Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]([C:12](=[O:14])[CH3:13])[C:9]([N:15]2[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]2)=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[N:7]2.[F:21][C:22]1[CH:30]=[CH:29][CH:28]=[CH:27][C:23]=1[C:24](Cl)=[O:25].C(N(CC)CC)C>C(Cl)Cl>[Cl:1][C:2]1[CH:11]=[C:10]([C:12](=[O:14])[CH3:13])[C:9]([N:15]2[CH2:16][CH2:17][N:18]([C:24](=[O:25])[C:23]3[CH:27]=[CH:28][CH:29]=[CH:30][C:22]=3[F:21])[CH2:19][CH2:20]2)=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[N:7]2
Reactant: CC(=O)c1cc(Cl)c2cccnc2c1N1CCNCC1
Reactant: O=C(Cl)c1ccccc1F
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)c1cc(Cl)c2cccnc2c1N1CCN(C(=O)c2ccccc2F)CC1
Reaction time: 2 h
Yield: 121.4 %

Procedure:
1-(5-Chloro-8-piperazin-1-ylquinolin-7-yl)ethanone (0.030 g, 0.10 mmol, from Example 47, Step 1) was combined with 2-fluorobenzoyl chloride (0.018 mL, 0.16 mmol) and triethylamine (0.043 mL, 0.31 mmol) in methylene chloride (1.0 mL) at room temperature and stirred for 2 hrs. The reaction was diluted with dichloromethane, washed with water, dried over MgSO4, concentrated and purified on silica gel (eluting with 0 to 5% methanol in dichloromethane) to give the desired product (50 mg). LCMS calculated for C22H20ClFN3O2 (M+H)+: m/z=412.1; Found: 412.1.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:55])[CH2:4][NH:5][C:6](=[O:54])[C@H:7]([NH:11][C:12](=[O:53])[C@H:13]([NH:35]C(OCC1C2C=CC=CC=2C2C1=CC=CC=2)=O)[CH2:14][S:15][C:16]([C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[CH:8](C)[CH3:9].N(CC)CC.[C:61]([NH:78][C@@H:79]([C:87](O)=[O:88])[CH2:80][C:81]1[CH:86]=[CH:85][CH:84]=[CH:83][CH:82]=1)([O:63][CH2:64][CH:65]1[C:77]2[C:72](=[CH:73][CH:74]=[CH:75][CH:76]=2)[C:71]2[C:66]1=[CH:67][CH:68]=[CH:69][CH:70]=2)=[O:62].C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.C(N(C(C)C)C(C)C)C>CC#N.C(Cl)Cl>[CH3:1][O:2][C:3](=[O:55])[CH2:4][NH:5][C:6]([C:7]1([NH:11][C:12](=[O:53])[C@H:13]([NH:35][C:87](=[O:88])[C@H:79]([NH:78][C:61]([O:63][CH2:64][CH:65]2[C:77]3[CH:76]=[CH:75][CH:74]=[CH:73][C:72]=3[C:71]3[C:66]2=[CH:67][CH:68]=[CH:69][CH:70]=3)=[O:62])[CH2:80][C:81]2[CH:82]=[CH:83][CH:84]=[CH:85][CH:86]=2)[CH2:14][S:15][C:16]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)([C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)[C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[CH2:9][CH2:8]1)=[O:54]
Reactant: O=C(N[C@H](Cc1ccccc1)C(=O)O)OCC1c2ccccc2-c2ccccc21
Reactant: COC(=O)CNC(=O)[C@H](NC(=O)[C@@H](CSC(c1ccccc1)(c1ccccc1)c1ccccc1)NC(=O)OCC1c2ccccc2-c2ccccc21)C(C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: ClCCl
Solvent: CCNCC
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)CNC(=O)C1(NC(=O)[C@@H](CSC(c2ccccc2)(c2ccccc2)c2ccccc2)NC(=O)[C@@H](Cc2ccccc2)NC(=O)OCC2c3ccccc3-c3ccccc32)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 82.9 %

Procedure:
To a solution of 1 (300 mg, 0.40 mmol, 1 eq) in MeCN (8 mL) was added Et2NH (0.8 mL, 10% v/v) dropwise at rt under Ar(g). The solution was stirred at rt for 2 h, then the solvent was removed in vacuo. The excess of amine was co-evaporated with MeCN (3×5 mL), then with a 1:5 mixture of CH2Cl2/hexane (10 mL). A white solid was obtained and the flask was dried under high vacuum for 2 h. To a solution of Fmoc-D-Phenylalanine (173 mg, 0.45 mmol, 1.1 eq) in MeCN (7 mL) at 0° C. was added PyBOP (233 mg, 0.45 mmol, 1.1 eq) and 176 μL of N-ethyldiisopropylamine (1.01 mmol, 2.5 eq) under Ar(g). The crude amine, dissolved in CH2Cl2 (6 mL) was added to the mixture dropwise. The reaction mixture was then left to warm to rt overnight. The mixture was then concentrated in vacuo and the residue was further purified by silica gel column chromatography with hexane/EtOAc (1:2→0:1) to yield 2 as a white solid (294 mg, 82%).
