Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([C:4]1[CH:17]=[CH:16][C:15](Cl)=[CH:14][C:5]=1[C:6]([N:8]1[CH2:13][CH2:12][O:11][CH2:10][CH2:9]1)=[O:7])([O-:3])=[O:2].[NH:19]([CH2:23][CH2:24][OH:25])[CH2:20][CH2:21][OH:22]>CS(C)=O>[N+:1]([C:4]1[CH:17]=[CH:16][C:15]([N:19]([CH2:23][CH2:24][OH:25])[CH2:20][CH2:21][OH:22])=[CH:14][C:5]=1[C:6]([N:8]1[CH2:13][CH2:12][O:11][CH2:10][CH2:9]1)=[O:7])([O-:3])=[O:2]
Reactant: OCCNCCO
Reactant: O=C(c1cc(Cl)ccc1[N+](=O)[O-])N1CCOCC1
Solvent: CS(C)=O
Product: O=C(c1cc(N(CCO)CCO)ccc1[N+](=O)[O-])N1CCOCC1
Temperature: 140 °C
Yield: 53.3 %

Procedure:
Dissolved in 4 ml of DMSO were 1.0 g (3.69 mmol) of N-(2-nitro-5-chlorobenzoyl)morpholine and 1.16 g (11 mmol) of diethanolamine. The resulting mixture was stirred under heat at 140° C. for 3 hours. After the reaction, the reaction mixture was concentrated and the resulting yellow syrup was purified by chromatography on a silica gel column (chloroform/methanol=10/1), whereby 667 mg of the title compound were obtained as yellow powder (yield: 53.5%).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][CH:7]=1.[NH2:8][C:9]1[C:10]([C:16](OC)=[O:17])=[N:11][C:12]([Br:15])=[CH:13][N:14]=1.N12CCCN=C1CCCCC2>O>[NH2:8][C:9]1[C:10]([C:16]([NH:1][C:2]2[CH:3]=[N:4][CH:5]=[CH:6][CH:7]=2)=[O:17])=[N:11][C:12]([Br:15])=[CH:13][N:14]=1
Reactant: Nc1cccnc1
Reactant: COC(=O)c1nc(Br)cnc1N
Solvent: O
Solvent: C1CCC2=NCCCN2CC1
Product: Nc1ncc(Br)nc1C(=O)Nc1cccnc1
Reaction time: 4 h
Yield: 59.3 %

Procedure:
To 3-aminopyridine (10 g, 106 mmol) at 70° C. were added methyl 3-amino-6-bromo-2-pyrazinecarboxylate (1.0 g, 4.3 mmol) and 1,8-diazabicyclo[5.4.0]undec-7-ene (645 μL, 4.3 mmol). The reaction solution was stirred for 4 h, diluted with water (75 mL) and extracted with methylene chloride. The combined organic layers were washed with a saturated ammonium chloride solution, dried (MgSO4), filtered and evaporated in vacuo. The crude product was purified on a silica gel column using methylene chloride/ethanol, (9:1), as the eluent to give 750 mg (59% yield) of the title compound as a yellow solid: 1H NMR (CDCl3, 400 MHz) δ 9.50 (br s, 1H) 8.82 (d, J=3 Hz, 1H), 8.43 (dd, J=5 and 1 Hz, 1H), 8.31 (s, 1H), 8.23 (ddd, J=8, 3 and 2 Hz, 1H), 7.34 (dd, J=8, 5 Hz, 1H); MS (TSP) m/z 294 (M++1).
Reaction SMILES: [CH2:1]([NH:3][CH2:4][C:5]([OH:7])=O)[CH3:2].[F:8][C:9]1[CH:14]=[CH:13][C:12]([CH:15]([N:17]=[C:18]=[S:19])[CH3:16])=[CH:11][CH:10]=1.C(N(CC)CC)C>C(Cl)(Cl)Cl>[CH2:1]([N:3]1[CH2:4][C:5](=[O:7])[N:17]([CH:15]([C:12]2[CH:13]=[CH:14][C:9]([F:8])=[CH:10][CH:11]=2)[CH3:16])[C:18]1=[S:19])[CH3:2]
Reactant: CC(N=C=S)c1ccc(F)cc1
Reactant: CCNCC(=O)O
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: CCN1CC(=O)N(C(C)c2ccc(F)cc2)C1=S
Yield: 33.1 %

