Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([NH:8][C:9]1[C:14]2[N:15]=[C:16](Cl)[N:17]=[C:18]([N:19]3[CH2:24][CH2:23][S:22](=[O:25])[CH2:21][CH2:20]3)[C:13]=2[N:12]=[CH:11][N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH:27][CH2:28][CH2:29][NH:30][CH3:31]>O1CCOCC1>[CH2:1]([NH:8][C:9]1[C:14]2[N:15]=[C:16]([N:30]([CH3:31])[CH2:29][CH2:28][OH:27])[N:17]=[C:18]([N:19]3[CH2:24][CH2:23][S:22](=[O:25])[CH2:21][CH2:20]3)[C:13]=2[N:12]=[CH:11][N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CNCCO
Reactant: O=S1CCN(c2nc(Cl)nc3c(NCc4ccccc4)ncnc23)CC1
Solvent: C1COCCO1
Product: CN(CCO)c1nc(N2CCS(=O)CC2)c2ncnc(NCc3ccccc3)c2n1

Procedure:
This compound was prepared analogous to Example 2 from 8-benzylamino-2-chloro-4-(1-oxido-thiomorpholino)pyrimido[5,4-d]pyrimidine (melting point: 232°-233° C.) and N-(2-hydroxy-ethyl)-methylamine in dioxane under reflux.
Reaction SMILES: FC1C=CC=CC=1NC(=S)NC1C=CC(C2C=C3C(=CC=2)C(=O)N([C@@H](C(C)C)C(OC)=O)C3)=CC=1.[NH2:36][C:37]1[CH:42]=[CH:41][C:40]([C:43]2[CH:44]=[C:45]3[C:49](=[CH:50][CH:51]=2)[C:48](=[O:52])[N:47]([C@@H:53]([CH:58]([CH3:60])[CH3:59])[C:54]([O:56][CH3:57])=[O:55])[CH2:46]3)=[CH:39][CH:38]=1.[F:61][C:62]([F:73])([F:72])[C:63]1[CH:64]=[C:65]([N:69]=[C:70]=[S:71])[CH:66]=[CH:67][CH:68]=1>>[CH3:59][CH:58]([CH3:60])[C@H:53]([N:47]1[CH2:46][C:45]2[C:49](=[CH:50][CH:51]=[C:43]([C:40]3[CH:41]=[CH:42][C:37]([NH:36][C:70]([NH:69][C:65]4[CH:66]=[CH:67][CH:68]=[C:63]([C:62]([F:61])([F:72])[F:73])[CH:64]=4)=[S:71])=[CH:38][CH:39]=3)[CH:44]=2)[C:48]1=[O:52])[C:54]([O:56][CH3:57])=[O:55]
Reactant: FC(F)(F)c1cccc(N=C=S)c1
Reactant: COC(=O)[C@H](C(C)C)N1Cc2cc(-c3ccc(N)cc3)ccc2C1=O
Agent: COC(=O)[C@H](C(C)C)N1Cc2cc(-c3ccc(NC(=S)Nc4ccccc4F)cc3)ccc2C1=O
Product: COC(=O)[C@H](C(C)C)N1Cc2cc(-c3ccc(NC(=S)Nc4cccc(C(F)(F)F)c4)cc3)ccc2C1=O

Procedure:
The compound of example 282 was prepared analogous to compound of example 256 by reaction of compound of example 223 with 3-trifluoromethyl phenyl isothiocyanate. The compound of example 282 was used directly without isolation, for the preparation of compound of example 283.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([N:8]2[CH2:13][CH2:12][O:11][CH:10]([C:14]3[NH:15][C:16]4[CH:21]=[CH:20][N:19]=[CH:18][C:17]=4[N:22]=3)[CH2:9]2)[N:5]=[C:4]([NH2:23])[N:3]=1.[F:24][C:25]1[CH:32]=[C:31](B2OC(C)(C)C(C)(C)O2)[CH:30]=[CH:29][C:26]=1[C:27]#[N:28].C([O-])([O-])=O.[Na+].[Na+]>O1CCOCC1.O.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>[NH2:23][C:4]1[N:3]=[C:2]([C:31]2[CH:30]=[CH:29][C:26]([C:27]#[N:28])=[C:25]([F:24])[CH:32]=2)[CH:7]=[C:6]([N:8]2[CH2:13][CH2:12][O:11][CH:10]([C:14]3[NH:15][C:16]4[CH:21]=[CH:20][N:19]=[CH:18][C:17]=4[N:22]=3)[CH2:9]2)[N:5]=1
Reactant: Nc1nc(Cl)cc(N2CCOC(c3nc4cnccc4[nH]3)C2)n1
Reactant: CC1(C)OB(c2ccc(C#N)c(F)c2)OC1(C)C
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: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: N#Cc1ccc(-c2cc(N3CCOC(c4nc5cnccc5[nH]4)C3)nc(N)n2)cc1F
Temperature: 140 °C
Reaction time: 1 h
Yield: 85.3 %

