Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([CH3:12])[C:6]([C:13](=[O:18])[C:14]([F:17])([F:16])[F:15])=[C:5]2[C:19]1[CH:24]=[CH:23][C:22]([S:25]([CH3:28])(=[O:27])=[O:26])=[CH:21][CH:20]=1.Cl.[F:30][C:31]1([F:37])[CH2:36][CH2:35][CH2:34][NH:33][CH2:32]1>>[F:30][C:31]1([F:37])[CH2:36][CH2:35][CH2:34][N:33]([C:2]2[CH:3]=[C:4]3[C:9](=[CH:10][CH:11]=2)[N:8]=[C:7]([CH3:12])[C:6]([C:13](=[O:18])[C:14]([F:17])([F:16])[F:15])=[C:5]3[C:19]2[CH:24]=[CH:23][C:22]([S:25]([CH3:28])(=[O:27])=[O:26])=[CH:21][CH:20]=2)[CH2:32]1
Reactant: Cc1nc2ccc(Br)cc2c(-c2ccc(S(C)(=O)=O)cc2)c1C(=O)C(F)(F)F
Reactant: FC1(F)CCCNC1
Agent: Cl
Product: Cc1nc2ccc(N3CCCC(F)(F)C3)cc2c(-c2ccc(S(C)(=O)=O)cc2)c1C(=O)C(F)(F)F
Yield: 50 %

Procedure:
The title compound was prepared from 1-[6-Bromo-4-(4-methanesulfonyl-phenyl)-2-methyl-quinolin-3-yl]-2,2,2-trifluoro-ethanone [example 23] and 3,3-difluoropiperidine hydrochloride according to the procedure of example 51. Yield: 50%; MS: m/z=. 513 (M+H).
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[CH:9][C:8]2[NH:7][C:6]3[CH:11]4[CH2:17][CH2:16][N:14]([CH2:15][C:5]=3[C:4]=2[CH:3]=1)[CH2:13][CH2:12]4.Br[C:19]1[CH:28]=[C:27]2[C:22]([CH:23]=[CH:24][N:25]=[CH:26]2)=[CH:21][CH:20]=1>>[CH:26]1[C:27]2[C:22](=[CH:21][CH:20]=[C:19]([N:7]3[C:8]4[CH:9]=[CH:10][C:2]([CH3:1])=[CH:3][C:4]=4[C:5]4[CH2:15][N:14]5[CH2:13][CH2:12][CH:11]([C:6]3=4)[CH2:17][CH2:16]5)[CH:28]=2)[CH:23]=[CH:24][N:25]=1
Reactant: Brc1ccc2ccncc2c1
Reactant: Cc1ccc2[nH]c3c(c2c1)CN1CCC3CC1
Product: Cc1ccc2c(c1)c1c(n2-c2ccc3ccncc3c2)C2CCN(CC2)C1

Procedure:
The reaction of 9-methyl-3,4,5,6-tetrahydro-1H-2,5-ethanoazepino[4,3-b]indole (226 mg, 1.0 mmol; Example 2B) and 7-bromoisoquinoline (312 mg, 1.5 mmol; Frontier) was performed as described in Example 68 to afford the title compound: 1H NMR (300 MHz, methanol-d4) δ ppm 1.94-2.20 (m, 4H) 2.42 (s, 3H) 2.91-2.98 (m, 1H) 3.08-3.29 (m, 4H) 4.32 (s, 2H) 6.90-6.96 (m, 1H) 6.98-7.04 (m, 1H) 7.22 (s, 1H) 7.73 (dd, J=8, 2 Hz, 1H) 7.94 (d, J=6 Hz, 1H) 8.09 (d, J=2 Hz, 1H) 8.15 (d, J=9 Hz, 1H) 8.53 (d, J=6 Hz, 1H) 9.33 (s, 1H); MS (DCI/NH3) m/z 354 (M+H)+.
Reaction SMILES: [F:1][C:2]([F:18])([F:17])[C:3]([C:5]1[C:13]2[C:8](=[CH:9][C:10]([N+:14]([O-:16])=[O:15])=[CH:11][CH:12]=2)[NH:7][CH:6]=1)=[O:4].C(=O)([O-])[O-].[K+].[K+].I[CH:26]([CH3:28])[CH3:27]>CN(C)C=O>[F:18][C:2]([F:1])([F:17])[C:3]([C:5]1[C:13]2[C:8](=[CH:9][C:10]([N+:14]([O-:16])=[O:15])=[CH:11][CH:12]=2)[N:7]([CH:26]([CH3:28])[CH3:27])[CH:6]=1)=[O:4]
Reactant: O=C(c1c[nH]c2cc([N+](=O)[O-])ccc12)C(F)(F)F
Reactant: CC(C)I
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)n1cc(C(=O)C(F)(F)F)c2ccc([N+](=O)[O-])cc21
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 50 %