Procedure:
A mixture of the crude N-ethyl glycine (18.4 g), 1-(4-fluorophenyl)-ethyl-isothiocyanate (18.1 g), triethyl amine (20.2 g) and chloroform (300 mL) was heated at reflux for 18 hours. The solvent was evaporated. The residue was dissolved in ethyl acetate (400 mL) and water (300 mL). The organic phase was washed with 1N HCl (2×300 mL), then evaporated to dryness. Crystallization from ethyl acetate afforded the title compound (8.8 g) as a light yellow solid, m.p. 93°-95° C. Anal. Calcd. for. C13H15F N2O S: C, 58.63; H, 5.68; N, 10.52. Found: C, 58.69; H, 5.64; N, 10.58. Mass spectrum (EI, M.+) m/z 266.
Reaction SMILES: [CH2:1]([N:8]([CH2:10][C:11]1[C:12]([C:43]([OH:45])=O)=[C:13]([N:28]([CH2:34][C:35]2[C:40]([F:41])=[CH:39][CH:38]=[CH:37][C:36]=2[F:42])[C:29](OCC)=[O:30])[S:14][C:15]=1[C:16]1[CH:21]=[CH:20][C:19]([NH:22][C:23]([NH:25][O:26][CH3:27])=[O:24])=[CH:18][CH:17]=1)[CH3:9])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.P(C#N)(OCC)(OCC)=O.[OH:56][C:57]([C:60]1[CH:66]=[CH:65][C:63]([NH2:64])=[CH:62][CH:61]=1)([CH3:59])[CH3:58].C(N(C(C)C)C(C)C)C.[O-]CC.[Na+]>C(O)C>[CH2:1]([N:8]([CH2:10][C:11]1[C:12]2[C:43](=[O:45])[N:64]([C:63]3[CH:62]=[CH:61][C:60]([C:57]([OH:56])([CH3:58])[CH3:59])=[CH:66][CH:65]=3)[C:29](=[O:30])[N:28]([CH2:34][C:35]3[C:36]([F:42])=[CH:37][CH:38]=[CH:39][C:40]=3[F:41])[C:13]=2[S:14][C:15]=1[C:16]1[CH:21]=[CH:20][C:19]([NH:22][C:23]([NH:25][O:26][CH3:27])=[O:24])=[CH:18][CH:17]=1)[CH3:9])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)N(Cc1c(F)cccc1F)c1sc(-c2ccc(NC(=O)NOC)cc2)c(CN(C)Cc2ccccc2)c1C(=O)O
Reactant: CC(C)(O)c1ccc(N)cc1
Agent: CCOP(=O)(C#N)OCC
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Solvent: CCN(C(C)C)C(C)C
Product: CONC(=O)Nc1ccc(-c2sc3c(c2CN(C)Cc2ccccc2)c(=O)n(-c2ccc(C(C)(C)O)cc2)c(=O)n3Cc2c(F)cccc2F)cc1
Yield: 21.2 %

Procedure:
The similar reaction as described in Example 40 by using 4-(N-benzyl-N-methylaminomethyl)-2-[N-(2,6-difluorobenzyl)-N-ethoxycarbonylamino]-5-[4-(3-methoxyureido)phenyl]thiophene-3-carboxylic acid (470 mg), diethyl cyanophosphate (167 μl), 4-(1-hydroxy-1-methylethyl)aniline (166 mg) and N-ethyldiisopropylamine (209 μl) gave a crude amide (422 mg). Furthermore, the similar reaction by using ethanol (25.5 ml) and sodium ethoxide (70 mg) gave the title compound (113 mg).
Reaction SMILES: CC1(C)C(C)(C)OB([C:9]2[CH:14]=[CH:13][C:12]([O:15][CH2:16][CH2:17][N:18]([CH2:31][C:32]([F:35])([F:34])[F:33])[C:19]3[CH:26]=[CH:25][C:22]([C:23]#[N:24])=[C:21]([C:27]([F:30])([F:29])[F:28])[CH:20]=3)=[CH:11][CH:10]=2)O1.I[C:38]1[O:39][CH:40]=[CH:41][N:42]=1>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>[O:39]1[CH:40]=[CH:41][N:42]=[C:38]1[C:9]1[CH:10]=[CH:11][C:12]([O:15][CH2:16][CH2:17][N:18]([CH2:31][C:32]([F:33])([F:34])[F:35])[C:19]2[CH:26]=[CH:25][C:22]([C:23]#[N:24])=[C:21]([C:27]([F:28])([F:29])[F:30])[CH:20]=2)=[CH:13][CH:14]=1
Reactant: Ic1ncco1
Reactant: CC1(C)OB(c2ccc(OCCN(CC(F)(F)F)c3ccc(C#N)c(C(F)(F)F)c3)cc2)OC1(C)C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Product: N#Cc1ccc(N(CCOc2ccc(-c3ncco3)cc2)CC(F)(F)F)cc1C(F)(F)F

