Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C@@H:2]1[CH2:7][CH2:6][CH2:5][CH2:4][C@H:3]1[NH:8][C:9]([C:11]1[C:16]([C:17]([F:20])([F:19])[F:18])=[N:15][C:14]([O:21][CH2:22][CH:23]2[CH2:25][CH2:24]2)=[C:13]([C:26]2[CH:31]=[CH:30][CH:29]=[C:28](Cl)[CH:27]=2)[N:12]=1)=[O:10].NC1C(C2C=CC([NH:51][S:52]([CH3:55])(=[O:54])=[O:53])=CC=2)=NC(Br)=C(C(F)(F)F)N=1>>[OH:1][C@@H:2]1[CH2:7][CH2:6][CH2:5][CH2:4][C@H:3]1[NH:8][C:9]([C:11]1[C:16]([C:17]([F:20])([F:19])[F:18])=[N:15][C:14]([O:21][CH2:22][CH:23]2[CH2:25][CH2:24]2)=[C:13]([C:26]2[CH:31]=[CH:30][C:29]([NH:51][S:52]([CH3:55])(=[O:54])=[O:53])=[CH:28][CH:27]=2)[N:12]=1)=[O:10]
Reactant: O=C(N[C@@H]1CCCC[C@H]1O)c1nc(-c2cccc(Cl)c2)c(OCC2CC2)nc1C(F)(F)F
Reactant: CS(=O)(=O)Nc1ccc(-c2nc(Br)c(C(F)(F)F)nc2N)cc1
Product: CS(=O)(=O)Nc1ccc(-c2nc(C(=O)N[C@@H]3CCCC[C@H]3O)c(C(F)(F)F)nc2OCC2CC2)cc1

Procedure:
In analogy to example 6 (6-(3-chloro-phenyl)-5-cyclopropylmethoxy-3-trifluoromethyl-pyrazine-2-carboxylic acid ((1R,2R)-2-hydroxy-cyclohexyl)-amide) the title compound was prepared by substituting 5-bromo-3-(3-chloro-phenyl)-6-trifluoromethyl-pyrazin-2-ylamine with N-[4-(3-amino-6-bromo-5-trifluoromethyl-pyrazin-2-yl)-phenyl]-methanesulfonamide.
Reaction SMILES: [CH3:1][O:2][CH:3]([O:6][CH3:7])[CH:4]=O.Cl.[CH3:9][C@@H:10]([NH2:14])[CH2:11][CH2:12][CH3:13].C(N(CC)CC)C>CO.[Pd]>[CH3:1][O:2][CH:3]([O:6][CH3:7])[CH2:4][NH:14][C@@H:10]([CH2:11][CH2:12][CH3:13])[CH3:9]
Reactant: CCC[C@@H](C)N
Reactant: COC(C=O)OC
Agent: [Pd]
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CO
Product: CCC[C@@H](C)NCC(OC)OC
Reaction time: 2 h

Procedure:
2,2-Dimethoxyacetaldehyde (0.59 mL) was added to a solution of (R)-pentan-2-amine hydrochloride (0.48 g) and triethylamine (0.54 mL) in methanol (4 mL) and the mixture stirred for 2 h. A slurry of palladium on carbon (10%, 20 mg) in methanol (1 mL) was added and the mixture hydrogenated at 5 bar for 20 h. The mixture was then filtered and in vacuo. The resulting residue was triturated with diethyl ether (5 mL) and the resulting white solid extracted with further diethyl ether (2×5 mL). The combined ether fractions were concentrated in vacuo to afford (R)—N-(2,2-dimethoxyethyl)pentan-2-amine (0.745 g) as an oil. 1H NMR (400 MHz, CDCl3) δ 4.92 (t, J=5.4 Hz, 1H), 3.47 (s, 3H), 3.47 (s, 3H), 3.25-3.15 (m, 1H), 2.99 (ddd, J=27.9, 12.7, 5.5 Hz, 2H), 1.86-1.77 (m, 1H), 1.64-1.54 (m, 1H), 1.49-1.32 (m, 5H), 0.95 (t, J=7.3 Hz, 3H)
Reaction SMILES: [CH3:1][CH2:2][O:3][C:4]([C:6]1[NH:7][C:8]2[C:13]([CH:14]=1)=[CH:12][C:11]([C:15]([OH:17])=O)=[CH:10][CH:9]=2)=[O:5].F[B-](F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.[NH:40]1[CH2:44][CH2:43][CH2:42][C@H:41]1[CH2:45][N:46]1[CH2:50][CH2:49][CH2:48][CH2:47]1.C(N(CC)C(C)C)(C)C>CN(C)C=O>[CH2:2]([O:3][C:4]([C:6]1[NH:7][C:8]2[C:13]([CH:14]=1)=[CH:12][C:11]([C:15]([N:40]1[CH2:44][CH2:43][CH2:42][C@H:41]1[CH2:45][N:46]1[CH2:50][CH2:49][CH2:48][CH2:47]1)=[O:17])=[CH:10][CH:9]=2)=[O:5])[CH3:1]
Reactant: CCOC(=O)c1cc2cc(C(=O)O)ccc2[nH]1
Reactant: C1CN[C@H](CN2CCCC2)C1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCOC(=O)c1cc2cc(C(=O)N3CCC[C@H]3CN3CCCC3)ccc2[nH]1
Yield: 90 %