Procedure:
A solution of 2,2,2-trifluoro-1-(6-nitro-1H-indol-3-yl)-ethanone (1.0 g, 3.87 mmol) in N,N-dimethylformamide (10 mL) at 25° C. was treated with potassium carbonate (1.34 g, 9.68 mmol). The resulting mixture was stirred at 25° C. for 10 min and then treated with 2-iodopropane (0.58 mL, 5.81 mmol). The reaction was heated at 65° C. for 3 h. At this time, the reaction was cooled to 25° C. and was partitioned between water (50 mL) and ethyl acetate (50 mL). This mixture was treated with a 1N aqueous hydrochloric acid solution (25 mL). The organic layer was washed with water (1×50 mL) and a saturated aqueous sodium chloride solution (1×50 mL), dried over magnesium sulfate, filtered, and concentrated in vacuo to afford 2,2,2-trifluoro-1-(1-isopropyl-6-nitro-1H-indol-3-yl)-ethanone (581 mg, 98%) as a yellow solid: mp 143-145° C.; EI-HRMS m/e calcd for C14H14F3NO (M+) 269.1027, found 269.1037.
Reaction SMILES: [CH3:1][N:2]1[C:10]2[CH2:9][CH2:8][CH2:7][CH2:6][C:5]=2[CH:4]=[N:3]1.[Cl:11][CH2:12][CH2:13][C:14](Cl)=[O:15].[Cl-].[Al+3].[Cl-].[Cl-]>ClC(Cl)C>[Cl:11][CH2:12][CH2:13][C:14]([C:4]1[C:5]2[CH2:6][CH2:7][CH2:8][CH2:9][C:10]=2[N:2]([CH3:1])[N:3]=1)=[O:15]
Reactant: O=C(Cl)CCCl
Reactant: Cn1ncc2c1CCCC2
Agent: [Al+3]
Agent: [Cl-]
Solvent: CC(Cl)Cl
Product: Cn1nc(C(=O)CCCl)c2c1CCCC2
Temperature: 0 °C
Yield: 60.1 %

Procedure:
4,5,6,7-Tetrahydro-1-methyl-1H-indazole (10 g) and 3-chloropropionyl chloride (26 g) were dissolved in dichloroethane (100 ml) and aluminum chloride (28 g) was gradually added under an ice bath while stirring the mixture The reaction mixture was stirred for 17 hours at room temperature and poured into ice water. The reaction mixture was stirred for 2 hours at room temperature and extracted twice with chloroform. The chloroform layer was washed with saturated aqueous sodium hydrogencarbonate solution and saturated brine and dried over magnesium sulfate. The magnesium sulfate was filtered off and the solvent was evaporated under reduced pressure. The obtained residue was subjected to silica gel column chromatography (silica gel 100 g) and 3-(3-chloropropionyl)-4,5,6,7-tetrahydro-1-methyl-1H-indazole (10 g) was obtained from an eluate of hexane:ethyl acetate=20:1.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[C:6]([OH:8])[N:5]=[C:4]([CH3:9])[N:3]=1.[N+:10]([O-])([OH:12])=[O:11]>>[OH:1][C:2]1[C:7]([N+:10]([O-:12])=[O:11])=[C:6]([OH:8])[N:5]=[C:4]([CH3:9])[N:3]=1
Reactant: O=[N+]([O-])O
Reactant: Cc1nc(O)cc(O)n1
Product: Cc1nc(O)c([N+](=O)[O-])c(O)n1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
Part A: 4,6-Dihydroxy-2-methylpyrimidine (60 g) was added in portions to fuming nitric acid (120 ML) at 0° C. while cooling the reaction flask. After completion of addtion, the reaction was stirred an additional 1 h at 0° C. followed by another 1 h at room temperature. The reaction mixture was then poured over ice (200 g) and the ice was allowed to melt. A light pink solid was isolated by filteration and washed with cold water (100 mL). The solid was dried in a vacuum oven overnight to yield 4,6-dihydroxy-2-methyl-5-nitropyrimidine (72.5 g).
Reaction SMILES: [CH2:1]([N:5]1[C:13]2[C:8](=[CH:9][CH:10]=[C:11]([Cl:14])[CH:12]=2)[C:7]([C:15](=[O:20])C(F)(F)F)=[CH:6]1)[CH2:2][CH2:3][CH3:4].[OH-:21].[Na+]>O>[CH2:1]([N:5]1[C:13]2[C:8](=[CH:9][CH:10]=[C:11]([Cl:14])[CH:12]=2)[C:7]([C:15]([OH:20])=[O:21])=[CH:6]1)[CH2:2][CH2:3][CH3:4]
Reactant: [OH-]
Reactant: CCCCn1cc(C(=O)C(F)(F)F)c2ccc(Cl)cc21
Agent: [Na+]
Solvent: O
Product: CCCCn1cc(C(=O)O)c2ccc(Cl)cc21
Temperature: 25 °C
Yield: 69.6 %