Procedure:
A mixture of 4-chloro-6-[2-(1H-imidazo[4,5-c]pyridin-2-yl)-4-morpholinyl]-2-pyrimidinamine (403 mg, 1.21 mmol), 2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzonitrile (390 mg, 1.58 mmol), Na2CO3 (322 mg, 3.04 mmol) and Pd(PPh3)4 (140 mg, 0.121 mmol) in 1,4-dioxane (6 mL) and water (2 mL) was heated at 140° C. under microwave conditions with stirring for 1 hour. The mixture was filtered, washed by EtOAc (150 mL), and evaporated to give a yellow solid which was chromatographed to afford the title compound (430 mg) as a yellow solid. LC-MS (ES) m/z=417 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:18]=[CH:17][CH:16]=[CH:15][C:3]=1[C:4]([NH:6][CH2:7][C:8]([C:10]1[CH:14]=[CH:13][S:12][CH:11]=1)=[O:9])=[O:5].[H-].[Na+].Br[CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24]>>[Cl:1][C:2]1[CH:18]=[CH:17][CH:16]=[CH:15][C:3]=1[C:4]([NH:6][CH:7]([C:8]([C:10]1[CH:14]=[CH:13][S:12][CH:11]=1)=[O:9])[CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24])=[O:5]
Reactant: CCOC(=O)CBr
Reactant: O=C(CNC(=O)c1ccccc1Cl)c1ccsc1
Agent: [H-]
Agent: [Na+]
Product: CCOC(=O)CC(NC(=O)c1ccccc1Cl)C(=O)c1ccsc1
Yield: 97.3 %

Procedure:
11.0 g of N-(2-chlorobenzoyl)-N-[(3-thienylcarbonyl)methyl]amine, 2.17 g of 50% sodium hydride and 7.9 g of ethyl bromoacetate are treated in the same manner as described in Preparation 1-(4). 14 g of ethyl 3-(2-chlorobenzoylamino)-3-(3-thienylcarbonyl)propionate are thereby obtained as an oil. Yield: 97.2%
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH:4]([C:7]([C:9]2[S:13][C:12]([NH2:14])=[N:11][C:10]=2[C:15]2[O:16][CH:17]=[CH:18][CH:19]=2)=[O:8])[CH2:3][CH2:2]1.C(N(CC)CC)C.[Br:27][CH2:28][C:29](Br)=[O:30].O>CN(C1C=CN=CC=1)C.C1COCC1>[Br:27][CH2:28][C:29]([NH:14][C:12]1[S:13][C:9]([C:7]([CH:4]2[CH2:5][CH2:6][O:1][CH2:2][CH2:3]2)=[O:8])=[C:10]([C:15]2[O:16][CH:17]=[CH:18][CH:19]=2)[N:11]=1)=[O:30]
Reactant: O=C(Br)CBr
Reactant: Nc1nc(-c2ccco2)c(C(=O)C2CCOCC2)s1
Agent: CN(C)c1ccncc1
Solvent: O
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: O=C(CBr)Nc1nc(-c2ccco2)c(C(=O)C2CCOCC2)s1
Temperature: 25 °C
Reaction time: 2 h
Yield: 79.6 %