Procedure:
The title compound was synthesized in analogy to example 1, intermediate a), from 1H-indole-2,5-dicarboxylic acid 2-ethyl ester, O-(benzotriazol-1-yl)-N,N,N′, N′-tetramethyluronium tetrafluoroborate (commercially available), (S)-(+)-1-(2-pyrrolidinylmethyl)pyrrolidine (commercially available) and N,N-diisopropylethylamine in N,N-dimethylformamide, to give the desired product as a light yellow foam (90%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[CH:10][C:6]([CH2:7][CH2:8]O)=[CH:5][CH:4]=1.S(Cl)([Cl:14])=O>ClCCl.[Cl-].[Na+].O>[Cl:14][CH2:8][CH2:7][C:6]1[CH:10]=[CH:11][C:3]([O:2][CH3:1])=[CH:4][CH:5]=1
Reactant: COc1ccc(CCO)cc1
Reactant: O=S(Cl)Cl
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Product: COc1ccc(CCCl)cc1
Temperature: 25 °C
Reaction time: 20 h
Yield: 51 %

Procedure:
4-methoxy-phenethyl alcohol (15.2 g, 10 mmol) were dissolved in 200 ml of dichloromethane and at 0° C., 7.35 ml of thionyl chloride were added. The reaction mixture was allowed to warm to room temperature over 1/2 hour. After stirring for 20 hours, the mixture was added to brine and extracted with dichloromethane. The dichloromethane was evaporated to obtain an oil which was chromatographed on silica gel using a mixture of 30% ethyl acetate/hexane as the eluent to obtain 8.8 g (51%) of the title product.
Reaction SMILES: [CH3:1][O:2][CH:3]([O:7][CH3:8])[CH2:4][NH:5][CH3:6].C(N(CC)CC)C.[CH3:16][N:17]1[CH:21]=[C:20]([S:22](Cl)(=[O:24])=[O:23])[CH:19]=[N:18]1>C(Cl)Cl>[CH3:1][O:2][CH:3]([O:7][CH3:8])[CH2:4][N:5]([CH3:6])[S:22]([C:20]1[CH:19]=[N:18][N:17]([CH3:16])[CH:21]=1)(=[O:24])=[O:23]
Reactant: CNCC(OC)OC
Reactant: Cn1cc(S(=O)(=O)Cl)cn1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(CN(C)S(=O)(=O)c1cnn(C)c1)OC
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Cool a solution of methylaminoacetaldehyde dimethyl acetal (22.5 mL, 0.18 mol) and triethylamine (26.5 mL, 0.19 mol) to 0° C. in CH2Cl2, then add dropwise a solution of 1-methyl-1H-pyrazole-4-sulfonyl chloride (30 g, 0.17 mol). Stir the reaction mixture at room temperature overnight, dilute with CH2Cl2 (500 mL), and wash with water. Dry the combined organics over Na2SO4, filter and concentrate. The resulting oil is placed under high vacuum and within two hours a resulting off white solid is formed, which is used without further purification (38.22 g, 87%).
Reaction SMILES: [I:1][C:2]1[C:3](=[O:36])[N:4](C(C2C=CC=CC=2)=O)[C:5](=[O:27])[N:6]([CH2:8][CH2:9][CH2:10][N:11]2[CH2:16][CH:15]3[C:13]([C:17]4[CH:22]=[CH:21][CH:20]=[C:19]([C:23]([F:26])([F:25])[F:24])[CH:18]=4)([CH2:14]3)[CH2:12]2)[CH:7]=1.CO>N>[I:1][C:2]1[C:3](=[O:36])[NH:4][C:5](=[O:27])[N:6]([CH2:8][CH2:9][CH2:10][N:11]2[CH2:16][CH:15]3[C:13]([C:17]4[CH:22]=[CH:21][CH:20]=[C:19]([C:23]([F:26])([F:25])[F:24])[CH:18]=4)([CH2:14]3)[CH2:12]2)[CH:7]=1
Reactant: O=C(c1ccccc1)n1c(=O)c(I)cn(CCCN2CC3CC3(c3cccc(C(F)(F)F)c3)C2)c1=O
Agent: N
Solvent: CO
Product: O=c1[nH]c(=O)n(CCCN2CC3CC3(c3cccc(C(F)(F)F)c3)C2)cc1I
Temperature: 25 °C
Reaction time: 3 h
Yield: 81 %

