Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][C:11]=1F)[C:6]([OH:8])=[O:7])#[N:2].[CH3:13][O:14][CH2:15][CH2:16][OH:17].[H-].[Na+].Cl>C(#N)C>[C:1]([C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][C:11]=1[O:17][CH2:16][CH2:15][O:14][CH3:13])[C:6]([OH:8])=[O:7])#[N:2]
Reactant: COCCO
Reactant: N#Cc1cc(C(=O)O)ccc1F
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CC#N
Product: COCCOc1ccc(C(=O)O)cc1C#N
Temperature: 70 °C
Yield: 93.2 %

Procedure:
3-Cyano-4-fluorobenzoic acid (500 mg, 3.03 mmol), 2-methoxyethanol (461 mg, 6.06 mmol), and 60% w/w NaH (363 mg, 9.08 mmol) were combined in acetonitrile (15 mL) and the reaction mixture was heated at 70° C. overnight. The reaction mixture was made acidic by the addition of 1N HCl and was extracted with ethyl acetate. The organics were dried over sodium sulfate, evaporated and purified by column chromatography (0-10% methanol in dichloromethane) to yield 3-cyano-4-(2-methoxyethoxy)benzoic acid (625 mg, 93%). 1H NMR (400 MHz, CD3CN) δ 9.60 (s, 1H), 8.26 (d, J=1.9 Hz, 1H), 8.22 (dd, J=8.9, 2.2 Hz, 1H), 7.22 (d, J=8.9 Hz, 1H), 4.34 (dd, J=5.2, 3.7 Hz, 2H), 3.79 (dd, J=5.2, 3.6 Hz, 2H), 3.41 (s, 3H). The following compound was synthesized using the procedures described above: 3-cyano-4-propoxybenzoic acid.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](O)=O)=[CH:4][CH:3]=1.[NH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[SH:18].P(Cl)(Cl)Cl.C([O-])(O)=O.[Na+]>C1(C)C=CC=CC=1>[Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]2[S:18][C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=3[N:11]=2)=[CH:4][CH:3]=1
Reactant: Nc1ccccc1S
Reactant: O=C(O)c1ccc(Br)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClP(Cl)Cl
Solvent: Cc1ccccc1
Product: Brc1ccc(-c2nc3ccccc3s2)cc1
Temperature: 25 °C
Yield: 27.9 %

Procedure:
A solution of 15.0 g of 4-bromobenzoic acid (74 mmol) and 13.9 g of 2-aminothiophenol (110 mmol) in 250 mL of dry toluene was heated to 45° C. and 10.1 mL of phosphorus trichloride (110 mmol) was slowly added to the reaction mixture via syringe. The mixture was allowed to reflux for 4 h. The reaction mixture was cooled to room temperature, filtered and the filtrate was concentrated under reduced pressure to afford a yellow solid. The solid was slowly added to 500 mL of saturated aq. NaHCO3 and the aqueous solution was extracted with 2×200 mL of ethyl acetate. The combined organic solutions were washed with water (3x), dried over sodium sulfate and concentrated to dryness. The crude product was purified by column chromatography to afford 6.0 g of 2-(4-bromophenyl)benzothiazole.
Reaction SMILES: [CH2:1]([C:9]1[N:13]=[C:12]([C:14]2[CH:21]=[CH:20][C:17]([CH:18]=O)=[CH:16][CH:15]=2)[O:11][N:10]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].[Cl:22][C:23]1[CH:24]=[C:25]([CH2:30][CH2:31][NH2:32])[CH:26]=[CH:27][C:28]=1[Cl:29]>>[Cl:22][C:23]1[CH:24]=[C:25]([CH2:30][CH2:31][NH:32][CH2:18][C:17]2[CH:20]=[CH:21][C:14]([C:12]3[O:11][N:10]=[C:9]([CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8])[N:13]=3)=[CH:15][CH:16]=2)[CH:26]=[CH:27][C:28]=1[Cl:29]
Reactant: CCCCCCCCc1noc(-c2ccc(C=O)cc2)n1
Reactant: NCCc1ccc(Cl)c(Cl)c1
Product: CCCCCCCCc1noc(-c2ccc(CNCCc3ccc(Cl)c(Cl)c3)cc2)n1

