=O)O
Reactant: O=Cc1ccc2cc(OC3CCC4(CCCCC4)CC3)ccc2c1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CCO
Product: O=C(O)C(F)(F)CNCc1ccc2cc(OC3CCC4(CCCCC4)CC3)ccc2c1
Temperature: 25 °C
Yield: 41.4 %

Procedure:
A solution of 6-(spiro[5.5]undec-3-yloxy)-naphthalene-2-carbaldehyde (150 mg, 0.46 mmol) and 3-amino-2,2-difluoro-propionic acid (58.2 mg, 0.465 mmol) in ethanol (0.7 mL, 10 mmol) was heated to reflux for 2 h. The yellow solution was then cooled to room temperature and sodium cyanoborohydride (35.1 mg, 0.558 mmol) was added portionwise. The resulting mixture was heated to reflux for 1 h. The reaction was then cooled to room temperature, and citric acid was added. The solution was stirred for several minutes and the solvent removed under vacuum. The resulting solid was suspended in water and filtered, and the collected solid was washed thoroughly with water (4×), ether (5×), and hexane (5×) to give (82.1 mg, 41%) of 2,2-difluoro-3-((6-(spiro[5.5]undecan-3-yloxy)naphthalen-2-yl)methylamino)propanoic acid. 1H NMR (400 MHz, CDCl3) δ: 7.93 (s, 1H), 7.86 (d, J=8.5 Hz, 1H), 7.83 (d, J=9.1 Hz, 1H), 7.52 (dd, J=8.4, 1.8 Hz, 1H), 7.30 (d, J=2.2 Hz, 1H), 7.22 (dd, J=9.0, 2.4 Hz, 1H), 4.52 (m, 1H), 4.45 (s, 2H), 3.60 (t, J=15.9 Hz, 2H), 1.76-1.35 (m, 18H).
Reaction SMILES: CC(C)N=C=NC(C)C.[Cl:10][C:11]1[CH:24]=[CH:23][C:14]([CH2:15][NH:16][C:17](=[O:22])[C:18]([CH3:21])([CH3:20])[CH3:19])=[CH:13][C:12]=1[NH:25][C:26]([NH:28][C:29]1[CH:30]=[C:31]([C:42](=[O:54])[NH:43][C@H:44]2[CH2:49][CH2:48][C@H:47]([C:50]([F:53])([F:52])[F:51])[CH2:46][CH2:45]2)[C:32]([O:37][CH2:38][CH:39]([F:41])[F:40])=[N:33][C:34]=1[NH:35][CH3:36])=S>CC#N>[Cl:10][C:11]1[CH:24]=[CH:23][C:14]([CH2:15][NH:16][C:17](=[O:22])[C:18]([CH3:21])([CH3:20])[CH3:19])=[CH:13][C:12]=1[NH:25][C:26]1[N:35]([CH3:36])[C:34]2=[N:33][C:32]([O:37][CH2:38][CH:39]([F:41])[F:40])=[C:31]([C:42](=[O:54])[NH:43][C@H:44]3[CH2:49][CH2:48][C@H:47]([C:50]([F:53])([F:52])[F:51])[CH2:46][CH2:45]3)[CH:30]=[C:29]2[N:28]=1
Reactant: CNc1nc(OCC(F)F)c(C(=O)N[C@H]2CC[C@H](C(F)(F)F)CC2)cc1NC(=S)Nc1cc(CNC(=O)C(C)(C)C)ccc1Cl
Agent: CC(C)N=C=NC(C)C
Solvent: CC#N
Product: Cn1c(Nc2cc(CNC(=O)C(C)(C)C)ccc2Cl)nc2cc(C(=O)N[C@H]3CC[C@H](C(F)(F)F)CC3)c(OCC(F)F)nc21
Temperature: 60 °C
Reaction time: 8 h

Procedure:
DIC (40 μL, 0.24 mmol) is added to a mixture of N-{4-chloro-3-[3-(trans-4-trifluoromethyl-cyclohexylcarbamoyl)-2-(2,2-difluoro-ethoxy)-6-methylamino-pyridin-5-ylthioureido]benzyl}-2,2-dimethyl-propionamide (135 mg, 0.20 mmol) and MeCN (3.5 mL). The reaction mixture is stirred at 60° C. overnight, allowed to cool and concentrated. The residue is treated with MeCN, filtered off and dried.
Reaction SMILES: [C:1]1([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[CH:6]=[CH:5][C:4]([CH2:7][C@H:8]([NH:26]C(OC(C)(C)C)=O)[C:9]([N:11]2[CH2:15][CH2:14][CH2:13][C@H:12]2[C:16]([O:18][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[O:17])=[O:10])=[CH:3][CH:2]=1.[ClH:40].O1CCOCC1>>[ClH:40].[NH2:26][C@@H:8]([CH2:7][C:4]1[CH:3]=[CH:2][C:1]([C:34]2[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=2)=[CH:6][CH:5]=1)[C:9]([N:11]1[CH2:15][CH2:14][CH2:13][C@H:12]1[C:16]([O:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=[O:17])=[O:10]
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccc(-c2ccccc2)cc1)C(=O)N1CCC[C@H]1C(=O)OCc1ccccc1
Agent: Cl
Solvent: C1COCCO1
Product: N[C@@H](Cc1ccc(-c2ccccc2)cc1)C(=O)N1CCC[C@H]1C(=O)OCc1ccccc1
Reaction time: 1 h