Procedure:
(1R,5S/1S,5R) 5-iodo-3-(phenylcarbonyl)-1-(3-{1-[3-(trifluoromethyl)phenyl]-3-azabicyclo[3.1.0]hex-3-yl}propyl)-2,4(1H,3H)-pyrimidinedione (Prep82, 250 mg, 0.410 mmol) was dissolved in 3% ammonia in MeOH, (4 mL, 5.55 mmol). The mixture was stirred at room temperature for 3 hours, the solvent was then evaporated under vacuum and the crude purified by SPE Si (20 g) with Toluene/acetone 80/20 to give a solid that was then loaded through a SCX (5 g) cartridge in order to recover the title compound (168 mg, 0.332 mmol, 81% yield) as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[N:13]([CH3:14])[N:12]=[C:11]([C:15](=O)[CH3:16])[C:10]=2[OH:18])[CH:5]=[CH:6][C:7]=1[Cl:8].[NH:19]([C:21]([NH:23][C:24]1[S:28][C:27]([C:29]([OH:31])=[O:30])=[CH:26][CH:25]=1)=[S:22])[NH2:20]>>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[N:13]([CH3:14])[N:12]=[C:11]([C:15](=[N:20][NH:19][C:21]([NH:23][C:24]3[S:28][C:27]([C:29]([OH:31])=[O:30])=[CH:26][CH:25]=3)=[S:22])[CH3:16])[C:10]=2[OH:18])[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: CC(=O)c1nn(C)c(-c2ccc(Cl)c(Cl)c2)c1O
Reactant: NNC(=S)Nc1ccc(C(=O)O)s1
Product: CC(=NNC(=S)Nc1ccc(C(=O)O)s1)c1nn(C)c(-c2ccc(Cl)c(Cl)c2)c1O

Procedure:
From 1-[5-(3,4-dichlorophenyl)-4-hydroxy-1-methyl-1H-pyrazol-3-yl]ethanone (40.0 mg, 0.14 mmol) and 5-hydrazinocabonothioylamino-2-thiophenecarboxylic acid (33.9 mg, 0.14 mmol), the desired product was obtained in the same manner as in Synthetic Example 114 as a pale yellow solid (62.2 mg, yield 92%).
Reaction SMILES: [ClH:1].[NH2:2][C:3]1[CH:4]=[C:5]([C:9]2[N:10]=[CH:11][N:12]([C:14]([N:16]([CH:18]3[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]3)[CH3:17])=[O:15])[CH:13]=2)[CH:6]=[CH:7][CH:8]=1.[N:24]#[C:25][NH2:26]>C(O)C>[ClH:1].[CH:18]1([N:16]([CH3:17])[C:14]([N:12]2[CH:13]=[C:9]([C:5]3[CH:6]=[CH:7][CH:8]=[C:3]([NH:2][C:25]([NH2:26])=[NH:24])[CH:4]=3)[N:10]=[CH:11]2)=[O:15])[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]1
Reactant: CN(C(=O)n1cnc(-c2cccc(N)c2)c1)C1CCCCC1
Reactant: N#CN
Agent: Cl
Solvent: CCO
Product: CN(C(=O)n1cnc(-c2cccc(NC(=N)N)c2)c1)C1CCCCC1
Yield: 68.4 %