Procedure:
Compound 454 (1.39 g, 5.00 mmol), triethylamine (3.06 mL, 22.0 mmol) and DMAP (61.0 mg, 0.500 mmol) were suspended in THF (30 mL), and bromoacetyl bromide (1.64 mL, 20.0 mmol) was added dropwise thereto at 0° C., followed by stirring at room temperature for 2 hours. Water was added to the reaction mixture, followed by extraction with ethyl acetate. The organic layer was washed with a saturated aqueous solution of sodium chloride and dried over anhydrous magnesium sulfate, and then the solvent was distilled away under reduced pressure. The resulting residue was purified through silica gel column chromatography (chloroform:methanol=99:1), followed by reslurrying with diethyl ether to afford the entitled Compound 531 (1.59 g, 80%) as a pale brown solid.
Reaction SMILES: [CH3:1][NH:2][C:3]([C:5]1C=[CH:9][C:8]([CH2:11][CH2:12][C:13]([OH:15])=O)=[CH:7][N:6]=1)=[O:4].[NH2:16][CH2:17][C:18]([N:20]([C:22]1[CH:27]=[CH:26][C:25]([Cl:28])=[C:24]([CH2:29][O:30][C:31]2[C:39]3[N:38]=[C:37]([O:40][CH3:41])[N:36]([CH2:42][C:43]4[CH:48]=[CH:47][CH:46]=[CH:45][N:44]=4)[C:35]=3[CH:34]=[CH:33][CH:32]=2)[C:23]=1[Cl:49])[CH3:21])=[O:19].ClC1C(COC2C3N=C(OC)[N:64](CC4C=CC=CN=4)C=3C=CC=2)=C(Cl)C=CC=1N(C)C(=O)CNC(=O)CCC1C=CC(C(NCCOC)=O)=CC=1>>[Cl:49][C:23]1[C:24]([CH2:29][O:30][C:31]2[C:39]3[N:38]=[C:37]([O:40][CH3:41])[N:36]([CH2:42][C:43]4[CH:48]=[CH:47][CH:46]=[CH:45][N:44]=4)[C:35]=3[CH:34]=[CH:33][CH:32]=2)=[C:25]([Cl:28])[CH:26]=[CH:27][C:22]=1[N:20]([CH3:21])[C:18](=[O:19])[CH2:17][NH:16][C:13](=[O:15])[CH2:12][CH2:11][CH:8]1[CH2:7][NH:6][C:5]([C:3]([NH:2][CH3:1])=[O:4])=[N:64][CH2:9]1
Reactant: CNC(=O)c1ccc(CCC(=O)O)cn1
Reactant: COc1nc2c(OCc3c(Cl)ccc(N(C)C(=O)CN)c3Cl)cccc2n1Cc1ccccn1
Reactant: COCCNC(=O)c1ccc(CCC(=O)NCC(=O)N(C)c2ccc(Cl)c(COc3cccc4c3nc(OC)n4Cc3ccccn3)c2Cl)cc1
Product: CNC(=O)C1=NCC(CCC(=O)NCC(=O)N(C)c2ccc(Cl)c(COc3cccc4c3nc(OC)n4Cc3ccccn3)c2Cl)CN1

Procedure:
3-(2-methylcarbamoyl-pyridine-5-yl)-propionic acid and 2-amino-N-(2,4-dichloro-3-(((2-methoxy-1-(pyridin-2-ylmethyl)-1H-benzo[d]imidazol-4-yl)oxy)methyl)phenyl)-N-methylacetamide were coupled as described for compound 1. MS (APCI) 695 (M+), 1HNMR (400 MHz, MeOD) δ 1.57-1.69 (m, 3H), 2.31 (m, 2H), 2.78 (s, 3H), 2.98 (m, 2H), 3.19 (s, 3H), 3.34-3.824 (m, 4H), 4.30 (s, 3H), 5.30 (s, 2H), 5.55 (m, 2H), 6.83 (m, 2H), 7.05 (m, 2H), 7.30 (m, 1H), 7.57 (m, 2H), 7.63 (m, 1H), 8.49 (d, 1H). C33H36Cl2N8O5+0.4 H2O, Calculated: C, 56.4; H, 5.28; N, 15.94. Found: C, 56.4; H, 5.35; N, 15.90.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][C:3]=1[CH3:9].[OH-].[K+].[CH3:12][O:13][CH:14]([O:17][CH3:18])[CH2:15]Br>CS(C)=O.O>[CH3:12][O:13][CH:14]([O:17][CH3:18])[CH2:15][O:8][C:5]1[CH:6]=[CH:7][C:2]([F:1])=[C:3]([CH3:9])[CH:4]=1
Reactant: COC(CBr)OC
Reactant: Cc1cc(O)ccc1F
Agent: [K+]
Agent: [OH-]
Solvent: CS(C)=O
Solvent: O
Product: COC(COc1ccc(F)c(C)c1)OC