Procedure:
Synthesized as described in Example 40B from 4-[(2-{[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]oxy}ethyl)(2,2,2-trifluoroethyl)amino]-2-(trifluoromethyl)benzonitrile (Example 40A) and 2-iodo-1,3-oxazole (step A above), with the following exceptions: additional 2-iodo-1,3-oxazole (0.3 equiv) was added after 2 h of heating, additional Pd(PPh3)4 (0.005 g) was added after 4 h of heating, and heating was maintained for only 6 h: MS (ESI) m/z 456 (M+1).
Reaction SMILES: [F:1][C:2]1[C:7]2[C:8]([C:18](=[O:21])[NH:19][CH3:20])=[C:9]([C:11]3[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=3)[O:10][C:6]=2[CH:5]=[CH:4][C:3]=1[C:22]1[C:23]([CH3:33])=[CH:24][C:25]([O:31][CH3:32])=[C:26]([CH:30]=1)[C:27](O)=[O:28].Cl.[N:35]1[CH:40]=[CH:39][C:38]([C:41]2([NH2:44])[CH2:43][CH2:42]2)=[N:37][CH:36]=1.CN([P+](ON1N=NC2C=CC=CC1=2)(N(C)C)N(C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C.O>[F:1][C:2]1[C:7]2[C:8]([C:18]([NH:19][CH3:20])=[O:21])=[C:9]([C:11]3[CH:12]=[CH:13][C:14]([F:17])=[CH:15][CH:16]=3)[O:10][C:6]=2[CH:5]=[CH:4][C:3]=1[C:22]1[CH:30]=[C:26]([C:27](=[O:28])[NH:44][C:41]2([C:38]3[CH:39]=[CH:40][N:35]=[CH:36][N:37]=3)[CH2:43][CH2:42]2)[C:25]([O:31][CH3:32])=[CH:24][C:23]=1[CH3:33]
Reactant: CNC(=O)c1c(-c2ccc(F)cc2)oc2ccc(-c3cc(C(=O)O)c(OC)cc3C)c(F)c12
Reactant: NC1(c2ccncn2)CC1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: O
Product: CNC(=O)c1c(-c2ccc(F)cc2)oc2ccc(-c3cc(C(=O)NC4(c5ccncn5)CC4)c(OC)cc3C)c(F)c12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a mixture of 5-(4-fluoro-2-(4-fluorophenyl)-3-(methylcarbamoyl)benzofuran-5-yl)-2-methoxy-4-methylbenzoic acid (0.080 g, 0.185 mmol, 1.0 eq), 1-(pyrimidin-4-yl)cyclopropanamine HCl (0.025 g, 0.185 mmol, 1.0 eq) in DMF and at 0° C. was added TEA (0.094 g, 0.930 mmol, 5.0 eq) and BOP reagent (0.120 g, 0.271 mmol, 1.5 eq). The reaction mixture was warmed to RT, and stirring was continued at RT overnight. The reaction mixture was diluted with water and extracted with EtOAc. The organic layer was washed with brine, dried over Na2SO4, filtered and concentrated. The crude product was purified by prep HPLC. Yield: 0.058 g (58.0%). 1H NMR (400 MHz, CD3OD): δ 9.03 (s, 1H), 8.64 (d, J=1.4 Hz, 1H), 7.97-7.79 (m., 2H), 7.76 (s, 1H), 7.65 (d, J=5.6 Hz, 1H), 7.52 (d, J=8.4 Hz, 1H), 7.31-7.25 (m, 3H), 7.19 (s, 1H), 4.09 (s, 3H), 2.95 (s, 3H), 2.30 (s, 3H), 1.88-1.85 (m, 2H), 1.55-1.52 (m, 2H). 19F NMR (376.57 MHz, CD3OD): δ −77.58 (TFA), −112.32, −122.76. LCMS: (ES+) m/z=569.2 (M+H)+
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([N:15]2[C:23]3[C:18](=[C:19]([NH:24][S:25]([CH3:28])(=[O:27])=[O:26])[CH:20]=[CH:21][CH:22]=3)[CH:17]=[CH:16]2)([CH2:13][CH3:14])[C:9]([O:11]C)=O)=[CH:4][CH:3]=1.[CH3:29][Li]>C1COCC1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([N:15]2[C:23]3[C:18](=[C:19]([NH:24][S:25]([CH3:28])(=[O:27])=[O:26])[CH:20]=[CH:21][CH:22]=3)[CH:17]=[CH:16]2)([CH2:13][CH3:14])[C:9](=[O:11])[CH3:29])=[CH:4][CH:3]=1
Reactant: [Li]C
Reactant: CCC(C(=O)OC)(c1ccc(Cl)cc1)n1ccc2c(NS(C)(=O)=O)cccc21
Solvent: C1CCOC1
Product: CCC(C(C)=O)(c1ccc(Cl)cc1)n1ccc2c(NS(C)(=O)=O)cccc21
Reaction time: 0.5 h