Procedure:
A mixture of 1-(1-butyl-6-chloro-1H-indol-3-yl)-2,2,2-trifluoro-ethanone (283.7 mg, 0.81 mmol) in a 20% aqueous sodium hydroxide solution (2.7 mL) was heated under reflux for 17 h. At this time, the reaction was cooled to 25° C. and was diluted with water (75 mL). This mixture was extracted with diethyl ether (1×50 mL). The aqueous layer was acidified to pH=1 with concentrated hydrochloric acid and then extracted with ethyl acetate (1×75 mL). The combined organic layers were washed with water (1×50 mL) and a saturated aqueous sodium chloride solution (1×50 mL), dried over sodium sulfate, filtered, and concentrated in vacuo to afford 1-butyl-6-chloro-1H-indole-3-carboxylic acid (141.4 mg, 69.6%) as a pale orange solid: mp 149-151° C.; EI-HRMS m/e calcd for C13H14ClNO2 (M+) 251.0713, found 251.0721.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[N:18]3[C:13]([CH:14]=[CH:15][CH:16]=[CH:17]3)=[CH:12][C:11]=2[C:19]([F:22])([F:21])[F:20])=[CH:6][CH:5]=1)([O-])=O.CCOC(C)=O>CO.[Pd]>[F:22][C:19]([F:20])([F:21])[C:11]1[CH:12]=[C:13]2[N:18]([C:10]=1[C:7]1[CH:8]=[CH:9][C:4]([NH2:1])=[CH:5][CH:6]=1)[CH2:17][CH2:16][CH2:15][CH2:14]2
Reactant: O=[N+]([O-])c1ccc(-c2c(C(F)(F)F)cc3ccccn23)cc1
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CO
Product: Nc1ccc(-c2c(C(F)(F)F)cc3n2CCCC3)cc1
Reaction time: 24 h
Yield: 84.6 %

Procedure:
To a solution of 400 mg (1.3 mmol) of 3-(4-Nitro-phenyl)-2-trifluoromethyl-indolizine in 12 mL MeOH was added 200 mg (10%) Pd/C. The solution was allowed to stir under a H2 atmosphere for 24 hrs then filtered through celite and concentrated in vacuo. The resulting oil was purified by silica gel chromatography Hexane:EtOAc (gradient 9:1-1:1) to yield 300 mg (1.1 mmol, 85%) of 4-(2-Trifluoromethyl-5,6,7,8-tetrahydro-indolizin-3-yl)-phenylamine.
Reaction SMILES: [Cl:1][C:2]1[CH:15]=[CH:14][C:5]([CH2:6][N:7]2[CH2:12][CH2:11][CH:10]([NH2:13])[CH2:9][CH2:8]2)=[CH:4][C:3]=1[O:16][CH2:17][CH3:18].[CH3:19][O:20][C:21]1[CH:22]=[C:23]([CH:27]=[C:28]([O:30][CH3:31])[CH:29]=1)[C:24](Cl)=[O:25]>>[Cl:1][C:2]1[CH:15]=[CH:14][C:5]([CH2:6][N:7]2[CH2:12][CH2:11][CH:10]([NH:13][C:24](=[O:25])[C:23]3[CH:27]=[C:28]([O:30][CH3:31])[CH:29]=[C:21]([O:20][CH3:19])[CH:22]=3)[CH2:9][CH2:8]2)=[CH:4][C:3]=1[O:16][CH2:17][CH3:18]
Reactant: CCOc1cc(CN2CCC(N)CC2)ccc1Cl
Reactant: COc1cc(OC)cc(C(=O)Cl)c1
Product: CCOc1cc(CN2CCC(NC(=O)c3cc(OC)cc(OC)c3)CC2)ccc1Cl
Yield: 56 %