Procedure:
A mixture of 4-fluoro-3-methylphenol (36.7 g), potassium hydroxide pellets (19.5 g) and bromoacetaldehyde dimethyl acetal (34.6 ml) in dimethyl sulphoxide (240 ml) was heated at 110° for 24 h. The mixture was cooled, diluted with water (350 ml) and extracted with hexane. Evaporation of the extracts gave the title compound as an oil (52.3 g).
Reaction SMILES: CC(C)([O-])C.[K+].[C:7]1([CH2:13]N2C3C=CC=CC=3N=C2)[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[C:23]1([CH:29]=NC2C=CC=CC=2)[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>CN(C=O)C>[C:23]1([C:29]#[C:13][C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: c1ccc(Cn2cnc3ccccc32)cc1
Reactant: C(=Nc1ccccc1)c1ccccc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: C(#Cc1ccccc1)c1ccccc1
Temperature: 0 °C
Yield: 73 %

Procedure:
To potassium t-butoxide (5.6 g, 50 mmol) in DMF (40 mL) at 75° C. was added N-(phenylmethyl)-1H-benzimidazole (2.08 g, 10 mmol) and N-(phenylmethylene)benzenamine (1.81 g, 10 mmol) dissolved in DMF (10 mL). After 5 hours the solution is poured into ice-cold water (150 mL), extracted with CHCl3 (3×50 mL) and chromatographed (PE). Diphenylacetylene was obtained in 73 % yield.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([F:23])[CH:18]=2)=[C:5]([C:7]([N:9]2[C@H:14]([CH2:15][NH2:16])[CH2:13][C@H:12]3[C@@H:10]2[CH2:11]3)=[O:8])[N:6]=1.[C:24]1([C:34](O)=[O:35])[C:33]2[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=2)[CH:27]=[CH:26][N:25]=1>>[NH2:1][C:2]1[S:3][C:4]([C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([F:23])[CH:18]=2)=[C:5]([C:7]([N:9]2[C@H:14]([CH2:15][NH:16][C:34]([C:24]3[C:33]4[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=4)[CH:27]=[CH:26][N:25]=3)=[O:35])[CH2:13][C@H:12]3[C@@H:10]2[CH2:11]3)=[O:8])[N:6]=1
Reactant: NC[C@@H]1C[C@@H]2C[C@@H]2N1C(=O)c1nc(N)sc1-c1cccc(F)c1
Reactant: O=C(O)c1nccc2ccccc12
Product: Nc1nc(C(=O)N2[C@H](CNC(=O)c3nccc4ccccc34)C[C@@H]3C[C@@H]32)c(-c2cccc(F)c2)s1

Procedure:
prepared by reaction of [2-amino-5-(3-fluoro-phenyl)-thiazol-4-yl]-((1S,3S,5S)-3-aminomethyl-2-aza-bicyclo[3.1.0]hex-2-yl)-methanone with isoquinoline-1-carboxylic acid. LC-MS (basic): tR=0.84 min; [M+H]+=488.1.
Reaction SMILES: CS(C)=O.C(Cl)(=O)C(Cl)=O.[Cl:11][C:12]1[N:17]=[CH:16][C:15]([CH2:18][OH:19])=[C:14]([NH:20][CH:21]([CH3:23])[CH3:22])[CH:13]=1.CCN(CC)CC>C(Cl)Cl>[Cl:11][C:12]1[CH:13]=[C:14]([NH:20][CH:21]([CH3:23])[CH3:22])[C:15]([CH:18]=[O:19])=[CH:16][N:17]=1
Reactant: CC(C)Nc1cc(Cl)ncc1CO
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Product: CC(C)Nc1cc(Cl)ncc1C=O
Temperature: -20 °C
Reaction time: 0.33 h