Reaction SMILES: [CH:1]([CH:3]([CH:9]=O)[C:4]([O:6][CH2:7][CH3:8])=[O:5])=O.[CH3:11][O:12][CH2:13][C:14]1[CH:15]=[C:16]([NH2:19])[NH:17][N:18]=1>C(O)C>[CH3:11][O:12][CH2:13][C:14]1[CH:15]=[C:16]2[N:19]=[CH:9][C:3]([C:4]([O:6][CH2:7][CH3:8])=[O:5])=[CH:1][N:17]2[N:18]=1
Reactant: COCc1cc(N)[nH]n1
Reactant: CCOC(=O)C(C=O)C=O
Solvent: CCO
Product: CCOC(=O)c1cnc2cc(COC)nn2c1
Reaction time: 8 h
Yield: 69.4 %

Procedure:
Ethyl 2-formyl-3-oxopropionate (775 mg) was added to a solution of the thus obtained 5-methoxymethyl-2H-pyrazol-3-ylamine (684 mg) in ethanol (50 ml), and stirred overnight. The reaction solution was concentrated under reduced pressure, and a saturated sodium bicarbonate solution was added to the residue which were then extracted with ethyl acetate. The organic phase was washed with a saturated saline solution and dried over sodium sulfate anhydrous. The resulting product was concentrated under reduced pressure, and the residue was purified by column chromatography (eluting solvent; n-hexane:ethyl acetate 4:1) to give ethyl 2-methoxymethylpyrazolo[1,5-a]pyrimidine-6-carboxylate (878 mg, Y.:69%). 1 M Boron tribromide solution in dichloromethane (0.51 ml) was added dropwise at −70° C. to a solution of the thus obtained ethyl 2-methoxymethylpyrazolo[1,5-a]pyrimidine-6-carboxylate (20 mg) in dichloromethane (2 ml). The temperature of the mixture under stirring was increased from −70° C. to −50° C. over 4.5 hours and then increased from −50° C. to room temperature over 2 hours. The reaction mixture was cooled to 0° C., water was added to the reaction mixture which was then extracted with ethyl acetate, and the extract was dried over sodium sulfate anhydrous. The resulting product was concentrated under reduced pressure to give ethyl 2-hydroxymethylpyrazolo[1,5-a]pyrimidine-6-carboxylate (19 mg, Y.:quant.).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH2:8][CH2:9][O:10][CH3:11])[N:3]=1.[NH2:12][C:13]1[S:14][C:15]([C:21]2[C:26]([F:27])=[CH:25][C:24]([C:28]([OH:31])([CH3:30])[CH3:29])=[CH:23][C:22]=2[F:32])=[CH:16][C:17]=1[C:18]([NH2:20])=[O:19]>>[F:32][C:22]1[CH:23]=[C:24]([C:28]([OH:31])([CH3:30])[CH3:29])[CH:25]=[C:26]([F:27])[C:21]=1[C:15]1[S:14][C:13]([NH:12][C:2]2[CH:7]=[CH:6][CH:5]=[C:4]([CH2:8][CH2:9][O:10][CH3:11])[N:3]=2)=[C:17]([C:18]([NH2:20])=[O:19])[CH:16]=1
Reactant: CC(C)(O)c1cc(F)c(-c2cc(C(N)=O)c(N)s2)c(F)c1
Reactant: COCCc1cccc(Br)n1
Product: COCCc1cccc(Nc2sc(-c3c(F)cc(C(C)(C)O)cc3F)cc2C(N)=O)n1

Procedure:
The title compound was prepared according to the general procedure in Example 1 using 2-bromo-6-(2-methoxyethyl)pyridine (42 mg, 0.19 mmol) and 2-amino-5-[2,6-difluoro-4-(1-hydroxy-1-methylethyl)phenyl]thiophene-3-carboxamide (60 mg, 0.19 mmol) as the starting materials.