Procedure:
To a solution of methyl 2-(4-chlorophenyl)-2-(4-(methylsulfonamido)-1H-indol-1-yl)butanoate (1 g, 2.38 mmol), as described in Example 3 Step C, in THF (30 mL) was added CH3Li (3.2 mL, 4.76 mmol, 1.5 M in ether) dropwise at 0° C. and stirred for 0.5 h. The mixture was quenched with saturated ammonium chloride solution, and extracted with ethyl acetate. The organic layer was washed with brine, dried over sodium sulfate, filtered and evaporated. The residue was purified by silica gel chromatography eluting with PE/EA (15/1 to 6/1, v/v) to afford the title compound as a colorless amorphous solid. LC/MS m/z=427.1 [M+Na]+.
Reaction SMILES: C([O:3][C:4]([C:6]1[NH:7][C:8]2[C:13]([CH:14]=1)=[CH:12][C:11]([C:15]1[CH:20]=[CH:19][C:18]([O:21][C:22]([F:25])([F:24])[F:23])=[CH:17][CH:16]=1)=[CH:10][CH:9]=2)=[O:5])C.Br[C:27]1[CH:32]=[CH:31][C:30]([O:33][CH3:34])=[CH:29][CH:28]=1>>[CH3:34][O:33][C:30]1[CH:31]=[CH:32][C:27]([N:7]2[C:8]3[C:13](=[CH:12][C:11]([C:15]4[CH:16]=[CH:17][C:18]([O:21][C:22]([F:23])([F:25])[F:24])=[CH:19][CH:20]=4)=[CH:10][CH:9]=3)[CH:14]=[C:6]2[C:4]([OH:3])=[O:5])=[CH:28][CH:29]=1
Reactant: COc1ccc(Br)cc1
Reactant: CCOC(=O)c1cc2cc(-c3ccc(OC(F)(F)F)cc3)ccc2[nH]1
Product: COc1ccc(-n2c(C(=O)O)cc3cc(-c4ccc(OC(F)(F)F)cc4)ccc32)cc1

Procedure:
The title compound was prepared from 5-(4-(trifluoromethoxy)-phenyl)indole-2-carboxylic acid ethyl ester (prepared in accordance with Example 1(a) from 5-bromoindole-2-carboxylic acid ethyl ester and 4-(trifluoromethoxy)phenylboronic acid) and 1-bromo-4-methoxybenzene in accordance with the procedure described in Example 9(b), followed by hydrolysis in accordance with the procedure described in Example 1(c).
Reaction SMILES: [Br:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH2:4][NH2:5].F[C:11]1[CH:19]=[N:18][CH:17]=[CH:16][C:12]=1[C:13]([OH:15])=[O:14]>>[Br:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH2:4][NH:5][C:16]1[CH:17]=[N:18][CH:19]=[CH:11][C:12]=1[C:13]([OH:15])=[O:14]
Reactant: O=C(O)c1ccncc1F
Reactant: NCc1ccccc1Br
Product: O=C(O)c1ccncc1NCc1ccccc1Br
Yield: 33 %