Procedure:
Gaseous anhydrous hydrogen chloride (0.096 mL, 1.156 mmol) was added to a stirred suspension of 4-(3-aminophenyl)-N-cyclohexyl-N-methyl-1H-imidazole-1-carboxamide (0.345 g, 1.156 mmol) and cyanamide (0.135 mL, 1.734 mmol) in ethanol (1.2 mL) at room temperature. The clear solution was allowed to stir at reflux for 1 h and a colourless solid formed. The reaction mixture was allowed to stir at reflux for further 7 h, whereupon the mixture was allowed to cool. The solid was separated by filtration and washed with ethanol to give the product as a colourless solid, (298 mg, 68%).
Reaction SMILES: Cl[C:2]1[C:3]([Cl:9])=[N:4][C:5]([Cl:8])=[N:6][CH:7]=1.[CH3:10][O:11][C:12]1[CH:13]=[C:14](B(O)O)[CH:15]=[CH:16][CH:17]=1.C(O)C.C(=O)(O)[O-].[Na+]>C1(C)C=CC=CC=1>[Cl:8][C:5]1[N:4]=[C:3]([Cl:9])[CH:2]=[C:7]([C:16]2[CH:15]=[CH:14][CH:13]=[C:12]([O:11][CH3:10])[CH:17]=2)[N:6]=1
Reactant: Clc1ncc(Cl)c(Cl)n1
Reactant: COc1cccc(B(O)O)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Solvent: Cc1ccccc1
Product: COc1cccc(-c2cc(Cl)nc(Cl)n2)c1
Temperature: 50 °C
Yield: 87.5 %

Procedure:
Trichloropyrimidine (11.83 g, 64.49 mmol) was added to a solution of 3-methoxyphenylboronic acid (9.8 g, 64.49 mmol) in a solvent mixture of ethanol (30 mL), toluene (30 mL) and 2M aqueous sodium bicarbonate (96.7 mL) at rt. The resulting mixture was degassed under vacuum for several min before the flask was purged with nitrogen. Dichloro[1,1′-bis(diphenylphosphino)ferrocene]palladium (II)dichloromethane adduct (2.4 g, 3.22 mmol) was added and the resulting mixture was heated for 3 h at 50° C. The cooled reaction mixture was filtered through a silica gel pad and the pad was washed with acetone. The filtrated was evaporated under reduced pressure. The crude material was purified by column chromatography eluting with a gradient of 0 to 45% ethyl acetate/hexanes to give 2,4-dichloro-6-(3-methoxy-phenyl)-pyrimidine as a white solid (14.4 g, 65.4%). MS ES 255 (M+H)+, calcd 255, RT=3.35 min.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[CH3:11])[C:5]([OH:7])=[O:6].OS(O)(=O)=O.[CH3:17][CH2:18]O>C1(C)C=CC=CC=1>[F:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[CH3:11])[C:5]([O:7][CH2:17][CH3:18])=[O:6]
Reactant: Cc1ccc(C(=O)O)cc1F
Reactant: CCO
Agent: O=S(=O)(O)O
Solvent: Cc1ccccc1
Product: CCOC(=O)c1ccc(C)c(F)c1
Yield: 92 %