Procedure:
The title compound (24 mg, 56%) was prepared analogously to example 7 by coupling of 1-(4-chloro-3-ethoxy-benzyl)piperidin-4-ylamine with 3,5-dimethoxybenzoyl chloride. MS: 433.5 (MH+).
Reaction SMILES: [C:1]([CH2:6][CH:7]1[CH2:11][CH2:10][CH2:9][C:8]1=[O:12])([O:3][CH2:4][CH3:5])=[O:2].[C:13](OC(=O)C)(=[O:15])[CH3:14].O.C1(C)C=CC(S(O)(=O)=O)=CC=1>>[C:13]([O:12][C:8]1[CH2:9][CH2:10][CH2:11][C:7]=1[CH2:6][C:1]([O:3][CH2:4][CH3:5])=[O:2])(=[O:15])[CH3:14]
Reactant: CCOC(=O)CC1CCCC1=O
Reactant: CC(=O)OC(C)=O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Product: CCOC(=O)CC1=C(OC(C)=O)CCC1

Procedure:
In the manner described in Example 10, treatment of 2-(carbethoxymethyl)cyclopentan-1-one (Example 210) with acetic anhydride and p-toluenesulfonic acid monohydrate gives an oil, b.p. 130°-131° C. (7 mm).
Reaction SMILES: [Cl:1][C:2]1[N:10]=[C:9]([CH3:11])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].S(Cl)(Cl)=O.[CH3:16][CH2:17]O>>[CH2:16]([O:5][C:4](=[O:6])[C:3]1[CH:7]=[CH:8][C:9]([CH3:11])=[N:10][C:2]=1[Cl:1])[CH3:17]
Reactant: CCO
Reactant: Cc1ccc(C(=O)O)c(Cl)n1
Solvent: O=S(Cl)Cl
Product: CCOC(=O)c1ccc(C)nc1Cl

Procedure:
A suspension of 2-chloro-6-methylnicotinic acid (7.23 mmol) and 1.2 mL of thionylchloride in 50 mL EtOH were heated to reflux overnight. The mixture was reduced to half of its volume, quenched with sat. aq. NaHCO3 solution and extracted with DCM (2×). The combined organic layers were dried over MgSO4 and concentrated in vacuo. Purification by (KP-SIL™ from Biotage) using Hept to Hept/EtOAc (1/1) gives the desired product as colorless oil;
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([S:11]([NH:14][C:15]2[C:20]([C:21]3[CH:26]=[CH:25][C:24]([CH3:27])=[CH:23][CH:22]=3)=[C:19](Cl)[N:18]=[CH:17][N:16]=2)(=[O:13])=[O:12])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[NH2:29][CH2:30][CH2:31][OH:32]>>[NH2:29][CH2:30][CH2:31][O:32][C:19]1[N:18]=[CH:17][N:16]=[C:15]([NH:14][S:11]([C:8]2[CH:9]=[CH:10][C:5]([C:1]([CH3:3])([CH3:2])[CH3:4])=[CH:6][CH:7]=2)(=[O:13])=[O:12])[C:20]=1[C:21]1[CH:26]=[CH:25][C:24]([CH3:27])=[CH:23][CH:22]=1
Reactant: NCCO
Reactant: Cc1ccc(-c2c(Cl)ncnc2NS(=O)(=O)c2ccc(C(C)(C)C)cc2)cc1
Product: Cc1ccc(-c2c(NS(=O)(=O)c3ccc(C(C)(C)C)cc3)ncnc2OCCN)cc1

Procedure:
According to Example 4b), 500 mg 4-tert.-butyl-N-[6-chloro-5-(p-tolyl)-4-pyrimidinyl]-benzene sulfonamide was reacted with 2-amino-ethanol to give 450 mg N-[6-(2-amino-ethoxy)-5-p-tolyl-pyrimidin-4-yl]4-tert.-butyl-benzenesulfonamide. LC-MS: tR=3.90 min, [M−1]−=439.44.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[N:15]([CH2:20][CH2:21][OH:22])[CH:16]=[C:17]([Br:19])[N:18]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[S:23](Cl)([CH3:26])(=[O:25])=[O:24]>C(Cl)Cl>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[N:15]([CH2:20][CH2:21][O:22][S:23]([CH3:26])(=[O:25])=[O:24])[CH:16]=[C:17]([Br:19])[N:18]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCC(c2nc(Br)cn2CCO)CC1
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCC(c2nc(Br)cn2CCOS(C)(=O)=O)CC1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 83.5 %