Procedure:
To a stirred solution of DMSO (13.43 mmol, 3.5 equiv.) in dry DCM (30 mL), oxalyl chloride (11.51 mmol, 3 equiv.) was added at −78° C. After being stirred for 20 min, (6-chloro-4-(isopropylamino)pyridin-3-yl)methanol (75) (770 mg, 3.84 mmol) was added to the above reaction mixture at −78° C. and stirred for 2 h. The reaction mixture was allowed to warm up to −20° C. and added Et3N (19.19 mmol, 5 equiv.) dropwise over a period of 5 mins. The reaction mixture was allowed to warm up to 0° C. over 30 mins and quenched with ice-flakes followed by 10% NaHCO3 solution. The organic layer was separated, aqueous layer was extracted with DCM (twice). The organic layers were collected together, dried over Na2SO4, filtered and concentrated to give crude aldehyde. The crude material obtained was purified by column chromatography through silica gel and EtOAc:pet ether as eluent provided the desired compound, 6-chloro-4-(isopropylamino)nicotinaldehyde. LC/MS: Acquity BEH C18 2.1×50 mm, 1.8 micron; Solvent A=0.1% TFA in water; Solvent B=0.1% TFA in ACN; gradient 0-100% B over 2 min; retention time: 0.76 min; LCMS (ES-API), m/z 199.26 (M+H).
Reaction SMILES: [C:1]([OH:10])(=[O:9])[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[OH:4].C(=O)([O-])[O-].[K+].[K+].S(OCC)(O[CH2:21][CH3:22])(=O)=O.[CH3:26][C:27](C)=O>>[CH2:21]([O:4][C:3]1[CH:5]=[CH:6][CH:7]=[CH:8][C:2]=1[C:1]([O:10][CH2:26][CH3:27])=[O:9])[CH3:22]
Reactant: O=C(O)c1ccccc1O
Reactant: CC(C)=O
Reactant: CCOS(=O)(=O)OCC
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CCOC(=O)c1ccccc1OCC
Temperature: 25 °C
Yield: 80 %

Procedure:
To a stirred solution of Salicylic acid (50 g, 143 mmol) in acetone (300 mL) was added anhydrous powdered potassium carbonate (80 g, 580 mmol). Diethyl sulfate (44.25 g, 290 mmol) was added in portions for about 10 min at room temperature. After the addition was complete, the solution was heated to reflux temperature on a water bath and maintained for 3 h. The solution was cooled to room temperature and then concentrated under reduced pressure. Distilled water (200 mL) was added to the reaction mixture, which was then extracted with ethyl acetate (200 mL). The organic layer was washed with distilled water (2×200 mL), dried over anhydrous sodium sulfate, and concentrated to yield the title Ethyl 2-Ethoxy-benzoate (45 g, 80%).
Reaction SMILES: [CH:1]1[CH:6]=[C:5]2[C:7]([N:9]([CH2:12][C:13]([OH:15])=O)[C:10](=[O:11])[C:4]2=[CH:3][CH:2]=1)=[O:8].[CH:16]12[N:23]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH:20]([CH2:21][CH2:22]1)[CH2:19][NH:18][CH2:17]2.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C>C(Cl)Cl.O>[O:11]=[C:10]1[C:4]2[C:5](=[CH:6][CH:1]=[CH:2][CH:3]=2)[C:7](=[O:8])[N:9]1[CH2:12][C:13]([N:18]1[CH2:17][CH:16]2[N:23]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH:20]([CH2:21][CH2:22]2)[CH2:19]1)=[O:15]
Reactant: O=C(O)CN1C(=O)c2ccccc2C1=O
Reactant: CC(C)(C)OC(=O)N1C2CCC1CNC2
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: O
Product: CC(C)(C)OC(=O)N1C2CCC1CN(C(=O)CN1C(=O)c3ccccc3C1=O)C2
Reaction time: 8 h
Yield: 75.6 %

Procedure:
To a stirred solution of N-phthaloylglycine (725 mg, 3.53 mmol) and tert-butyl 3,8-diazabicyclo[3.2.1]octane-8-carboxylate (500 mg, 2.36 mmol) in CH2Cl2 (20 mL) were added HOBt (481 mg, 3.53 mmol) and WSC (677 mg, 3.53 mmol) at room temperature and the mixture was stirred overnight. To the mixture was added H2O (5 mL) and the organic layer was separated, washed with saturated aqueous NaHCO3, brine, dried over MgSO4, filtered and concentrated in vacuo. Flash chromatography (SiO2, 230-400 mesh, 309, CH2Cl2-MeOH=98/2 to 92/8) afforded the product as a white solid (713 mg, 81%).
Reaction SMILES: [I:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][C:11]3[C:14]([C:28]([F:31])([F:30])[F:29])=[N:15][N:16]([C:17]4[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][C:18]=4[C:19](O)=[O:20])[C:10]=3[C:9]2=[O:32])=[CH:4][CH:3]=1.S(Cl)([Cl:35])=O>C(Cl)(Cl)Cl>[I:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][C:11]3[C:14]([C:28]([F:31])([F:30])[F:29])=[N:15][N:16]([C:17]4[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][C:18]=4[C:19]([Cl:35])=[O:20])[C:10]=3[C:9]2=[O:32])=[CH:4][CH:3]=1
Reactant: O=S(Cl)Cl
Reactant: COc1ccc(-n2nc(C(F)(F)F)c3c2C(=O)N(c2ccc(I)cc2)CC3)c(C(=O)O)c1
Solvent: ClC(Cl)Cl
Product: COc1ccc(-n2nc(C(F)(F)F)c3c2C(=O)N(c2ccc(I)cc2)CC3)c(C(=O)Cl)c1