Procedure:
A solution of 10.2 g (66.2 mmol) of 3-fluoro-4-methylbenzoic acid in 50 mL of EtOH and 25 mL of toluene containing 0.2 mL of H2SO4 was heated gradually to 120° C. (oil bath temperature), and the solvent was removed by distillation over a period of 2.25 h through a 10-cm Vigreux column. The residue was cooled, treated with a further 50 mL of EtOH and 25 mL of toluene, and the distillation was repeated. The residual solution, containing some white solid, was poured into 75 mL of aqueous NaHCO3 and extracted with hexane (75 mL, then 50 mL). The extract was washed with water (2×75 mL), dried (Na2SO4), and concentrated. The pale-yellow liquid was distilled, bp 49°-58° C. (0.01-0.05 mm) to give 11.1 g (92% yield) of ethyl 3-fluoro-4-methylbenzoate as a colorless liquid: IR (CHCl3) 1720 (C=O), 1580, 1420, 1370, 1290, 1190, 1130, 1090, 1020, 940, 895 cm-1 ; 1H NMR (CDCl3) δ 1.40 (t, J=7 Hz, 3, CO2CH2CH3), 2.32 (d, J=2 Hz, 3, ArCH3), 4.37 (q, J=7 Hz, 2, CO2CH2CH3), 7.22 (dd, J=8 Hz, J=8 Hz, 1, 6' H), 7.68 (m, 2, 3', 5' H); MS calcd for C10H11FO2 182.0743, found 182.0729.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([N+:11]([O-])=O)[CH:6]=1)(=[O:4])=[O:3].[Cl-].[NH4+]>C(O)C.O>[CH3:1][S:2]([C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([NH2:11])[CH:6]=1)(=[O:3])=[O:4]
Reactant: CS(=O)(=O)c1cccc([N+](=O)[O-])c1
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: CCO
Product: CS(=O)(=O)c1cccc(N)c1
Yield: 85.5 %

Procedure:
(3-Nitro)phenyl methyl sulphone (prepared as described in Step 1 above) (5.396 g) reduced iron (7.5 g) and ammonium chloride (7.18 g) were mixed together in ethanol/water (2:1) (150 ml) and heated under reflux for 2 hours. The black solution was filtered through `Celite` and the pad washed with ethyl acetate. The solvents were removed under reduced pressure and the residue taken up in ethyl acetate/water. The organic layer was separated and the aqueous layer extracted with 3 further portions of ethyl acetate. The combined organic layers were washed with brine and the solvent removed under reduced pressure to give a dark orange oil (3.9275 g). This was chromatographed on silica gel using ethyl acetate-hexane (45:55 to 50:50) as eluant to give the title compound as an orange oil, yield 3.607 g.
Reaction SMILES: [CH3:1][C:2]([CH3:26])([CH3:25])[CH:3]([O:14][C:15]1[N:20]=[C:19]([O:21][CH3:22])[N:18]=[C:17]([O:23][CH3:24])[N:16]=1)[C:4]([O:6]CC1C=CC=CC=1)=[O:5].C(O)(=O)C.[H][H]>[C].[Pd].C(O)C>[CH3:1][C:2]([CH3:26])([CH3:25])[CH:3]([O:14][C:15]1[N:16]=[C:17]([O:23][CH3:24])[N:18]=[C:19]([O:21][CH3:22])[N:20]=1)[C:4]([OH:6])=[O:5]
Reactant: COc1nc(OC)nc(OC(C(=O)OCc2ccccc2)C(C)(C)C)n1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Solvent: CC(=O)O
Product: COc1nc(OC)nc(OC(C(=O)O)C(C)(C)C)n1
Temperature: 25 °C
Yield: 91.8 %

Procedure:
4.5 g of benzyl 3,3-dimethyl-2-(4,6-dimethoxy-S-triazin-2-yl)oxybutyrate and 0.5 g (10%) of palladium carbon wetted with 2 ml of acetic acid were added to 100 ml of ethanol. 257 ml of hydrogen was added thereto at room temperature under stirring. The reaction solution was subjected to filtration, and the filtrate was extracted twice with 200 ml of ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain 3.1 g of the desired product.
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[NH2:8][CH:9]1[CH2:14][CH:13]2[CH2:15][CH2:16][CH:10]1[CH2:11][C:12]2=[O:17].[CH:18](=O)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>C(Cl)Cl>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[C:19]1([CH:18]2[CH:11]3[C:12](=[O:17])[CH:13]4[CH2:15][CH2:16][CH:10]3[CH:9]([CH2:14]4)[NH:8]2)[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: O=Cc1ccccc1
Reactant: NC1CC2CCC1CC2=O
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C1C2CCC3C(C2)NC(c2ccccc2)C13
Yield: 90.8 %