Procedure:
Add 4-[4-bromo-1-(2-hydroxy-ethyl)-1H-imidazol-2-yl]-piperidine-1-carboxylic acid tert-butyl ester (10.0 g; 0.027 mol; 1.0 equiv), TEA (11.6 mL; 0.080 mol; 3.0 equiv) to DCM (150 mL) and cool to 0° C. Add drop-wise mesyl chloride (2.6 mL; 0.032 mol; 1.2 equiv) and stir for 30 min. Quench the reaction with saturated NaHCO3 aqueous and extract with DCM. Evaporate the organic layer to give the title compound (10.2 g; 84%).
Reaction SMILES: C([O:8][C:9]([C@@H:11]1[CH2:15][CH2:14][CH2:13][N:12]1[C:16](=[O:29])[C@H:17]([NH:24][C:25]([O:27][CH3:28])=[O:26])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=[O:10])C1C=CC=CC=1>CO.O1CCCC1.[Pd]>[CH3:28][O:27][C:25]([NH:24][C@H:17]([C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1)[C:16]([N:12]1[CH2:13][CH2:14][CH2:15][C@H:11]1[C:9]([OH:10])=[O:8])=[O:29])=[O:26]
Reactant: COC(=O)N[C@@H](C(=O)N1CCC[C@H]1C(=O)OCc1ccccc1)c1ccccc1
Agent: [Pd]
Solvent: CO
Solvent: C1CCOC1
Product: COC(=O)N[C@@H](C(=O)N1CCC[C@H]1C(=O)O)c1ccccc1
Yield: 38.8 %

Procedure:
1.5 g of 1-[(R)-methoxycarbonylamino-phenyl-acetyl]-pyrrolidine-2-(S)-carboxylic acid benzyl ester were dissolved in a mixture of 15 mL of methanol and 15 ML of tetrahydrofuran and hydrogenated for 3 h at room temperature using 0.4 g palladium on charcoal (10%) as catalyst. Filtration followed by concentration in vacuo affords 0.45 g (100%) of the title compound as a white solid. (+)-APCI-MS: 307 (MH+).
Reaction SMILES: [C:1]([O:5][C:6](=[O:23])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]#[C:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[CH:10][C:9]=1[NH2:22])([CH3:4])([CH3:3])[CH3:2].C([O:28][C:29](=O)[CH2:30][C:31]([C:33]1[CH:38]=[CH:37][N:36]=[C:35]([C:39]#[N:40])[CH:34]=1)=[O:32])(C)(C)C>>[C:1]([O:5][C:6](=[O:23])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]#[C:15][C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)=[CH:10][C:9]=1[NH:22][C:29](=[O:28])[CH2:30][C:31]([C:33]1[CH:38]=[CH:37][N:36]=[C:35]([C:39]#[N:40])[CH:34]=1)=[O:32])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)Nc1ccc(C#Cc2ccccc2)cc1N
Reactant: CC(C)(C)OC(=O)CC(=O)c1ccnc(C#N)c1
Product: CC(C)(C)OC(=O)Nc1ccc(C#Cc2ccccc2)cc1NC(=O)CC(=O)c1ccnc(C#N)c1

Procedure:
Prepared from (2-amino-4-phenylethynyl-phenyl)-carbamic acid tert.-butyl ester (Example G2) and 3-(2-cyano-pyridin-4-yl)-3-oxo-propionic acid tert.-butyl ester (Example H10) according to the general procedure K. Obtained as a white solid (174 mg).
Reaction SMILES: [Si]([O:8][CH2:9][CH2:10][N:11]([C@H:19]1[C:27]2[C:22](=[C:23]([C:28]3[N:32]=[C:31]([C:33]4[S:34][C:35]([C:44]([F:47])([F:46])[F:45])=[C:36]([C:38]5[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=5)[CH:37]=4)[O:30][N:29]=3)[CH:24]=[CH:25][CH:26]=2)[CH2:21][CH2:20]1)C(=O)OC(C)(C)C)(C(C)(C)C)(C)C.Cl.CCOCC>C(Cl)Cl>[C:38]1([C:36]2[CH:37]=[C:33]([C:31]3[O:30][N:29]=[C:28]([C:23]4[CH:24]=[CH:25][CH:26]=[C:27]5[C:22]=4[CH2:21][CH2:20][C@H:19]5[NH:11][CH2:10][CH2:9][OH:8])[N:32]=3)[S:34][C:35]=2[C:44]([F:46])([F:47])[F:45])[CH:39]=[CH:40][CH:41]=[CH:42][CH:43]=1
Reactant: CC(C)(C)OC(=O)N(CCO[Si](C)(C)C(C)(C)C)[C@@H]1CCc2c(-c3noc(-c4cc(-c5ccccc5)c(C(F)(F)F)s4)n3)cccc21
Agent: Cl
Solvent: CCOCC
Solvent: ClCCl
Product: OCCN[C@@H]1CCc2c(-c3noc(-c4cc(-c5ccccc5)c(C(F)(F)F)s4)n3)cccc21
Temperature: 25 °C
Reaction time: 12 h
Yield: 65 %