Procedure:
The title compound was prepared in 33% yield from 2-bromobenzylamine and 3-fluoroisonicotinic acid according to the procedure for the preparation of Example 3. [M+H] calc'd for C13H11BrN2O2, 307, 309; found 307, 309.
Reaction SMILES: [CH3:1][C:2]([CH3:8])=[CH:3][CH2:4][CH2:5][Mg]Br.[CH3:9][Si:10]([CH3:19])([CH3:18])[C:11]1[O:15][CH:14]=[C:13]([CH:16]=[O:17])[CH:12]=1.S(=O)(=O)(O)O>C(OCC)C>[OH:17][CH:16]([C:13]1[CH:12]=[C:11]([Si:10]([CH3:19])([CH3:18])[CH3:9])[O:15][CH:14]=1)[CH2:5][CH2:4][CH:3]=[C:2]([CH3:8])[CH3:1]
Reactant: C[Si](C)(C)c1cc(C=O)co1
Reactant: CC(C)=CCC[Mg]Br
Agent: O=S(=O)(O)O
Solvent: CCOCC
Product: CC(C)=CCCC(O)c1coc([Si](C)(C)C)c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a stirred solution of 4-methyl-3-pentenylmagnesium bromide (0.74 mmol, prepared from 0.74 mmol 5-bromo-2-methyl-2-pentene and 1.46 mmol magnesium) in two ml anhydrous ethyl ether at 0° under argon was added dropwise 5-trimethylsilyl-3-furaldehyde (0.124 g., 0.74 mmol) in 1.5 ml ethyl ether. This solution was allowed to warm to room temperature, stirred for 30 minutes, and then poured over crushed ice containing several drops of concentrated sulfuric acid. The resulting mixture was partitioned between ethyl ether and 5% sodium bicarbonate. The organic portion was washed with water, saturated sodium chloride, dried over magnesium sulfate, filtered and concentrated to give a colorless oil. This material was purified by flash chromatography (silica, 10% ethyl acetate/hexane) to give the desired alcohol.
Reaction SMILES: Br[C:2]1[N:3]=[C:4]2[C:10]([C:11]([NH:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])=[CH:9][N:8]([CH2:18][O:19][CH2:20][CH2:21][Si:22]([CH3:25])([CH3:24])[CH3:23])[C:5]2=[N:6][CH:7]=1.[CH3:26][N:27]1[C:35]2[CH2:34][CH2:33][CH2:32][CH2:31][C:30]=2[C:29]([Sn](CCCC)(CCCC)CCCC)=[N:28]1>CN(C=O)C.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.[Cu]I>[C:14]([NH:13][C:11]([C:10]1[C:4]2[C:5](=[N:6][CH:7]=[C:2]([C:29]3[C:30]4[CH2:31][CH2:32][CH2:33][CH2:34][C:35]=4[N:27]([CH3:26])[N:28]=3)[N:3]=2)[N:8]([CH2:18][O:19][CH2:20][CH2:21][Si:22]([CH3:25])([CH3:24])[CH3:23])[CH:9]=1)=[O:12])([CH3:17])([CH3:16])[CH3:15]
Reactant: CC(C)(C)NC(=O)c1cn(COCC[Si](C)(C)C)c2ncc(Br)nc12
Reactant: CCCC[Sn](CCCC)(CCCC)c1nn(C)c2c1CCCC2
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Product: Cn1nc(-c2cnc3c(n2)c(C(=O)NC(C)(C)C)cn3COCC[Si](C)(C)C)c2c1CCCC2
Temperature: 90 °C
Reaction time: 2.5 h
Yield: 22.1 %

Procedure:
2-Bromo-N-tert-butyl-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxamide (100 mg, 234 μmol) and 1-methyl-3-(tributylstannyl)-4,5,6,7-tetrahydro-1H-indazole (99.5 mg, 234 μmol) were dissolved in DMF (2.5 mL) under argon, tetrakis(triphenylphosphine)palladium (0) (13.5 mg, 11.7 μmol) and CuI (8.91 mg, 46.8 μmol, Eq: 0.20) were added and the mixture sonicated for 5 min with bubbling argon. The reaction mixture was stirred at 90° C. (oil bath temperature) for 2.5 h. The reaction mixture was concentrated under high vacuum and the residue was purified by chromatography (60 g column, 50 μm from Analogix, 0-50% EtOAc in hexanes over 30 min) to give N-tert-butyl-2-(1-methyl-4,5,6,7-tetrahydro-1H-indazol-3-yl)-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxamide (25 mg, 51.8 μmol, 22.1%) as an off-white solid. MS (M+Na)+=505; 1H NMR (CDCl3) δ: 9.12 (s, 1H), 8.33 (s, 1H), 8.02 (s, 1H), 5.73 (s, 2H), 3.90 (s, 3H), 3.54-3.68 (m, 2H), 3.06 (t, J=6.0 Hz, 2H), 2.63-2.78 (m, 2H), 1.91-2.06 (m, 2H), 1.77-1.90 (m, 2H), 1.62 (s, 9H), 0.95-1.02 (m, 2H), 0.00 (s, 9H).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]([C:13](=[O:15])[CH3:14])=[C:11]([CH3:16])[O:10][N:9]=2)=[CH:4][CH:3]=1.[Br:17]Br>C(Cl)(Cl)(Cl)Cl.CC(O)=O>[Br:17][CH2:14][C:13]([C:12]1[C:8]([C:5]2[CH:4]=[CH:3][C:2]([Br:1])=[CH:7][CH:6]=2)=[N:9][O:10][C:11]=1[CH3:16])=[O:15]
Reactant: BrBr
Reactant: CC(=O)c1c(-c2ccc(Br)cc2)noc1C
Solvent: ClC(Cl)(Cl)Cl
Solvent: CC(=O)O
Product: Cc1onc(-c2ccc(Br)cc2)c1C(=O)CBr
Temperature: 25 °C
Yield: 46.7 %