Procedure:
A three neck 3 L flask, fitted with a well isolated soxhlet (300 mL) filled with molecular sieves (3 Å), was charged with 5-amino-bicyclo[2.2.2]octan-2-one trifluoro-acetic acid salt (Preparation 76, 85.0 g, 336 mmol, 1.0 eq), benzaldehyde (37.5 mL, 369 mmol, 1.1 eq) and DCM (1.25 L). The suspension was heated to reflux. The clear reaction mixture was concentrated to a tan solid. The latter was suspended in a mixture of diethyl ether (600 mL) and EtOH (50 mL). The solids were collected by filtration (P3) and thoroughly washed with ethyl acetate and diethyl ether. The filter cake was dried in vacuo to yield title compound as an off-white solid (104 g, 305 mmol, 91%, 97.3% pure (HPLC)).
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[C:8](=[O:15])[NH:7]1)=[O:5])[CH3:2].[H-].[Na+].I[CH:19]([Cl:22])[CH2:20][CH3:21].O>CN(C=O)C>[CH2:1]([O:3][C:4]([N:6]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[C:8](=[O:15])[N:7]1[CH2:21][CH2:20][CH2:19][Cl:22])=[O:5])[CH3:2]
Reactant: CCC(Cl)I
Reactant: CCOC(=O)n1[nH]c(=O)c2ccccc21
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)n1c2ccccc2c(=O)n1CCCCl
Temperature: 25 °C
Reaction time: 1 h
Yield: 13.8 %

Procedure:
To a solution of 3-oxo-2,3-dihydro-indazole-1-carboxylic acid ethyl ester (410 mg, 2 mmol) dissolved in dry DMF (10 ml) is added sodium hydride (60% w/w in oil, 120 mg, 3 mmol). The resulting cloudy solution is allowed to stir for 1 h at rt and is added dropwise under inert atmosphere via a syringe onto a solution of iodochloropropane (268 μl, 2.5 mmol) in dry DMF (2 ml). The resulting solution is allowed to stir at rt overnight. By addition of water and evaporation under reduced pressure most of the DMF is removed from the crude mixture. The residue is dissolved in AcOEt (25 ml) and the resulting organic phase is washed 3 times with water and once with brine. The crude product is purified by chromatography on silica gel (AcOEt/heptane, 2:3), yielding the title compound (78 mg) in 15% as a colourless oil: tR=2.17 min (LC-2), ESI-MS (pos.): m/z 283.05 [M+H]+; 1H-NMR (CDCl3): δ (ppm) 1.38 (t, 3H, CH3), 2.08 (quint., 2H, CH2CH2N), 3.42 (t, 2H, CH2Cl), 4.25 (t, 2H, NCH2), 4.39 (q, 2H, OCH2CH3), 7.22 (t, 1Harom), 7.53 (t, 1Harom), 7.79 (t, 2Harom), and 3-(3-chloro-propoxy)-indazole-1-carboxylic acid ethyl ester (125 mg) in 24% as a colourless oil: tR=2.49 min (LC-2), ESI-MS (pos.): m/z 283.05 [M+H]+; 1H-NMR (CDCl3): δ (ppm) 1.44 (t, 3H, CH3), 2.26 (quint., 2H, CH2CH2N), 3.71 (t, 2H, CH2Cl), 4.49 (q, 2H, OCH2CH3), 4.59 (t, 2H, OCH2CH2), 7.20 (t, 1H, m), 7.46 (t, 1Harom), 7.59 (d, 1 Harom), 8.02 (d, 1Harom). 3-(3-Chloro-propoxy)-indazole-1-carboxylic acid ethyl ester is used as alkylating agent D-06d in the preparation of Precursor D-06b.
Reaction SMILES: [C:1]([C@@H:4]1[N:8](C(OC)=O)[C@H:7]([C:13]([O:15][CH3:16])=[O:14])[CH2:6][CH2:5]1)#[C:2][CH3:3].I[Si](C)(C)C>C(Cl)(Cl)Cl>[C:1]([C@@H:4]1[NH:8][C@H:7]([C:13]([O:15][CH3:16])=[O:14])[CH2:6][CH2:5]1)#[C:2][CH3:3]
Reactant: CC#C[C@H]1CC[C@@H](C(=O)OC)N1C(=O)OC
Agent: C[Si](C)(C)I
Solvent: ClC(Cl)Cl
Product: CC#C[C@H]1CC[C@@H](C(=O)OC)N1
Temperature: 25 °C