Procedure:
To (R)-tert-butyl 2-(tert-butyldimethylsilyloxy)ethyl(4-(5-(4-phenyl-5-(trifluoromethyl)thiophen-2-yl)-1,2,4-oxadiazol-3-yl)-2,3-dihydro-1H-inden-1-yl)carbamate INT-63 (0.108 g, 0.16 mmol) dissolved in DCM (1.5 mL) was added 2N HCl in ether (1.45 mL, 2.9 mmol). The solution was stirred at room temperature for 12 h. The solvent was removed under a stream of nitrogen and the product dried under vacuum to afford 0.052 g (65%) of (R)-2-(4-(5-(4-phenyl-5-(trifluoromethyl)thiophen-2-yl)-1,2,4-oxadiazol-3-yl)-2,3-dihydro-1H-inden-1-ylamino) ethanol 67 as the HCl salt. LCMS-ESI (m/z): calcd for C24H20F3N3O2S: 471.5; found 472.1 [M+H]+, tR=7.43 min (Method 2). 1H NMR (400 MHz, CDCl3) δ 9.62 (s, 1H), 8.19 (d, J=7.6, 1H), 8.03 (d, J=7.5, 1H), 7.87 (t, J=1.5, 1H), 7.53-7.40 (m, 6H), 4.86 (d, J=4.8, 1H), 3.88 (s, 2H), 3.74-3.50 (m, 1H), 3.41 (ddd, J=13.3, 9.4, 4.4, 1H), 3.06 (m, 1H), 2.98 (m, 1H), 2.67-2.42 (m, 2H). 13C NMR (100 MHz, DMSO) δ 169.22, 168.07, 145.68, 144.75, 139.39, 135.43, 132.42, 129.42, 129.37, 129.25, 128.69, 128.27, 127.62, 126.41, 123.16, 122.37, 120.47, 61.10, 56.63, 46.54, 31.66, 27.80.
Reaction SMILES: [CH3:1][O:2][C:3]([C@@H:5]1[CH2:9][C@@H:8]([S:10]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[Cl:19])(=[O:12])=[O:11])[CH2:7][NH:6]1)=[O:4].Cl[C:21]1[S:22][C:23]([C:26]([F:29])([F:28])[F:27])=[N:24][N:25]=1>>[CH3:1][O:2][C:3]([C@@H:5]1[CH2:9][C@@H:8]([S:10]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[Cl:19])(=[O:11])=[O:12])[CH2:7][N:6]1[C:21]1[S:22][C:23]([C:26]([F:29])([F:28])[F:27])=[N:24][N:25]=1)=[O:4]
Reactant: FC(F)(F)c1nnc(Cl)s1
Reactant: COC(=O)[C@@H]1C[C@@H](S(=O)(=O)c2ccccc2Cl)CN1
Product: COC(=O)[C@@H]1C[C@@H](S(=O)(=O)c2ccccc2Cl)CN1c1nnc(C(F)(F)F)s1