Reaction SMILES: [C:1]([C:3]1[CH2:8][CH2:7][CH2:6][CH2:5][CH:4]=1)#[CH:2].[H-].[Na+].[CH3:11][CH:12]1[CH:17]([CH3:18])[CH2:16][CH2:15][CH:14]([CH3:19])[C:13]1=[O:20].O>O1CCCC1.CCOCC>[C:1]([C:3]1[CH2:8][CH2:7][CH2:6][CH2:5][CH:4]=1)#[CH:2].[CH3:11][CH:12]1[CH:17]([CH3:18])[CH2:16][CH2:15][CH:14]([CH3:19])[C:13]1([C:2]#[C:1][C:3]1[CH2:8][CH2:7][CH2:6][CH2:5][CH:4]=1)[OH:20]
Reactant: CC1CCC(C)C(C)C1=O
Agent: C#CC1=CCCCC1
Agent: [H-]
Agent: [Na+]
Solvent: CCOCC
Solvent: C1CCOC1
Solvent: O
Product: CC1CCC(C)C(O)(C#CC2=CCCCC2)C1C
Reaction time: 8 h

Procedure:
21.5 g of ethynylcyclohexene are added dropwise to a suspension of 6 g of 80% strength sodium hydride in 200 ml of tetrahydrofuran under reflux, and the reaction mixture is kept under reflux conditions until no further gas is evolved. 28 g of 2,3,6-trimethyl-cyclohexanone are then added dropwise at room temperature and the mixture is left overnight, whilst being stirred, in order to complete the reaction. Water is added to the reaction mixture, the reaction product is taken up in ether and the ether solution is washed with water, dried and concentrated. Fractional distillation gives 9 g of unconverted ethynylcyclohexene, 8 g of starting ketone, and 22 g of 1-(2,3,6-trimethyl-1-hydroxy-cyclohexyl)-2-(cyclohex-1-en-1-yl)-acetylene of boiling point 120° C/0.1 mm Hg and refractive index nD25 = 1.5143. This corresponds to a yield of 68% of theory, based on trimethylcyclohexanone converted. Fragrance note: faint, tart, herbaceous.
Reaction SMILES: [Cl:1][C:2]1[C:10]2[C:5](=[N:6][CH:7]=[CH:8][C:9]=2[NH:11][C:12]2[CH:17]=[CH:16][C:15]([NH2:18])=[CH:14][C:13]=2[F:19])[NH:4][CH:3]=1.[Cl:20][C:21]1[CH:26]=[C:25](Cl)[N:24]=[C:23]([NH2:28])[N:22]=1.Cl.[OH-].[Na+]>O>[Cl:20][C:21]1[N:22]=[C:23]([NH2:28])[N:24]=[C:25]([NH:18][C:15]2[CH:16]=[CH:17][C:12]([NH:11][C:9]3[CH:8]=[CH:7][N:6]=[C:5]4[NH:4][CH:3]=[C:2]([Cl:1])[C:10]=34)=[C:13]([F:19])[CH:14]=2)[CH:26]=1
Reactant: Nc1nc(Cl)cc(Cl)n1
Reactant: Nc1ccc(Nc2ccnc3[nH]cc(Cl)c23)c(F)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: Nc1nc(Cl)cc(Nc2ccc(Nc3ccnc4[nH]cc(Cl)c34)c(F)c2)n1
Temperature: 100 °C
Reaction time: 8 h

Procedure:
57 mg (210 mmol) of N1-(3-chloro-1H-pyrrolo[2,3-b]pyridin-4-yl)-2-fluorobenzene-1,4-diamine and 47 mg (290 μmol) of 4,6-dichloropyrimidine-2-amine are suspended in 5 ml of water. 290 μl (290 mmol) of 1 M hydrochloric acid are added, and the mixture is stirred at 100° C. overnight. Using 1N aqueous sodium hydroxide solution, the suspension is then adjusted to pH 10, resulting in the precipitation of crystals. The solid is filtered off and washed with water. The crude product is purified by column chromatography on silica gel (mobile phase: dichloromethane/methanol (7M ammonia) 100:1 to 10:1) and subsequent preparative RP-HPLC.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[N:4]=[C:3]1[CH2:13]O.O=S(Cl)[Cl:17]>>[Cl:17][CH2:13][C:3]1[N:2]([CH3:1])[CH:6]=[C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[N:4]=1