Procedure:
To a solution of 1-[3-(4-bromo-phenyl)-5-methyl-isoxazol-4-yl]-ethanone (2.49 g, 8.89 mmol) in carbontetrachloride (5.8 mL) and AcOH (0.3 mL) at 48° C. was added a solution of bromine (0.48 mL, 8.89 mmol) in carbontetrachloride (4.7 mL) over 10 min keeping the temperature below 50° C. After addition the reaction mixture was allowed to cool down to room temperature and poured into ice-water (20 mL). The layers were separated and the aqueous layer extracted with dichloromethane. The combined organic layers were then washed with water and brine, dried over Na2SO4 and evaporated. Purification by chromatography (SiO2, heptane:ethyl acetate:=8:2) afforded the title compound (1.49 g, 47%) as a light yellow oil. MS m/e: 355.9/358.1/360.0 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=O)=[CH:4][C:3]=1[O:11][CH3:12].[NH2:13][CH:14]1[CH2:19][CH2:18][N:17]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:16][CH2:15]1.CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[NH2:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([NH:13][CH:14]2[CH2:15][CH2:16][N:17]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:18][CH2:19]2)=[O:8])=[CH:4][C:3]=1[O:11][CH3:12]
Reactant: COc1cc(C(=O)O)ccc1N
Reactant: CC(C)(C)OC(=O)N1CCC(N)CC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COc1cc(C(=O)NC2CCN(C(=O)OC(C)(C)C)CC2)ccc1N

Procedure:
To a solution of 4-amino-3-methoxybenzoic acid (Aldrich; 2.4 g, 14.36 mmol) in DMF (100 mL) was added 4-amino-1-bocpiperidine (Aldrich; 3.15 g, 15.72 mmol) and DIPEA (7.5 mL, 43.06 mmol). The resultant solution was carefully treated portionwise (2-3 portions) with HATU (6.88 g, 18.09 mmol) and the resultant mixture was stirred, under nitrogen, at ambient temperature overnight.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:20])[C:4]1[CH:9]=[C:8]([NH2:10])[C:7]([NH:11][CH3:12])=[CH:6][C:5]=1[N:13]1[CH2:17][CH2:16][C:15]([F:19])([F:18])[CH2:14]1.[Cl:21][C:22]1[C:35]([N:36]=[C:37]=S)=[C:34]([Cl:39])[CH:33]=[CH:32][C:23]=1[CH2:24][NH:25][C:26](=[O:31])[C:27]([CH3:30])([CH3:29])[CH3:28].CC(C)N=C=NC(C)C>CN(C=O)C>[CH3:1][O:2][C:3]([C:4]1[C:5]([N:13]2[CH2:17][CH2:16][C:15]([F:19])([F:18])[CH2:14]2)=[CH:6][C:7]2[N:11]([CH3:12])[C:37]([NH:36][C:35]3[C:34]([Cl:39])=[CH:33][CH:32]=[C:23]([CH2:24][NH:25][C:26](=[O:31])[C:27]([CH3:30])([CH3:29])[CH3:28])[C:22]=3[Cl:21])=[N:10][C:8]=2[CH:9]=1)=[O:20]
Reactant: CNc1cc(N2CCC(F)(F)C2)c(C(=O)OC)cc1N
Reactant: CC(C)(C)C(=O)NCc1ccc(Cl)c(N=C=S)c1Cl
Agent: CC(C)N=C=NC(C)C
Solvent: CN(C)C=O
Product: COC(=O)c1cc2nc(Nc3c(Cl)ccc(CNC(=O)C(C)(C)C)c3Cl)n(C)c2cc1N1CCC(F)(F)C1