Procedure:
In analogy to the procedure described in example 335a, (2S,4R)-4-(2-chloro-benzenesulfonyl)-pyrrolidine-2-carboxylic acid methyl ester (example 253a) was reacted with 2-chloro-5-trifluoromethyl-[1,3,4]thiadiazole (CAS Reg. No. 53645-98-0) in a shaking reactor at 55° C. for 12 h to give the title compound as orange oil. MS (ESI): m/z=456.0 [M+H]
Reaction SMILES: C([O:3][C:4](=[O:47])[CH2:5][CH2:6][N:7]([C:15]1[CH:20]=[C:19]([C:21]([NH:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH3:33])=[O:22])[CH:18]=[C:17]([C:34]([NH:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH3:46])=[O:35])[CH:16]=1)CCC(OCC)=O)C.[OH-:48].[Na+]>CO>[C:4]([CH2:5][CH2:6][C:16]1[C:17]([C:34]([NH:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH3:46])=[O:35])=[CH:18][C:19]([C:21]([NH:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH3:33])=[O:22])=[CH:20][C:15]=1[NH:7][CH2:6][CH2:5][C:4]([OH:3])=[O:47])([OH:3])=[O:48]
Reactant: [OH-]
Reactant: CCCCCCCCCCNC(=O)c1cc(C(=O)NCCCCCCCCCC)cc(N(CCC(=O)OCC)CCC(=O)OCC)c1
Agent: [Na+]
Solvent: CO
Product: CCCCCCCCCCNC(=O)c1cc(NCCC(=O)O)c(CCC(=O)O)c(C(=O)NCCCCCCCCCC)c1
Yield: 123 %

Procedure:
A solution of 0.23 g (0.35 mmol) of 3-[[3,5-bis[(decylamino)carbonyl]phenyl](3-ethoxy-3-oxopropyl)amino]propanoic acid ethyl ester and 1.4 ml (1.4 mmol) of 1N NaOH in 10 ml of methanol was stirred at room temperature for 16 hours. The solvent was removed at reduced pressure, the residue was dissolved in water and acidified with 0.2 ml of acetic acid. The precipitate was filtered and recrystallized from acetone-hexane to give 0.13 g (60% yield, mp 139°-141°)of 3-[[(2-carboxyethyl)-3,5-bis[(decylamino)carbonyl]phenyl]amino]propanoicacid.
Reaction SMILES: Br[CH:2]([C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([F:11])[C:6]=1[F:12])[CH2:3][CH3:4].C[Si]([C:17]#[N:18])(C)C>>[F:12][C:6]1[C:7]([F:11])=[CH:8][CH:9]=[CH:10][C:5]=1[CH:2]([CH2:3][CH3:4])[C:17]#[N:18]
Reactant: CCC(Br)c1cccc(F)c1F
Reactant: C[Si](C)(C)C#N
Product: CCC(C#N)c1cccc(F)c1F

Procedure:
rac-2-(2,3-Difluoro-phenyl)-butyronitrile was prepared from rac-1-(1-bromo-propyl)-2,3-difluoro-benzene and trimethylsilyl cyanide in analogy to Example 23 c): colourless oil.
Reaction SMILES: Br[C:2]1[N:3]=[C:4]2[C:10]([C:11](=[O:16])[C:12]([CH3:15])([CH3:14])[CH3:13])=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1.[CH3:17][O:18][C:19]1[CH:24]=[CH:23][C:22](B(O)O)=[CH:21][CH:20]=1.C(=O)([O-])[O-].[K+].[K+].O1CCOCC1>O>[CH3:17][O:18][C:19]1[CH:24]=[CH:23][C:22]([C:2]2[N:3]=[C:4]3[C:10]([C:11](=[O:16])[C:12]([CH3:15])([CH3:14])[CH3:13])=[CH:9][NH:8][C:5]3=[N:6][CH:7]=2)=[CH:21][CH:20]=1
Reactant: COc1ccc(B(O)O)cc1
Reactant: CC(C)(C)C(=O)c1c[nH]c2ncc(Br)nc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Product: COc1ccc(-c2cnc3[nH]cc(C(=O)C(C)(C)C)c3n2)cc1
Temperature: 150 °C
Reaction time: 0.5 h
Yield: 47.7 %