Procedure:
The same procedure as employed in the preparation of Example 357 (step a) but using 4-(3-octyl-1,2,4-oxadiazol-5-yl)benzaldehyde and 2-(3,4-dichlorophenyl)ethylamine gave the title compound as an oil.
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][O:11][C@H:10]([CH2:14][C:15]2[CH:20]=[CH:19][C:18]([OH:21])=[C:17]([Br:22])[CH:16]=2)[CH2:9]1)(OC(C)(C)C)=O.C(=O)([O-])[O-].[K+].[K+].Br[CH2:30][CH2:31][O:32][CH3:33]>CC(C)=O>[Br:22][C:17]1[CH:16]=[C:15]([CH:20]=[CH:19][C:18]=1[O:21][CH2:30][CH2:31][O:32][CH3:33])[CH2:14][C@H:10]1[O:11][CH2:12][CH2:13][NH:8][CH2:9]1
Reactant: CC(C)(C)OC(=O)N1CCO[C@H](Cc2ccc(O)c(Br)c2)C1
Reactant: COCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: COCCOc1ccc(C[C@@H]2CNCCO2)cc1Br
Temperature: 55 °C
Reaction time: 16 h

Procedure:
N-BOC-(R)-2-(3-bromo-4-hydroxybenzyl)morpholine, example 4, intermediate (a), (70 mg, 0.19 mmo) was dissolved in acetone (1.5 mL) and treated with potassium carbonate (78 mg, 0.56 mmol) and 2-bromoethylmethyl ether (78 mg, 0.56 mmol) was added and the resulting reaction was shaken at 55° C. for 16 hrs. The reaction was filtered and concentrated under a flow of nitrogen. The crude residue was dissolved in tetrahydrofuran (8 mL) with polymer supported diphenylphosphine (0.5 g) and shaken for 4 hrs. The reaction was then filtered and concentrated under a high flow of nitrogen. The crude residue was dissolved in TFA (20% v/v solution in dichloromethane, 2.5 mL) and shaken for 3 hrs at room temperature. The reaction mixture was added directly to an SCX-2 column (2 g) and washed with dichloromethane (2 mL×2) and methanol (2 mL×2). The SCX-2 column was then washed with ammonia (2N in methanol, 3×2 mL). Combined ammonia washes were concentrated in vacuo to yield the desired morpholine example 36 as a colorless oil (31 mg).
Reaction SMILES: Cl[C:2]1[C:7]([Cl:8])=[C:6]([Cl:9])[CH:5]=[CH:4][C:3]=1[N+:10]([O-:12])=[O:11].[C:13]([N:23]1[CH2:28][CH2:27][NH:26][CH:25]([C:29]([OH:31])=[O:30])[CH2:24]1)([O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[O:14]>>[C:13]([N:23]1[CH2:28][CH2:27][N:26]([C:2]2[C:7]([Cl:8])=[C:6]([Cl:9])[CH:5]=[CH:4][C:3]=2[N+:10]([O-:12])=[O:11])[CH:25]([C:29]([OH:31])=[O:30])[CH2:24]1)([O:15][CH2:16][C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1)=[O:14]
Reactant: O=C(O)C1CN(C(=O)OCc2ccccc2)CCN1
Reactant: O=[N+]([O-])c1ccc(Cl)c(Cl)c1Cl
Product: O=C(O)C1CN(C(=O)OCc2ccccc2)CCN1c1c([N+](=O)[O-])ccc(Cl)c1Cl
Yield: 43.6 %