Procedure:
A solution of (S)-benzyl 1-((S)-3-(biphenyl-4-yl)-2-(tert-butoxycarbonylamino)propanoyl)pyrrolidine-2-carboxylate (429 mg, 0.812 mmol) and HCl in 1,4-dioxane (2.03 ml, 8.12 mmol) was allowed to stir for 1 hour and concentrated under reduced pressure to give (S)-benzyl 1-((S)-2-amino-3-(biphenyl-4-yl)propanoyl)pyrrolidine-2-carboxylate hydrochloride (396 mg); Retention time=1.00 minutes (condition B); MS (m+1)=429.2.
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].FC(F)(F)C(O)=O.[Cl:15][C:16]1[CH:17]=[N:18][C:19]2[NH:20][C:21]3[CH:22]=[CH:23][CH:24]=[C:25]([CH:46]=3)[CH2:26][CH2:27][C:28]3[CH:36]=[C:32]([NH:33][C:34]=1[N:35]=2)[CH:31]=[CH:30][C:29]=3[NH:37][C:38]([CH:40]1[CH2:45][CH2:44][NH:43][CH2:42][CH2:41]1)=[O:39].[C:47]1([CH2:53][C:54](Cl)=[O:55])[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=1>>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[Cl:15][C:16]1[CH:17]=[N:18][C:19]2[NH:20][C:21]3[CH:22]=[CH:23][CH:24]=[C:25]([CH:46]=3)[CH2:26][CH2:27][C:28]3[CH:36]=[C:32]([NH:33][C:34]=1[N:35]=2)[CH:31]=[CH:30][C:29]=3[NH:37][C:38]([CH:40]1[CH2:45][CH2:44][N:43]([C:54](=[O:55])[CH2:53][C:47]2[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=2)[CH2:42][CH2:41]1)=[O:39]
Reactant: O=C(Nc1ccc2cc1CCc1cccc(c1)Nc1ncc(Cl)c(n1)N2)C1CCNCC1
Reactant: O=C(Cl)Cc1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: O=C(Nc1ccc2cc1CCc1cccc(c1)Nc1ncc(Cl)c(n1)N2)C1CCN(C(=O)Cc2ccccc2)CC1
Yield: 70 %

Procedure:
The desired compound was prepared according to the procedure of Example A20, using N-[6-chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7).1(9,13)]docosa-1(20), 3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]piperidine-4-carboxamide bis(trifluoroacetate) and benzeneacetyl chloride as starting materials in 70% yield. 1H NMR (300 MHz, DMSO-d6): δ 9.61 (s, 1H), 9.44 (s, 1H), 9.32 (s, 1H), 8.18 (s, 1H), 7.97 (s, 1H), 7.72 (s, 1H), 7.20 (m, 7H), 7.03 (m, 2H), 6.89 (d, 1H), 6.79 (d, 1H), 4.42 (d, 1H), 4.01 (d, 1H), 3.73 (s, 2H), 3.02 (m, 1H), 2.81 (m, 4H), 2.63 (m, 2H), 1.80 (m, 2H), 1.41 (m, 2H). LCMS for C32H32ClN6O2(M+H)+: m/z=567.2.
Reaction SMILES: [CH3:1][N:2]([CH2:6][CH2:7][OH:8])[CH2:3][CH2:4][OH:5].[C:9]([OH:28])(=O)[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16]/[CH:17]=[CH:18]\[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26]>>[CH3:1][N:2]([CH2:6][CH2:7][O:8][C:9](=[O:28])[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16]/[CH:17]=[CH:18]\[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])[CH2:3][CH2:4][O:5][C:9](=[O:28])[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16]/[CH:17]=[CH:18]\[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26]
Reactant: CCCCCCCC/C=C\CCCCCCCC(=O)O
Reactant: CN(CCO)CCO
Product: CCCCCCCC/C=C\CCCCCCCC(=O)OCCN(C)CCOC(=O)CCCCCCC/C=C\CCCCCCCC

Procedure:
Compound A-6 (333 mg, 51.4%) was obtained in the same manner as that in Reference Example 2, by using N-methyldiethanolamine (Tokyo Chemical Industry Co., Ltd.; 119 mg, 1.00 mmol) and oleic acid (Tokyo Chemical Industry Co., Ltd.; 621 mg, 2.20 mmol)