Procedure:
2-[6-(4-Iodo-phenyl)-7-oxo-3-trifluoromethyl-4,5,6,7-tetrahydro-pyrazolo[3,4-c]pyridin-1-yl]-5-methoxy-benzoic acid (186 mg, 0.334 mmol) was dissolved in dry chloroform (10 mL) to which was added thionyl chloride (243 μL, 3.34 mmol), and the reaction heated to reflux. The solvent was evaporated, and the residue dried under vacuum to give 2-[6-(4-iodo-phenyl)-7-oxo-3-trifluoromethyl-4,5,6,7-tetrahydro-pyrazolo[3,4-c]pyridin-1-yl]-5-methoxy-benzoyl chloride as a pale yellow foam. This material was dissolved in dry methylene chloride (10 mL) to which were added pyridine (0.14 mL, 1.67 mmol), N,N-dimethylaminopyridine (4 mg, 0.033 mmol), and lastly C-(1H-imidazol-2-yl)-methylamine bis-hydrochloride (114 mg, 0.668 mmol). Upon completion of the reaction the solvent was evaporated, and the residue was purified by preparative HPLC to give the title compound (69 mg, 24%) as a colorless solid. MS (ES+) 636.9 (M+H)+(100%).
Reaction SMILES: [CH3:1][S:2]([O:5][C:6]1[N:11]=[C:10]2[N:12]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[O:22][C:23]([F:26])([F:25])[F:24])[C:13](O)=[N:14][C:9]2=[CH:8][CH:7]=1)(=[O:4])=[O:3].P(Cl)(Cl)([Cl:29])=O>>[CH3:1][S:2]([O:5][C:6]1[N:11]=[C:10]2[N:12]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[O:22][C:23]([F:26])([F:25])[F:24])[C:13]([Cl:29])=[N:14][C:9]2=[CH:8][CH:7]=1)(=[O:4])=[O:3]
Reactant: CS(=O)(=O)Oc1ccc2nc(O)n(-c3ccccc3OC(F)(F)F)c2n1
Reactant: O=P(Cl)(Cl)Cl
Product: CS(=O)(=O)Oc1ccc2nc(Cl)n(-c3ccccc3OC(F)(F)F)c2n1
Temperature: 80 °C