Procedure:
By the same procedure described for Example 7 A, from 0.86 g of 2,3,4-trichloronitro-benzene and 1.0 g of 4-carbobenzyloxypiperazine-2-carboxylic acid, there was obtained 0.75 g of the desired product as a brown oil.
Reaction SMILES: [NH2:1][C:2]1[C:6]2[N:7]=[C:8]([C:10](=[O:21])[NH:11][C:12]([CH3:20])([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[CH3:13])[S:9][C:5]=2[N:4]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[N:3]=1.Cl.Cl.[CH3:31][N:32]1[CH2:37][CH2:36][N:35]([C:38]2[CH:46]=[CH:45][C:41]([C:42](Cl)=[O:43])=[CH:40][CH:39]=2)[CH2:34][CH2:33]1.[Cl-].[Na+]>N1C=CC=CC=1>[CH3:13][C:12]([NH:11][C:10]([C:8]1[S:9][C:5]2[N:4]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[N:3]=[C:2]([NH:1][C:42](=[O:43])[C:41]3[CH:40]=[CH:39][C:38]([N:35]4[CH2:34][CH2:33][N:32]([CH3:31])[CH2:37][CH2:36]4)=[CH:46][CH:45]=3)[C:6]=2[N:7]=1)=[O:21])([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[CH3:20]
Reactant: CN1CCN(c2ccc(C(=O)Cl)cc2)CC1
Reactant: CC(C)(C)OC(=O)n1nc(N)c2nc(C(=O)NC(C)(C)c3ccccc3)sc21
Agent: Cl
Agent: [Cl-]
Agent: [Na+]
Solvent: c1ccncc1
Product: CN1CCN(c2ccc(C(=O)Nc3nn(C(=O)OC(C)(C)C)c4sc(C(=O)NC(C)(C)c5ccccc5)nc34)cc2)CC1
Temperature: 25 °C
Reaction time: 15 h
Yield: 43.7 %

Procedure:
2.0 g (5.0 mmol) of tert-butyl 3-amino-5-(1-methyl-1-phenylethylcarbamoyl)-1H-pyrazolo[4,3-d]thiazole-1-carboxylate dissolved in 40 ml of pyridine are placed in a 250 ml round-bottomed flask under argon. 1.56 g (5.0 mmol) of 4-(4-methylpiperazin-1-yl)benzoyl chloride dihydrochloride (prepared according to WO 2005/113494) are then gradually added and the mixture is stirred for 15 hours at 25° C. The reaction medium is then concentrated to dryness under reduced pressure (40° C.) and the residue is taken up in 50 ml of dichloromethane and 50 ml of water, and basified with 0.1N sodium hydroxide solution. The emulsion obtained is resorbed by saturation with sodium chloride. After separation of the phases by settling, the organic phase is dried over magnesium sulfate and concentrated to dryness under reduced pressure. The residue is purified by flash chromatography (msilica=30 g; eluent: 95/5 dichloromethane/methanol). 1.32 g of tert-butyl 5-(1-methyl-1-phenylethylcarbamoyl)-3-[4-(4-methylpiperazin-1-yl)benzoylamino]-1H-pyrazolo[4,3-d]thiazole-1-carboxylate are thus obtained in the form of a yellow foam. 1H NMR (400 MHz, DMSO-d6): δ ppm 1.62 (s, 9H); 1.70 (s, 6H); 2.22 (s, 3H); 2.44 (m, 4H); 3.32 (m, 4H); 7.02 (d, J=8.5 Hz, 2H); 7.20 (t, J=7.5 Hz, 1H); 7.30 (t, J=7.5 Hz, 2H); 7.40 (d, J=7.5 Hz, 2H); 7.95 (d, J=8.5 Hz, 2H); 8.71 (s, 1H); 11.05 (s, 1H). LC-MS-DAD-ELSD: 602(−)=(M−H)(−); 604(+)=(M+H)(+).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]2[C:12](=[CH:13][CH:14]=1)[NH:11][C:10]1[CH:9]([C:15]3[CH:20]=[CH:19][CH:18]=[C:17]([OH:21])[CH:16]=3)[NH:8][CH2:7][CH2:6][C:5]2=1.CCN(CC)CC.[NH:29]([C:41]([O:43][C:44]([CH3:47])([CH3:46])[CH3:45])=[O:42])[CH2:30][C:31](ON1C(=O)CCC1=O)=[O:32]>C1COCC1>[C:44]([O:43][C:41]([NH:29][CH2:30][C:31]([N:8]1[CH2:7][CH2:6][C:5]2[C:4]3[C:12](=[CH:13][CH:14]=[C:2]([CH3:1])[CH:3]=3)[NH:11][C:10]=2[CH:9]1[C:15]1[CH:16]=[C:17]([OH:21])[CH:18]=[CH:19][CH:20]=1)=[O:32])=[O:42])([CH3:47])([CH3:46])[CH3:45]
Reactant: CC(C)(C)OC(=O)NCC(=O)ON1C(=O)CCC1=O
Reactant: Cc1ccc2[nH]c3c(c2c1)CCNC3c1cccc(O)c1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: Cc1ccc2[nH]c3c(c2c1)CCN(C(=O)CNC(=O)OC(C)(C)C)C3c1cccc(O)c1
Reaction time: 2 h