Procedure:
A mixture of 1-(2-bromo-5H-pyrrolo[2,3-b]pyrazin-7-yl)-2,2-dimethyl-propan-1-one (60 mg, 0.21 mmol), 4-methoxyphenyl boronic acid (33 mg, 0.22 mmol), potassium carbonate (69 mg, 0.5 mmol), Pd(dppf)Cl2CH2Cl2 (13 mg, 0.016 mmol), 1.7 mL dioxane and 0.4 mL water was stirred at 150° C. in a microwave for 30 min. The resulting mixture was partitioned between ethyl acetate and water. The combined organic layers were dried over Na2SO4 and concentrated to give a dark brown solid. The crude product was purified by preparative thin layer chromatography using 90:9.5:0.5 CH2Cl2:MeOH:conc NH4OH as eluant. The resultant brown solid was washed with ethyl ether to provide 31 mg (50%) of 1-[2-(4-methoxy-phenyl)-5H-pyrrolo[2,3-b]pyrazin-7-yl]-2,2-dimethyl-propan-1-one as a brown solid. MP 207-208° C., M+H 310.
Reaction SMILES: C(O)(=O)C.C(=O)C.[CH:8]([O:11][C:12]([N:14]1[CH2:20][CH2:19][CH2:18][CH:17]([N:21]([C:37](=O)[CH3:38])[CH2:22][C:23]2[CH:28]=[C:27]([C:29]([F:32])([F:31])[F:30])[CH:26]=[C:25]([C:33]([F:36])([F:35])[F:34])[CH:24]=2)[C:16]2[CH:40]=[CH:41][C:42]([Cl:44])=[CH:43][C:15]1=2)=[O:13])([CH3:10])[CH3:9].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>CN(C)C=O>[CH:8]([O:11][C:12]([N:14]1[CH2:20][CH2:19][CH2:18][CH:17]([N:21]([CH2:22][C:23]2[CH:28]=[C:27]([C:29]([F:32])([F:31])[F:30])[CH:26]=[C:25]([C:33]([F:35])([F:34])[F:36])[CH:24]=2)[CH2:37][CH3:38])[C:16]2[CH:40]=[CH:41][C:42]([Cl:44])=[CH:43][C:15]1=2)=[O:13])([CH3:9])[CH3:10]
Reactant: CC(=O)N(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)C1CCCN(C(=O)OC(C)C)c2cc(Cl)ccc21
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: CC=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CN(C)C=O
Product: CCN(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)C1CCCN(C(=O)OC(C)C)c2cc(Cl)ccc21
Temperature: 25 °C
Reaction time: 2 h
Yield: 26.3 %

Procedure:
Add acetic acid (0.05 mL, 0.078 mmol) and acetaldehyde (34 mg, 0.78 mmol) to a solution of 5-(3,5-Bis-trifluoromethyl-benzylamino)-8-chloro-2,3,4,5-tetrahydro-benzo[b]azepine-1-carboxylic acid isopropyl ester (see example 3) (40 mg, 0.078 mmol) in dimethylformamide (1 mL). Stir at room temperature for 2 h. Add sodium triacetoxyborohydride (33 mg, 0.16 mmol) and stir the mixture at room temperature for 2 h. Add saturated solution of sodium bicarbonate and extract with ethyl acetate (3×10 mL). Dry the organic layer over anhydrous sodium sulfate, filter and remove the solvent under reduced pressure. Chromatograph the residue over silica cartridge, eluting with hexanes/ethyl acetate (10:1), to afford the title compound (11 mg, 26%). MS (ES+): 537 (M+H).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:10]([CH2:11]O)=[C:9]([S:13][C:14]2[CH:19]=[C:18]([Cl:20])[CH:17]=[C:16]([Cl:21])[CH:15]=2)[N:8]([CH:22]([CH3:24])[CH3:23])[N:7]=1)=[O:5])[CH3:2].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(Br)(Br)(Br)[Br:45]>ClCCl>[CH2:1]([O:3][C:4]([C:6]1[C:10]([CH2:11][Br:45])=[C:9]([S:13][C:14]2[CH:19]=[C:18]([Cl:20])[CH:17]=[C:16]([Cl:21])[CH:15]=2)[N:8]([CH:22]([CH3:24])[CH3:23])[N:7]=1)=[O:5])[CH3:2]
Reactant: BrC(Br)(Br)Br
Reactant: CCOC(=O)c1nn(C(C)C)c(Sc2cc(Cl)cc(Cl)c2)c1CO
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: CCOC(=O)c1nn(C(C)C)c(Sc2cc(Cl)cc(Cl)c2)c1CBr
Reaction time: 8 h
Yield: 62.7 %

Procedure:
To a solution of 504 mg 5-(3,5-dichlorophenylthio)-4-hydroxymethyl-1-isopropyl-1H-pyrazole-3-carboxylic acid ethyl ester in 5 ml of dichloromethane was added 375 mg of triphenylphosphine and 474 mg of carbon tetrabromide. The reaction mixture was stirred overnight. The solvent was removed and the residue was purified by flash chromatography on silica gel using diethyl ether/iso-hexane for the elution to give 367 mg of 4-bromomethyl-5-(3,5-dichlorophenylthio)-1-isopropyl-1H-pyrazole-3-carboxylic acid ethyl ester as a colourless gum. Mass spectrum (ES) m/z 451 [M+H]+.