Procedure:
2-Hydroxy-3-(2-(trifluoromethoxy)phenyl)-3H-imidazo[4,5-b]pyridin-5-yl methanesulfonate (0.50 g, 1.3 mmol) taken up in phosphoryl trichloride (3.0 mL) was heated in a sealed tube to 80° C. for 48 h. The mixture was concentrated under reduced pressure and NaHCO3 was added to the residue until it turned basic. The solution was further diluted with water and extracted with EtOAc (3×). The combined organic extracts were dried over MgSO4 and concentrated under reduced pressure. The residue was purified column chromatography to give 2-chloro-3-(2-(trifluoromethoxy)phenyl)-3H-imidazo[4,5-b]pyridin-5-yl methanesulfonate, which was dissolved in a 1:4:1 solution of 1 M LiOH/THF/MeOH (10 mL) and stirred at room temperature for 1 hour. The mixture was concentrated under reduced pressure and the remaining was acidified with 1 N HCl. The resulting precipitate was collected by vacuum filtration and purified via preparative HPLC to give the title compound (0.11 g, 0.32 mmol, 25%). LCMS m/z=330.2 [M+H]+, 1H NMR (400 MHz, methanol-d4) δ ppm 6.70 (d, J=8.7 Hz, 1H), 7.58-7.68 (m, 3H), 7.73 (m, 1H), 7.90 (d, J=8.7 Hz, 1H).
Reaction SMILES: CS(O[CH2:6][C:7]1[CH:12]=[C:11]([F:13])[C:10]([C:14]#[N:15])=[CH:9][C:8]=1[F:16])(=O)=O.[N-:17]=[N+:18]=[N-:19].[Na+]>O.CN(C=O)C>[N:17]([CH2:6][C:7]1[C:8]([F:16])=[CH:9][C:10]([C:14]#[N:15])=[C:11]([F:13])[CH:12]=1)=[N+:18]=[N-:19]
Reactant: CS(=O)(=O)OCc1cc(F)c(C#N)cc1F
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: N#Cc1cc(F)c(CN=[N+]=[N-])cc1F
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of 4-cyano-2,5-difluorobenzyl methanesulfonate (4.5 g, 0.0182 mol; see step (iv) above) and sodium azide (2.0 g, 0.031 mol) in 20 mL of water and 40 mL of DMF was stirred at room temperature for 2 h. It was subsequently poured into 300 mL of water and extracted three times with diethyl ether. The combined ethereal phase washed several times with water, dried (Na2SO4) and evaporated. A small sample was evaporated for NMR purposes and the product crystallised. The rest was evaporated cautiously but not until complete dryness. Yield (theoretically 3.5 g) is assumed to be almost quantitative based on NMR and analytical HPLC.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[O:8][C:7]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[CH:6][C:5]2=[O:18].Br[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][Cl:26].[OH:27][CH2:28][CH2:29][N:30]1[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]1>>[ClH:26].[OH:27][CH2:28][CH2:29][N:30]1[CH2:35][CH2:34][N:33]([CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][O:1][C:2]2[CH:11]=[CH:10][C:9]3[O:8][C:7]([C:12]4[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=4)=[CH:6][C:5](=[O:18])[C:4]=3[CH:3]=2)[CH2:32][CH2:31]1
Reactant: O=c1cc(-c2ccccc2)oc2ccc(O)cc12
Reactant: ClCCCCCCBr
Reactant: OCCN1CCNCC1
Product: Cl
Product: O=c1cc(-c2ccccc2)oc2ccc(OCCCCCCN3CCN(CCO)CC3)cc12

Procedure:
The compound was prepared by the method of Example 3 from 6-hydroxyflavone, 1-bromo-6-chlorohexane, and 4-(2-Hydroxyethyl)piperazine: mp 239°-241° C.
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[F:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[N:20]=[CH:19][C:18]([O:21][CH2:22][C:23]([OH:25])=O)=[CH:17][CH:16]=2)=[CH:11][CH:10]=1.[NH2:26][C:27]1[S:28][CH:29]=[CH:30][N:31]=1>>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[F:8][C:9]1[CH:10]=[CH:11][C:12]([C:15]2[N:20]=[CH:19][C:18]([O:21][CH2:22][C:23]([NH:26][C:27]3[S:28][CH:29]=[CH:30][N:31]=3)=[O:25])=[CH:17][CH:16]=2)=[CH:13][CH:14]=1
Reactant: Nc1nccs1
Reactant: O=C(O)COc1ccc(-c2ccc(F)cc2)nc1
Solvent: O=C(O)C(F)(F)F
Product: O=C(COc1ccc(-c2ccc(F)cc2)nc1)Nc1nccs1

Procedure:
The title compound was prepared analogously as described in Example 30(d) from 95 mg (0.26 mmol) of [6-(4-fluoro-phenyl)-pyridin-3-yloxy]-acetic acid trifluoroacetic acid salt and 39.5 mg (0.39 mmol) of 2-aminothiazole. Yield: 20 mg.
Reaction SMILES: [NH2:1][C:2]([CH3:17])([CH2:5][N:6]1[N:10]=[C:9]2[CH:11]=[CH:12][C:13]([C:15]#[N:16])=[CH:14][C:8]2=[N:7]1)[C:3]#[N:4].[F:18][C:19]([F:30])([F:29])[C:20]1[CH:28]=[CH:27][C:23]([C:24](Cl)=[S:25])=[CH:22][CH:21]=1>>[C:3]([C:2]([NH:1][C:24](=[S:25])[C:23]1[CH:22]=[CH:21][C:20]([C:19]([F:18])([F:29])[F:30])=[CH:28][CH:27]=1)([CH3:17])[CH2:5][N:6]1[N:10]=[C:9]2[CH:11]=[CH:12][C:13]([C:15]#[N:16])=[CH:14][C:8]2=[N:7]1)#[N:4]
Reactant: CC(N)(C#N)Cn1nc2ccc(C#N)cc2n1
Reactant: FC(F)(F)c1ccc(C(=S)Cl)cc1
Product: CC(C#N)(Cn1nc2ccc(C#N)cc2n1)NC(=S)c1ccc(C(F)(F)F)cc1