Procedure:
The title compound is prepared in analogy to 6c from methyl-2-[3,3-difluoro-pyrrolidinyl]-4-methylamino-5-amino-benzoate (1.19 g, 4.17 mmol), and N-(2,4-dichloro-3-isothiocyanato-benzyl)-2,2-dimethyl-propionamide (1.32 g, 4.17 mmol), DIC (0.65 mL, 4.2 mmol) and DMF (20 mL).
Reaction SMILES: [Na].[Br:2][C:3]1[CH:4]=[CH:5][C:6]([N+]([O-])=O)=[N:7][CH:8]=1.[CH3:12][O:13][CH2:14][CH2:15][OH:16]>>[Br:2][C:3]1[CH:4]=[CH:5][C:6]([O:16][CH2:15][CH2:14][O:13][CH3:12])=[N:7][CH:8]=1
Reactant: O=[N+]([O-])c1ccc(Br)cn1
Reactant: COCCO
Agent: [Na]
Product: COCCOc1ccc(Br)cn1
Yield: 86 %

Procedure:
To a stirred solution of sodium (591 mg, 24.6 mmol) in 2-methoxyethanol (20 mL) was added a solution of 5-bromo-2-nitropyridine (17-1, 5.00 g, 24.6 mmol) in 2-methoxyethanol (10 mL) at room temperature. The reaction mixture was stirred at reflux for 2.5 h. The solution was concentrated and the residue was diluted with CH2Cl2 and H2O. The organic layer was dried and evaporated under reduced pressure to give 5-bromo-2-(2-methoxyethoxy)pyridine (17-2, 4.9 g) in 86% yield: 1H NMR (500 MHz, CDCl3) δ 8.16 (d, J=2.6 Hz, 1 H), 7.64 (dd, J=8.7, 2.6 Hz, 1 H), 6.72 (d, J=8.7 Hz, 1 H), 4.43 (t, J=6.6 Hz, 2 H), 3.73 (t, 2H), 3.41 (s, 3 H). ESI-MS: m/z 232.0 (M+H)+.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[CH:5][C:6]2[O:11][C:10]([CH3:13])([CH3:12])[C@@H:9](O)[C@H:8]([N:15](C3C=CN=CC=3)[C:16]([NH2:18])=[O:17])[C:7]=2[CH:25]=1)#[N:2].[CH2:26](N=C=O)[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>C(O)C>[C:1]([C:3]1[CH:4]=[CH:5][C:6]2[O:11][C:10]([CH3:12])([CH3:13])[CH2:9][CH:8]([NH:15][C:16]([NH:18][CH2:26][C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)=[O:17])[C:7]=2[CH:25]=1)#[N:2]
Reactant: CC1(C)Oc2ccc(C#N)cc2[C@@H](N(C(N)=O)c2ccncc2)[C@@H]1O
Reactant: O=C=NCc1ccccc1
Solvent: CCO
Product: CC1(C)CC(NC(=O)NCc2ccccc2)c2cc(C#N)ccc2O1
Yield: 89.7 %

Procedure:
A solution of (-)-4-amino-6-cyano-3,4-dihydro-2,2-dimethyl-2H-1-benzopyran (2.0 g, 9.9 mmole, from Example 19, part B) and benzyl isocyanate (1.32 g, 9.9 mmole) in ethanol (15 ml) under argon was heated at reflux for two hours. The solvent ws recovered under vacuum and the crude product was triturated with isopropyl ether to obtain 2.98 g (89.7%) of the title compound as a pure white solid. m.p.=140-141° C., [α]D25DMF=-41.2°. 1H NMR (DMSO-d6) δ 7.59 (s, 1H), 7.56 (d. J=1.76 Hz, 1H), 7.38-7.22 (m, 5H), 6.89 (d, J=8.21 Hz, 1H), 6.56 (t, J=5.87 Hz, 1H), 6.49 (d, J=8.79 Hz, 1H), 4.94 (m, 1H), 4.30 (d, J=5.87 Hz, 1H), 2.11(dd, J=6.16 and 13.19 Hz, 1H), 1.74 (d, J=12.32 Hz, 1H), 1.41 (s. 3H), 1.28 (s, 3H). 13C NMR (DMSO-d) δ 158.19, 157.27, 140.80, 132.25, 132.15, 128.31, 126.98, 126.69, 126.18, 119.28, 118.13, 102.06., 77.37, 43.08, 42.01, 37.80, 29.15, 24.47. MS: (M+H)+ @336.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:26]=[CH:27][C:28]=1[Cl:29])[O:5][CH:6]1[CH2:11][CH2:10][N:9]([CH2:12][CH:13]2[CH2:18][CH2:17][N:16](C(OC(C)(C)C)=O)[CH2:15][CH2:14]2)[CH2:8][CH2:7]1.C(O)(C(F)(F)F)=O>ClCCl>[Cl:1][C:2]1[CH:3]=[C:4]([CH:26]=[CH:27][C:28]=1[Cl:29])[O:5][CH:6]1[CH2:7][CH2:8][N:9]([CH2:12][CH:13]2[CH2:14][CH2:15][NH:16][CH2:17][CH2:18]2)[CH2:10][CH2:11]1
Reactant: CC(C)(C)OC(=O)N1CCC(CN2CCC(Oc3ccc(Cl)c(Cl)c3)CC2)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Clc1ccc(OC2CCN(CC3CCNCC3)CC2)cc1Cl
Temperature: 25 °C
Reaction time: 1 h
Yield: 64.6 %