Procedure:
A solution of dimethyl (2S,5R)-5-propynyl-pyrrolidine-1,2-dicarboxylate (4.25 g, 18.90 mmol) and iodotrimethylsilane (3.23 mL, 22.7 mmol, Example 85A) in chloroform (60 mL) was heated to 65° C. for 3 hours, was cooled to room temperature, concentrated under reduced pressure and flash chromatographed with 35% ethyl acetate/65% hexane to provide the titled compound. MS (DCI/NH3) m/e 168 (M+H)+.
Reaction SMILES: Cl[C:2]1[S:6][C:5]([CH2:7][C@H:8]2[CH2:12][NH:11][C@H:10]([C:13]([NH:15][C:16]3[CH:21]=[CH:20][C:19]([O:22][C:23]4[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=4)=[CH:18][CH:17]=3)=[O:14])[CH2:9]2)=[CH:4][CH:3]=1.C([O-])=O.[NH4+]>[Pd].CO>[F:29][C:26]1[CH:25]=[CH:24][C:23]([O:22][C:19]2[CH:18]=[CH:17][C:16]([NH:15][C:13]([C@@H:10]3[CH2:9][C@@H:8]([CH2:7][C:5]4[S:6][CH:2]=[CH:3][CH:4]=4)[CH2:12][NH:11]3)=[O:14])=[CH:21][CH:20]=2)=[CH:28][CH:27]=1
Reactant: O=C(Nc1ccc(Oc2ccc(F)cc2)cc1)[C@@H]1C[C@@H](Cc2ccc(Cl)s2)CN1
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CO
Product: O=C(Nc1ccc(Oc2ccc(F)cc2)cc1)[C@@H]1C[C@@H](Cc2cccs2)CN1
Temperature: 80 °C
Reaction time: 0.5 h
Yield: 73.9 %

Procedure:
A flask was charged with (2S,4S)-4-((5-chlorothien-2-yl)methyl)-N-(4-(4-fluorophenoxy)phenyl)pyrrolidine-2-carboxamide (340 mg, 0.861 mmol), prepared as in Reference 6, palladium on carbon (10%, 50 mg), ammonium formate (200 mg, 3.33 mmol) and methanol (10 mL) and the mixture was heated to 80° C. The mixture was stirred at 80° C. for 30 minutes, filtered and then concentrated to give crude (2S,4S)—N-(4-(4-fluorophenoxy)phenyl)-4-(thien-2-ylmethyl)pyrrolidine-2-carboxamide (0.252 mg, 0.636 mmol), which was carried forward without further purification.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][NH:5][C:4](=[O:8])[CH:3]=1.[C:9]1([C:14](Cl)=[O:15])[S:13][CH:12]=[CH:11][CH:10]=1>>[C:9]1([C:14]([O:1][C:2]2[CH:7]=[CH:6][NH:5][C:4](=[O:8])[CH:3]=2)=[O:15])[S:13][CH:12]=[CH:11][CH:10]=1
Reactant: O=C(Cl)c1cccs1
Reactant: O=c1cc(O)cc[nH]1
Product: O=C(Oc1cc[nH]c(=O)c1)c1cccs1
Yield: 74.8 %

Procedure:
The general procedure of Example 18 was followed using 2.00 g of 4-hydroxy-2-pyridone and 3.17 g of 2-thenoyl chloride, thereby producing 2.98 g of the title compound in a yield of 75%.
Reaction SMILES: Br[C:2]1[S:3][C:4]([NH:27]C(=O)OC(C)(C)C)=[C:5]([C:7](=[O:26])[NH:8][C:9]2[CH:10]=[N:11][N:12]([CH2:22][CH:23]([F:25])[F:24])[C:13]=2[N:14]2[CH2:20][CH2:19][CH2:18][CH:17]([OH:21])[CH2:16][CH2:15]2)[N:6]=1.[F:35][C:36]1[CH:41]=[CH:40][C:39]([F:42])=[CH:38][C:37]=1B(O)O>>[NH2:27][C:4]1[S:3][C:2]([C:40]2[CH:41]=[C:36]([F:35])[CH:37]=[CH:38][C:39]=2[F:42])=[N:6][C:5]=1[C:7]([NH:8][C:9]1[CH:10]=[N:11][N:12]([CH2:22][CH:23]([F:24])[F:25])[C:13]=1[N:14]1[CH2:20][CH2:19][CH2:18][CH:17]([OH:21])[CH2:16][CH2:15]1)=[O:26]
Reactant: OB(O)c1cc(F)ccc1F
Reactant: CC(C)(C)OC(=O)Nc1sc(Br)nc1C(=O)Nc1cnn(CC(F)F)c1N1CCCC(O)CC1
Product: Nc1sc(-c2cc(F)ccc2F)nc1C(=O)Nc1cnn(CC(F)F)c1N1CCCC(O)CC1
Yield: 57.6 %