Reactant: Cn1cc(-c2ccccc2)nc1CO
Reactant: O=S(Cl)Cl
Product: Cn1cc(-c2ccccc2)nc1CCl
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of (1-Methyl-4-phenyl-1H-imidazol-2-yl)-methanol 5 (0.2 g, 0.097 mmol) was added SOCl2 (0.14 g, 0.121 mmol), and the mixture was stirred at room temperature overnight. The mixture was evaporated to afford 2-Chloromethyl-1-methyl-4-phenyl-1H-imidazole 6, which was used without purification. 1H NMR (400 MHz, DMSO-d6): δ8.24 (s, 1H), 7.87 (d, J=6.8 Hz, 2H), 7.54-7.49 (m, 2H), 7.43-7.41 (m, 1H), 5.24 (s, 2H), 3.89 (s, 3H).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:55])[CH2:5][N:6]([C:8](=[O:54])[C@@H:9]([NH:25][C:26](=[O:53])[C@@H:27]([NH2:52])[CH2:28][CH2:29][CH2:30][NH:31]/[C:32](/[NH2:51])=[N:33]\[S:34]([C:37]1[C:38]([CH3:50])=[C:39]([CH3:49])[C:40]2[O:44][C:43]([CH3:46])([CH3:45])[CH2:42][C:41]=2[C:47]=1[CH3:48])(=[O:36])=[O:35])[CH2:10][N:11]([CH3:24])[S:12]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[N+:21]([O-:23])=[O:22])(=[O:14])=[O:13])[CH3:7])[CH3:2].CCN(C(C)C)C(C)C.[CH3:65][C:66](OC(C)=O)=[O:67]>C(Cl)(Cl)Cl>[CH2:1]([O:3][C:4](=[O:55])[CH2:5][N:6]([C:8](=[O:54])[C@@H:9]([NH:25][C:26](=[O:53])[C@@H:27]([NH:52][C:66](=[O:67])[CH3:65])[CH2:28][CH2:29][CH2:30][NH:31]/[C:32](/[NH2:51])=[N:33]\[S:34]([C:37]1[C:38]([CH3:50])=[C:39]([CH3:49])[C:40]2[O:44][C:43]([CH3:45])([CH3:46])[CH2:42][C:41]=2[C:47]=1[CH3:48])(=[O:35])=[O:36])[CH2:10][N:11]([CH3:24])[S:12]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[N+:21]([O-:23])=[O:22])(=[O:14])=[O:13])[CH3:7])[CH3:2]
Reactant: CC(=O)OC(C)=O
Reactant: CCOC(=O)CN(C)C(=O)[C@H](CN(C)S(=O)(=O)c1ccccc1[N+](=O)[O-])NC(=O)[C@@H](N)CCCN/C(N)=N\S(=O)(=O)c1c(C)c(C)c2c(c1C)CC(C)(C)O2
Solvent: CCN(C(C)C)C(C)C
Solvent: ClC(Cl)Cl
Product: CCOC(=O)CN(C)C(=O)[C@H](CN(C)S(=O)(=O)c1ccccc1[N+](=O)[O-])NC(=O)[C@H](CCCN/C(N)=N\S(=O)(=O)c1c(C)c(C)c2c(c1C)CC(C)(C)O2)NC(C)=O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 82.7 %

Procedure:
To a solution of compound F (6.6 g, 7.8 mmol) in CHCl3 (50 mL) at 5° C. was added DIPEA (4.8 mL, 27.4 mmol) followed by Ac2O (0.9 mL, 9.4 mmol). The reaction mixture was stirred at ambient temperature for 30 min. Solvents were removed in vacuo, and then the residue was diluted with water (500 mL) and EtOAc (500 mL). The organic layer was separated and washed with water (300 mL), 2% aqueous H2SO4 (200 mL), water (2×300 mL) and brine (100 mL). The organic layer was separated, dried over Na2SO4 and solvent removed in vacuo to afford compound G (5.5 g, 82%). LC-MS [M+H] 853.4 (C36H52N8O12S2+H, calc: 853.9). Purity >95% (UV/254 nm). Compound G was used without further purification.