Procedure:
1,1-Dimethylethyl 4-[[4-(3,4-dichlorophenoxy)-1-piperidinyl]methyl]-1-piperidinecarboxylate (1.0 g) was added to a mixture of 20% TFA in dichloromethane (20 mL) and the mixture was stirred at room temperature for 1 h. Solvent was removed by evaporation and 2M sodium hydroxide solution (25 mL) was added to the residue. Product was extracted with ethyl acetate. The organic phase was washed with brine, dried, filtered and evaporated to give the title compound (0.5 g).
Reaction SMILES: F[C:2]1[CH:3]=[N:4][C:5]([N:8]2[C:16]3[CH:15]=[CH:14][N:13]=[C:12]([CH3:17])[C:11]=3[N:10]=[CH:9]2)=N[CH:7]=1.[CH3:18]O>[Pd].[Pt].CC(O)=O>[CH3:17][C@H:12]1[C:11]2[N:10]=[CH:9][N:8]([C:5]3[CH:18]=[CH:7][CH:2]=[CH:3][N:4]=3)[C:16]=2[CH2:15][CH2:14][NH:13]1
Reactant: CO
Reactant: Cc1nccc2c1ncn2-c1ncc(F)cn1
Agent: [Pd]
Agent: [Pt]
Solvent: CC(=O)O
Product: C[C@@H]1NCCc2c1ncn2-c1ccccn1

Procedure:
The title compound was prepared in a manner analogous to Example 153, Step D substituting the product from Example 191, Step 2 for 1-(5-fluoropyrimidin-2-yl)-4-methyl-1H-imidazo[4,5-c]pyridine, Pd/C for Pt/C and MeOH for AcOH. MS (ESI) mass calcd. C12H14N4, 214.1. m/z found, 215.1 [M+H]+.
Reaction SMILES: C(N)CN.P([O-])([O-])([O-])=O.[K+].[K+].[K+].[Cl:13][C:14]1[CH:19]=[C:18]([O:20][CH2:21][CH:22]=[C:23]([Cl:25])[Cl:24])[CH:17]=[C:16]([Cl:26])[C:15]=1[O:27][CH2:28][CH2:29][CH2:30][O:31][C:32]1[CH:37]=[CH:36][C:35](I)=[CH:34][CH:33]=1.[O:39]1[CH2:43][CH2:42][NH:41][C:40]1=[O:44]>O1CCOCC1.[Cu]I>[Cl:13][C:14]1[CH:19]=[C:18]([O:20][CH2:21][CH:22]=[C:23]([Cl:25])[Cl:24])[CH:17]=[C:16]([Cl:26])[C:15]=1[O:27][CH2:28][CH2:29][CH2:30][O:31][C:32]1[CH:37]=[CH:36][C:35]([N:41]2[CH2:42][CH2:43][O:39][C:40]2=[O:44])=[CH:34][CH:33]=1
Reactant: O=C1NCCO1
Reactant: ClC(Cl)=CCOc1cc(Cl)c(OCCCOc2ccc(I)cc2)c(Cl)c1
Agent: [Cu]I
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: NCCN
Solvent: C1COCCO1
Product: O=C1OCCN1c1ccc(OCCCOc2c(Cl)cc(OCC=C(Cl)Cl)cc2Cl)cc1

Procedure:
7 mg of copper(I) iodide, 2 mg of ethylenediamine and 155 mg of tripotassium phosphate are added, under argon, to a solution of 200 mg of 1,3-dichloro-5-(3,3-dichloro-allyloxy)-2-[3-(4-iodophenoxy)-propoxy]-benzene and 38 mg of 2-oxazolidinone in 4 ml of dioxane. After 17 hours at 110° C. the reaction mixture is filtered and concentrated. Purification over silica gel yields the title compound (compound 29.3).