Procedure:
Following the procedure for Example 105, tert-butyl 2-bromo-4-(1-(2,2-difluoroethyl)-5-(4-hydroxyazepan-1-yl)-1H-pyrazol-4-ylcarbamoyl)thiazol-5-ylcarbamate (130 mg, 0.23 mmol) and 2,5-difluorobenzeneboronic acid (55 mg, 0.35 mmol) were reacted to give 118 as a dark green solid (66 mg, 57% over two steps). 1H NMR (400 MHz, d4-MeOD) δ 8.10-8.00 (m, 1H), 7.68 (s, 1H), 7.30-7.20 (m, 1H), 7.19-7.11 (m, 1H), 6.24 (tt, J=55.6, 4.2 Hz, 1H), 4.51-4.40 (m, 2H), 4.01-3.92 (m, 1H), 3.45-3.30 (m, 2H), 3.31-3.16 (m, 3H), 2.13-1.91 (m, 2H), 1.90-1.67 (m, 2H). LCMS (ES+) m/z 499 (M+1).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:12]=[CH:13][CH:14]=1)[CH2:5][N:6]1[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:22][CH2:23][CH2:24][C:25]#[N:26].O>CN(C)C=O>[N:6]1([CH2:5][C:4]2[CH:3]=[C:2]([CH:14]=[CH:13][CH:12]=2)[O:1][CH2:22][CH2:23][CH2:24][C:25]#[N:26])[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11]1
Reactant: Oc1cccc(CN2CCCCC2)c1
Reactant: N#CCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: N#CCCCOc1cccc(CN2CCCCC2)c1
Temperature: 25 °C
Reaction time: 17 h

Procedure:
A mixture of N-3-hydroxybenzylpiperidine (9.55 g) and anhydrous potassium carbonate (13.8 g) in dimethylformamide (100 ml) was stirred at ambient temperature for 17 hours. 4-Bromobutyronitrile (5 ml) was added and the mixture stirred at ambient temperature for 24 hours. Water (10 volumes) was added and the resulting mixture extracted with ethyl acetate. The extracts were washed with water, dried and the solvent removed to leave an oil which was purified by distillation (190°-200° C./0.1 mm) or by chromatography on a column packed with an activated magnesium silicate (sold under the trade name FLORISIL) to give 4-(3-piperidinomethylphenoxy)butyronitrile as an oil.
Reaction SMILES: [CH2:1]([NH:8][C:9]1[CH:14]=[C:13](Cl)[N:12]=[CH:11][C:10]=1[CH2:16][C:17]([NH2:19])=[O:18])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.CS(O)(=O)=O>C1(OC2C=CC=CC=2)C=CC=CC=1.C(Cl)(Cl)Cl>[CH2:1]([NH:8][C:9]1[CH:14]=[C:13]([NH:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[N:12]=[CH:11][C:10]=1[CH2:16][C:17]([NH2:19])=[O:18])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Nc1ccccc1
Reactant: NC(=O)Cc1cnc(Cl)cc1NCc1ccccc1
Agent: CS(=O)(=O)O
Solvent: ClC(Cl)Cl
Solvent: c1ccc(Oc2ccccc2)cc1
Product: NC(=O)Cc1cnc(Nc2ccccc2)cc1NCc1ccccc1
Temperature: 180 °C
Reaction time: 0.5 h
Yield: 99.5 %

Procedure:
To 25 mg of 4-(benzylamino)-6-chloropyridine-3-carboxyamide suspended in 0.2 mL of diphenylether, 18 mg of aniline and 9 mg of methanesulfonic acid were added and stirred at 180° C. for 30 minutes. After cooling, the reaction mixture was dissolved in chloroform, washed with saturated aqueous sodium bicarbonate, and dried on anhydrous sodium sulfate. The solvent was evaporated and the residue was purified by silica gel column chromatography (chloroform:methanol=40:1-10:1) to obtain 30 mg (99%) of the title compound as a slight yellow crystalline powder.