Reaction SMILES: [CH3:1][N:2]([CH2:4][C:5]([CH3:7])=[CH2:6])[CH3:3].C([Li])CCC.C(=O)=O.[CH2:16]([O:18][C:19]([N:21]1[CH2:26][CH2:25][C:24](=[O:27])[CH2:23][CH2:22]1)=[O:20])[CH3:17]>C1COCC1>[CH2:16]([O:18][C:19]([N:21]1[CH2:22][CH2:23][C:24]([OH:27])([CH2:6][C:5]([CH2:4][N:2]([CH3:3])[CH3:1])=[CH2:7])[CH2:25][CH2:26]1)=[O:20])[CH3:17]
Reactant: C=C(C)CN(C)C
Reactant: CCOC(=O)N1CCC(=O)CC1
Agent: O=C=O
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: C=C(CN(C)C)CC1(O)CCN(C(=O)OCC)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 104.7 %

Procedure:
2-[(Dimethylamino)methyl]propene (29.75 g, 300 mmol) in anhydrous THF (300 ml) was cooled to -78° and butyl lithium (2.5M, 120 ml, 300 mmol) was added dropwise, the temperature of addition being maintained below 0°. The dry-ice bath was replaced by an ice-bath and the reaction mixture maintained at 0° for 3 hours and then cooled to -78°. 1-Ethoxycarbonyl-4-piperidinone (25.68 g, 150 mmol) in anhydrous THF (50 ml) was added dropwise and the reaction mixture maintained at -78° for 1.5 hours and then stirred at room temperature overnight. Approximately 50 g of ice was added and the reaction mixture washed with saturated NaCl several times and dried (MgSO4), yielding a tan, viscous oil (42.47 g). Purification by flash chromatography eluting with ethylacetate in hexane gave the sub-title compound (9.33 g)
Reaction SMILES: Cl([O-])=O.[Na+].CC(=CC)C.P([O-])(O)(O)=[O:11].[Na+].[F:16][C:17]([F:46])([F:45])[C:18]1[CH:44]=[CH:43][CH:42]=[CH:41][C:19]=1[O:20][CH:21]1[CH2:26][CH2:25][N:24]([C:27]2[N:32]=[CH:31][C:30]([N:33]3[CH:37]=[C:36]([CH2:38][CH:39]=[O:40])[N:35]=[N:34]3)=[CH:29][N:28]=2)[CH2:23][CH2:22]1>O.CC(C)=O>[F:46][C:17]([F:45])([F:16])[C:18]1[CH:44]=[CH:43][CH:42]=[CH:41][C:19]=1[O:20][CH:21]1[CH2:26][CH2:25][N:24]([C:27]2[N:32]=[CH:31][C:30]([N:33]3[CH:37]=[C:36]([CH2:38][C:39]([OH:11])=[O:40])[N:35]=[N:34]3)=[CH:29][N:28]=2)[CH2:23][CH2:22]1
Reactant: O=P([O-])(O)O
Reactant: O=CCc1cn(-c2cnc(N3CCC(Oc4ccccc4C(F)(F)F)CC3)nc2)nn1
Agent: CC=C(C)C
Agent: [Na+]
Agent: [O-][Cl+][O-]
Solvent: O
Solvent: CC(C)=O
Product: O=C(O)Cc1cn(-c2cnc(N3CCC(Oc4ccccc4C(F)(F)F)CC3)nc2)nn1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Into a 10-mL round-bottom flask equipped with a magnetic stirbar was added sodium chlorite (28 mg, 0.31 mmol), 2-methyl-2-butene (32 μL, 0.31 mmol) and sodium dihydrogen phosphate (37 mg, 0.31 mmol) in water (1.0 mL). To this solution was added [1-(2-{4-[2-(trifluoromethyl)phenoxy]piperidin-1-yl}pyrimidin-5-yl)-1H-1,2,3-triazol-4-yl]acetaldehyde (22 mg, 0.05 mmol) dissolved in acetone (1.0 mL). The reaction was stirred at room temperature for 1 h. The reaction was concentrated, poured into a 50-mL separatory funnel containing saturated aqueous KH2PO4 solution (30 mL) and the mixture was extracted with ethyl acetate (3×10 mL). The combined organic layers were washed with brine, dried over magnesium sulfate, filtered and the solvent was evaporated under reduced pressure to give the desired product.