Procedure:
To a solution of 6-methyl-1-(3-hydroxyphenyl)-1,2,3,4-tetrahydro-beta-carboline (1 equiv) in THF was added Et3N (2.2 equiv) and Boc-Gly-OSu (1.2 equiv). After 2 h, the solvent was removed to give a residue, which was purified via prep-HPLC to give 3-{2-[N-(tert-butoxycarbonyl)-glycyl]-6-methyl-2,3,4,9-tetrahydro-1H-beta-carbolin-1-yl)}phenol 11.
Reaction SMILES: Cl.Cl.Cl.[O:4]1[C:8]2[CH:9]=[CH:10][CH:11]=[C:12]([N:13]3[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][C@H:21]4[CH2:26][CH2:25][C@H:24]([NH2:27])[CH2:23][CH2:22]4)[CH2:15][CH2:14]3)[C:7]=2[O:6][CH2:5]1.[OH:28][C:29]1([C:33](O)=[O:34])[CH2:32][CH2:31][CH2:30]1>>[O:4]1[C:8]2[CH:9]=[CH:10][CH:11]=[C:12]([N:13]3[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][C@H:21]4[CH2:26][CH2:25][C@H:24]([NH:27][C:33]([C:29]5([OH:28])[CH2:32][CH2:31][CH2:30]5)=[O:34])[CH2:23][CH2:22]4)[CH2:15][CH2:14]3)[C:7]=2[O:6][CH2:5]1
Reactant: O=C(O)C1(O)CCC1
Reactant: N[C@H]1CC[C@H](CCN2CCN(c3cccc4c3OCO4)CC2)CC1
Agent: Cl
Product: O=C(N[C@H]1CC[C@H](CCN2CCN(c3cccc4c3OCO4)CC2)CC1)C1(O)CCC1

Procedure:
The title compound, white solid (15 mg, 48.7%), MS (ISP) m/z=430.2 [(M+H)+], was prepared in accordance with the general method of example 1 from Trans-4-[2-(4-Benzo[1,3]dioxol-4-yl-piperazin-1-yl)-ethyl]-cyclohexylamine trihydrochloride (Intermediate A) (30 mg, 68.1 mmol) and 1-hydroxycyclobutancarboxylic acid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[C:11](=[O:26])[NH:12][C:13]1[CH:18]=[CH:17][C:16]([Cl:19])=[C:15]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=2)[CH:14]=1)[C:5]([OH:7])=O.[NH2:27][C:28]1[CH:29]=[N:30][CH:31]=[CH:32][CH:33]=1>>[Cl:1][C:2]1[CH:3]=[C:4]([C:5]([NH:27][C:28]2[CH:29]=[N:30][CH:31]=[CH:32][CH:33]=2)=[O:7])[CH:8]=[CH:9][C:10]=1[C:11]([NH:12][C:13]1[CH:18]=[CH:17][C:16]([Cl:19])=[C:15]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=2)[CH:14]=1)=[O:26]
Reactant: O=C(O)c1ccc(C(=O)Nc2ccc(Cl)c(-c3ccccn3)c2)c(Cl)c1
Reactant: Nc1cccnc1
Product: O=C(Nc1cccnc1)c1ccc(C(=O)Nc2ccc(Cl)c(-c3ccccn3)c2)c(Cl)c1