Procedure:
Using a procedure similar to that described in Example 1, except using 2-amino-3-(5-cyano-2H-benzotriazol-2-yl)-2-methylpropionitrile, described in Example 21, and 4-trifluoromethylthiobenzoyl chloride, the title compound was isolated as a white solid (0.46 g, 81%). Rf=0.45 (1:1 EA/heptane). MS (ES): M/Z [M+H]=431. 1H NMR: (400 MHz, DMSO-d6): 1.76 (s, 3H), 5.46-5.59 (m, 2H), 7.76 (dd, J=8.9, 1.3 Hz, 1H), 7.84-7.93 (m, 4H), 8.18 (d, J=8.9 Hz, 1H), 8.78 (br s, 1H) and 9.01 (br s, 1H). 19F NMR (376 MHz, DMSO-d6): −41.93 (s, 3F).
Reaction SMILES: [CH2:1]([C:5]1[N:6]([CH2:13][C:14]2[CH:19]=[CH:18][C:17]([CH:20]([CH:28]3[CH2:32][CH2:31][CH2:30][CH2:29]3)[C:21]([O:23]C(C)(C)C)=[O:22])=[CH:16][CH:15]=2)[C:7]([CH:11]=[O:12])=[C:8]([Cl:10])[N:9]=1)[CH2:2][CH2:3][CH3:4].FC(F)(F)C(O)=O>ClCCl>[CH2:1]([C:5]1[N:6]([CH2:13][C:14]2[CH:15]=[CH:16][C:17]([CH:20]([CH:28]3[CH2:29][CH2:30][CH2:31][CH2:32]3)[C:21]([OH:23])=[O:22])=[CH:18][CH:19]=2)[C:7]([CH:11]=[O:12])=[C:8]([Cl:10])[N:9]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1nc(Cl)c(C=O)n1Cc1ccc(C(C(=O)OC(C)(C)C)C2CCCC2)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCCCc1nc(Cl)c(C=O)n1Cc1ccc(C(C(=O)O)C2CCCC2)cc1

Procedure:
2.3 g (5 mmol) of the compound of Example IV are stirred in 5 ml of dichloromethane and 5 ml of trifluoroacetic acid for 5 hours at 25° C. After concentration, the crude product is chromatographed over silica gel 60 using dichloromethane/methanol (100:5). Yield: 1.8 g (87.6% of theory)
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1.CCN(CC)CC.[NH2:32][CH:33]1[CH2:38][CH2:37][N:36]([C:39]([C:41]2[C:49]3[C:44](=[CH:45][C:46]([Cl:50])=[CH:47][CH:48]=3)[NH:43][CH:42]=2)=[O:40])[CH2:35][CH2:34]1>C(Cl)Cl>[Cl:50][C:46]1[CH:45]=[C:44]2[C:49]([C:41]([C:39]([N:36]3[CH2:35][CH2:34][CH:33]([NH:32][C:4](=[O:6])[C:3]4[CH:7]=[CH:8][CH:9]=[CH:10][C:2]=4[F:1])[CH2:38][CH2:37]3)=[O:40])=[CH:42][NH:43]2)=[CH:48][CH:47]=1
Reactant: O=C(O)c1ccccc1F
Reactant: NC1CCN(C(=O)c2c[nH]c3cc(Cl)ccc23)CC1
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(NC1CCN(C(=O)c2c[nH]c3cc(Cl)ccc23)CC1)c1ccccc1F
Temperature: 25 °C
Reaction time: 8 h
Yield: 57 %

Procedure:
To a stirred solution of 50 mg (0.36 mmol) 2-fluoro-benzoic acid in 5 ml CH2Cl2 were added 90 mg (0.47 mmol) EDC, 63 mg (0.47 mmol) HOBt, 60 μl (0.47 mmol) Et3N and 100 mg (0.36 mmol) (4-amino-piperidin-1-yl)-(6-chloro-1H-indol-3-yl)-methanone. The mixture was stirred overnight at RT and then poured onto water and extracted with CH2Cl2. The combined organic phases were dried over Na2SO4 and concentrated in vacuo. Flash chromatography (ethyl acetate) afforded 82 mg (57%) N-[1-(6-Chloro-1H-indole-3-carbonyl)-piperidin-4-yl]-2-fluoro-benzamide of as a white solid.