Reaction SMILES: C1([C@H]2C[C@H]3N(C)[C@H](CC3)[C@H]2C(OC)=O)C=CC=CC=1.[F:20][C:21]1[CH:26]=[CH:25][C:24]([C@H:27]2[CH2:33][C@H:32]3[N:34]([CH3:35])[C@H:29]([CH2:30][CH2:31]3)[C@H:28]2[C:36](OC)=[O:37])=[CH:23][CH:22]=1>>[CH:36]([C@H:28]1[C@@H:27]([C:24]2[CH:23]=[CH:22][C:21]([F:20])=[CH:26][CH:25]=2)[CH2:33][C@H:32]2[N:34]([CH3:35])[C@@H:29]1[CH2:30][CH2:31]2)=[O:37]
Reactant: COC(=O)[C@H]1[C@@H](c2ccc(F)cc2)C[C@@H]2CC[C@H]1N2C
Agent: COC(=O)[C@H]1[C@@H](c2ccccc2)C[C@@H]2CC[C@H]1N2C
Product: CN1[C@H]2CC[C@@H]1[C@@H](C=O)[C@@H](c1ccc(F)cc1)C2

Procedure:
Using a procedure similar to that described in Example 8, sub-part b, except replacing the compound 15 used therein with compound 17, the compound 20 was prepared as a colorless oil: 1H NMR (CDCl3) δ1.74 (d,1H, J=8.5), 1.64-1.82 (m,1H), 1.91 (dt,1H, J=3.8 and 12.7), 2.21 (s,3H), 2.10-2.33 (m,2H), 2.39-2.54 (m,2H), 3.16 (dt,1H, J=5.7 and 12.9), 3.40-3.48 (m,1H), 3.50-3.60 (m,1H), 7.00 (t, 2H, J=8.7), 7.19 (dd, 2H, J=6.0 and 8.4), 9.64 (d,1H, J=3.2).
Reaction SMILES: O[C:2]1([C:10]2[CH:17]=[CH:16][C:13]([C:14]#[N:15])=[CH:12][CH:11]=2)[C:9]2[N:5]([CH:6]=[N:7][CH:8]=2)[CH2:4][CH2:3]1>O1CCCC1.Cl>[CH:8]1[N:7]=[CH:6][N:5]2[CH2:4][CH:3]=[C:2]([C:10]3[CH:17]=[CH:16][C:13]([C:14]#[N:15])=[CH:12][CH:11]=3)[C:9]=12
Reactant: N#Cc1ccc(C2(O)CCn3cncc32)cc1
Agent: Cl
Solvent: C1CCOC1
Product: N#Cc1ccc(C2=CCn3cncc32)cc1
Temperature: 50 °C
Reaction time: 12 h

Procedure:
A mixture of 2.35 mmol of 4-(7-hydroxyl-6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-7-yl)-benzonitrile in 5 ml of tetrahydrofuran and 10 ml of 4N HCl is stirred at 50° C. for 12 hours. The reaction mixture is cooled to room temperature, poured onto ice/4N NaOH and extracted with ethyl acetate (3×). The combined organic phases are dried with sodium sulphate and evaporated. From the residue the title compound is obtained by means of flash chromatography (SiO2 60 F) as a light brown solid. Rt=4.55 (Gradient I).