Procedure:
50 mg of 3-chloro-4-(4-chloro-3-(pyridin-2-yl)phenylcarbamoyl)benzoic acid was coupled to 3-aminopyridine via Procedure G. The product was purified on reverse phase HPLC to yield 2-chloro-N1-(4-chloro-3-(pyridin-2-yl)phenyl)-N4-(pyridin-3-yl)terephthalamide. MS (Q1) 463 (M)+.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:34]=[CH:35][CH:36]=1)[CH2:5][N:6]([C@@H:24]1[C:33]2[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=2)[CH2:27][CH2:26][CH2:25]1)[C:7]([C:9]1[CH:14]=[C:13]([C:15]([OH:17])=[O:16])[C:12]([C:18]([OH:20])=[O:19])=[CH:11][C:10]=1[C:21]([OH:23])=[O:22])=[O:8].[Cl:37][C:38]1[CH:39]=[C:40](B(O)O)[CH:41]=[CH:42][C:43]=1[F:44]>>[Cl:37][C:38]1[CH:39]=[C:40]([C:2]2[CH:36]=[CH:35][CH:34]=[C:4]([CH2:5][N:6]([C@@H:24]3[C:33]4[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=4)[CH2:27][CH2:26][CH2:25]3)[C:7]([C:9]3[CH:14]=[C:13]([C:15]([OH:17])=[O:16])[C:12]([C:18]([OH:20])=[O:19])=[CH:11][C:10]=3[C:21]([OH:23])=[O:22])=[O:8])[CH:3]=2)[CH:41]=[CH:42][C:43]=1[F:44]
Reactant: O=C(O)c1cc(C(=O)O)c(C(=O)N(Cc2cccc(Br)c2)[C@H]2CCCc3ccccc32)cc1C(=O)O
Reactant: OB(O)c1ccc(F)c(Cl)c1
Product: O=C(O)c1cc(C(=O)O)c(C(=O)N(Cc2cccc(-c3ccc(F)c(Cl)c3)c2)[C@H]2CCCc3ccccc32)cc1C(=O)O

Procedure:
The product from Example 15B (165 mg, 0.3 mmol) and 3-chloro-4-fluorophenylboronic acid were processed as described in Example 85 to provide the title compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([NH2:9])=[C:5]([NH2:10])[CH:4]=1.C(N(CC)CC)C.Br[CH:19]([C:25](OCC)=[O:26])[C:20]([O:22][CH2:23][CH3:24])=[O:21]>C(O)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:6](=[CH:7][CH:8]=1)[N:9]=[C:19]([C:20]([O:22][CH2:23][CH3:24])=[O:21])[C:25](=[O:26])[NH:10]2
Reactant: COc1ccc(N)c(N)c1
Reactant: CCOC(=O)C(Br)C(=O)OCC
Solvent: CCO
Solvent: CCN(CC)CC
Product: CCOC(=O)c1nc2ccc(OC)cc2[nH]c1=O

Procedure:
A solution of 4-methoxy-o-phenylenediamine (9.5 g) and triethylamine (7 g) in ethanol (100 ml) was cooled to 0°-5° and stirred in an atmosphere of nitrogen. Diethyl bromomalonate (23.7 g) in ethaol (50 ml) was added during 30 minutes. The temperature of the mixture was maintained at 0°-5° for a further 6 hours and then allowed to rise to 20° and stirred at this temperature for 16 hours. The solid was filtered off, stirred with dilute hydrochloric acid (400 ml., 0.2N), filtered off, washed with water, dried and crystallised from a mixture of ethyl acetate and methanol, m.p. 229°.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][CH:9]2[CH2:14][CH2:13][N:12]([C:15](=[O:25])[CH2:16][C:17]3[CH:24]=[CH:23][C:20]([CH:21]=O)=[CH:19][CH:18]=3)[CH2:11][CH2:10]2)=[CH:4][CH:3]=1.[CH3:26][C@@H:27]1[CH2:32][NH:31][CH2:30][C@H:29]([CH3:33])[N:28]1[C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C([O-])(O)=O.[Na+]>ClCCCl>[F:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][CH:9]2[CH2:10][CH2:11][N:12]([C:15](=[O:25])[CH2:16][C:17]3[CH:18]=[CH:19][C:20]([CH2:21][N:31]4[CH2:32][C@H:27]([CH3:26])[N:28]([C:34]([O:36][C:37]([CH3:38])([CH3:40])[CH3:39])=[O:35])[C@H:29]([CH3:33])[CH2:30]4)=[CH:23][CH:24]=3)[CH2:13][CH2:14]2)=[CH:6][CH:7]=1
Reactant: O=Cc1ccc(CC(=O)N2CCC(Nc3ccc(F)cc3)CC2)cc1
Reactant: C[C@@H]1CNC[C@H](C)N1C(=O)OC(C)(C)C
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCCl
Product: C[C@@H]1CN(Cc2ccc(CC(=O)N3CCC(Nc4ccc(F)cc4)CC3)cc2)C[C@H](C)N1C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 60.6 %