Reaction SMILES: [F:1][C:2]([F:23])([F:22])[C:3]1[CH:4]=[C:5]([N:9]2[C:13]([C:14]([Cl:17])([Cl:16])[Cl:15])=[N:12][C:11]([C:18]([O:20]C)=[O:19])=[N:10]2)[CH:6]=[CH:7][CH:8]=1.[OH-].[Na+]>CO.O>[F:23][C:2]([F:1])([F:22])[C:3]1[CH:4]=[C:5]([N:9]2[C:13]([C:14]([Cl:16])([Cl:17])[Cl:15])=[N:12][C:11]([C:18]([OH:20])=[O:19])=[N:10]2)[CH:6]=[CH:7][CH:8]=1
Reactant: COC(=O)c1nc(C(Cl)(Cl)Cl)n(-c2cccc(C(F)(F)F)c2)n1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: O=C(O)c1nc(C(Cl)(Cl)Cl)n(-c2cccc(C(F)(F)F)c2)n1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
210 g (0.54 mole) of 1-(3-trifluoromethylphenyl)-3-methoxycarbonyl-5-trichloromethyl-1,2,4-triazole in 540 ml of methanol were initially taken, and 0.57 mole (22.8 g) of NaOH in 100 ml of water was added. After being stirred at room temperature for 5 hours, the mixture was poured into 4,000 ml of water, the undissolved substance was filtered off and the clear filtrate was adjusted to pH 1 with hydrochloric acid. Colorless crystals were precipitated and were filtered off with suction and washed with water. The substance which remained undissolved in water--the sodium salt of the carboxylic acid--was dissolved in a mixture of 2,000 ml of methanol and 1,000 ml of water, the pH of the solution was adjusted to 1 with hydrochloric acid, and the colorless crystalline precipitate was filtered off with suction and washed with water.
Reaction SMILES: Cl.C(O[N:5]=[CH:6][C:7]1[CH:8]=[C:9]2[C:13](=[CH:14][CH:15]=1)[NH:12][N:11]=[C:10]2[C:16]1[CH:17]=[C:18]([NH:22][C:23](=[O:29])[CH2:24][C:25]([CH3:28])([CH3:27])[CH3:26])[CH:19]=[CH:20][CH:21]=1)C.[NH2:30][NH:31][C:32](=O)[CH2:33][N:34]([CH3:36])[CH3:35].C[O-].[Na+]>CO>[CH3:35][N:34]([CH2:33][C:32]1[NH:31][N:30]=[C:6]([C:7]2[CH:8]=[C:9]3[C:13](=[CH:14][CH:15]=2)[NH:12][N:11]=[C:10]3[C:16]2[CH:17]=[C:18]([NH:22][C:23](=[O:29])[CH2:24][C:25]([CH3:26])([CH3:28])[CH3:27])[CH:19]=[CH:20][CH:21]=2)[N:5]=1)[CH3:36]
Reactant: CCON=Cc1ccc2[nH]nc(-c3cccc(NC(=O)CC(C)(C)C)c3)c2c1
Reactant: CN(C)CC(=O)NN
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: CN(C)Cc1nc(-c2ccc3[nH]nc(-c4cccc(NC(=O)CC(C)(C)C)c4)c3c2)n[nH]1

Procedure:
The title compound was prepared according to the procedure described in Example 329 C using N-{3-[5-(ethoxyiminomethyl)(1H-indazol-3-yl)]phenyl}-3,3-dimethylbutanamide hydrochloride (0.360 g, 0.87 mmol), N-amino-2-(dimethylamino)acetamide (0.304 g, 2.60 mmol) and sodium methoxide in methanol (0.398 mL, 4.37 M). The title compound was isolated after purification by preparative HPLC (0.093 g, 25% yield): 1H NMR (CD3OD) δ 8.72 (s, 1H), 8.16 (t, 1H), 8.08 (dt, 1H), 7.75 (dt, 2H), 7.66 (d, 1H), 7.50 (t, 1H), 3.71 (s, 2H), 2.37 (s, 6H), 2.30 (s, 2H), 1.12 (s, 9H); ES-MS (m/z) 432 [M+H]+.
Reaction SMILES: [CH3:1][CH:2]([O:4][C:5](=[O:22])[NH:6][C@H:7]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14](Br)[CH:15]=2)[N:10]([C:18](=[O:20])[CH3:19])[C@@H:9]([CH3:21])[CH2:8]1)[CH3:3].CC1(C)C(C)(C)OB([C:31]2[CH:32]=[N:33][N:34]([CH2:36][CH2:37][OH:38])[CH:35]=2)O1.C([O-])([O-])=O.[K+].[K+].C(=O)=O>O1CCOCC1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1(C)C=CC=CC=1.CCO>[C:18]([N:10]1[C:11]2[C:16](=[CH:15][C:14]([C:31]3[CH:32]=[N:33][N:34]([CH2:36][CH2:37][OH:38])[CH:35]=3)=[CH:13][CH:12]=2)[C@H:7]([NH:6][C:5](=[O:22])[O:4][CH:2]([CH3:3])[CH3:1])[CH2:8][C@@H:9]1[CH3:21])(=[O:20])[CH3:19]
Reactant: CC1(C)OB(c2cnn(CCO)c2)OC1(C)C
Reactant: CC(=O)N1c2ccc(Br)cc2[C@H](NC(=O)OC(C)C)C[C@@H]1C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: O=C=O
Solvent: CCO
Solvent: C1COCCO1
Solvent: Cc1ccccc1
Product: CC(=O)N1c2ccc(-c3cnn(CCO)c3)cc2[C@H](NC(=O)OC(C)C)C[C@@H]1C
Temperature: 80 °C
Reaction time: 18 h
Yield: 15 %

Procedure:
A flask was charged with 1-methylethyl[(2S,4R)-1-acetyl-6-bromo-2-methyl-1,2,3,4-tetrahydro-4-quinolinyl]carbamate (for a preparation see Example 4) (0.185 g, 0.500 mmol), 2-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl]ethanol (for a preparation see Intermediate 118) (143 mg, 0.600 mmol), K2CO3 (90 mg, 0.650 mmol) and tetrakis(triphenylphosphine)palladium(0) (28.9 mg, 0.025 mmol) then filled with EtOH (1 mL) and toluene (1 mL) and the resulting mixture was stirred at 80° C. for 18 h then cooled to room temperature and concentrated in vacuo. The residue was partitioned between AcOEt (10 mL) and water (10 mL) and the layers were separated. The aqueous layer was extracted with AcOEt and the combined organic phases were washed with brine (25 mL), dried over Na2SO4 and concentrated in vacuo. Purification of the residue using MDAP (modifier: formic acid) gave an oil which was dissolved in 1,4-dioxane, freezed using an acetone bath cooled with solid CO2 and left on a freeze drier for 16 h to give 1-methylethyl {(2S,4R)-1-acetyl-6-[1-(2-hydroxyethyl)-1H-pyrazol-4-yl]-2-methyl-1,2,3,4-tetrahydro-4-quinolinyl}carbamate (33.3 mg, 0.083 mmol, 15%) as a white solid.
Reaction SMILES: CC(C)([O-])C.[K+].[NH2:7][CH:8]([CH3:11])[CH2:9][SH:10].Cl[C:13]1[S:14][C:15]([S:23](=[O:26])(=[O:25])[NH2:24])=[CH:16][C:17]=1[C:18](OCC)=[O:19]>C(O)C>[CH3:11][CH:8]1[NH:7][C:18](=[O:19])[C:17]2[CH:16]=[C:15]([S:23](=[O:25])(=[O:26])[NH2:24])[S:14][C:13]=2[S:10][CH2:9]1
Reactant: CC(N)CS
Reactant: CCOC(=O)c1cc(S(N)(=O)=O)sc1Cl
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CCO
Product: CC1CSc2sc(S(N)(=O)=O)cc2C(=O)N1
Reaction time: 24 h
Yield: 72.5 %

Procedure:
To a mixture of potassium tert-butoxide (8.56 g, 0.076 mol) in ethanol (75 mL) was added 2(R,S)-aminopropanethiol (3.1 g, 0.0246 mol) and ethyl 2-chloro-5-sulfamoylthiophene-3-carboxylate (5.98 g, 0.022 mol). The mixture was heated at reflux for 24 hours, and then allowed to stand at room temperature for 24 hours. Following removal of most of the solvent by vacuum concentration, the mixture was acidified to pH 3 with dilute hydrochloric acid. The resulting solids were removed by filtration and dried to give 4.44 g of the title compound, mp 184°-187° C.