Procedure:
A mixture of D4 (149 mg, 0.438 mmol) and 1,1-dimethylethyl (2R,6S)-2,6-dimethyl-1-piperazinecarboxylate (94 mg, 0.438 mmol) in 1,2-DCE (3 ml) was stirred for 5 mins at room temperature. Sodium tri(acetoxy)borohydride (139 mg, 0.66 mmol) was added and the mixture was stirred for 3 h then saturated aq. NaHCO3 solution was added. The mixture was stirred for 15 mins then extracted with EtOAc. The combined extracts were dried (Na2SO4) and concentrated in vacuo to give the crude product which was purified by chromatography. Elution with 20-90% EtOAc/pentane gave 1,1-dimethylethyl (2R,6S)-4-{[4-(2-{4-[(4-fluorophenyl)amino]-1-piperidinyl}-2-oxoethyl)phenyl]methyl}-2,6-dimethyl-1-piperazinecarboxylate (143 mg). δH (CDCl3, 400 MHz) 1.06 (1H, m), 1.27 (6H, d), 1.30 (1H, m), 1.46 (9H, s), 1.93 (1H, m), 2.05 (1H, m), 2.12 (2H, dd), 2.59 (2H, d), 2.88 (1H, m), 3.13 (1H, m), 3.29 (1H, m), 3.38 (1H, m), 3.45 (2H, s), 3.74 (2H, s), 3.86 (1H, m), 4.07 (2H, m), 4.50 (1H, m), 6.50 (2H, m), 6.87 (2H, t), 7.20 (2H, m), 7.31 (2H, d). MS (ES): MH+ 539
Reaction SMILES: [C:1]([O:5][C:6]([CH:8]1[CH:14]([C:15](O)=[O:16])[CH2:13][CH:12]=[CH:11][CH2:10][N:9]1[S:18]([C:21]1[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][CH:22]=1)(=[O:20])=[O:19])=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.ClC(OCC(C)C)=O>C1COCC1>[C:1]([O:5][C:6]([CH:8]1[CH:14]([CH2:15][OH:16])[CH2:13][CH:12]=[CH:11][CH2:10][N:9]1[S:18]([C:21]1[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][CH:22]=1)(=[O:20])=[O:19])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: COc1ccc(S(=O)(=O)N2CC=CCC(C(=O)O)C2C(=O)OC(C)(C)C)cc1
Agent: CC(C)COC(=O)Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: COc1ccc(S(=O)(=O)N2CC=CCC(CO)C2C(=O)OC(C)(C)C)cc1
Reaction time: 1 h

Procedure:
To a stirred solution of 1-(4-Methoxy-benzenesulfonyl)-2,3,4,7-tetrahydro-1H-azepine-2,3-dicarboxylic acid 2-tert-butyl ester (1.17 g, 2.65 mmoL) in 26.5 mL THF at 0° C. was added triethylamine (0.406 mL, 2.915 mmoL) followed by isobutyl chloroformate (0.378 mL, 2.915 mmoL). This suspention was allowed to stir for one hour. The suspention was then filtered into a dropping funnel which was added dropwise to a previously prepared sodium borohydride (321 mg, 8,48 mmoL) solution in 1.63 mL of water at 0° C. After 2.5 hours the solvent was stripped and the residue was diluted with ethyl acetate and water. The solution was washed once with 0.5N HCL, the layers separated, and the organic layer was dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by column chromatography (silica: 25% to 35% ethyl acetate in hexanes) to yield 3-Hydroxymethyl-1-(4-methoxy-benzenesulfonyl)-2,3,4,7-tetrahydro-1H-azepine-2-carboxylic acid tert butyl ester; MS: (M+H)+ =398, (M+NH4)+ =415.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([OH:15])[CH2:9][N:10]2[CH:14]=[N:13][CH:12]=[N:11]2)=[CH:4][CH:3]=1.[H-].[Na+].[CH2:18](Br)[CH2:19][CH2:20][CH3:21]>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([O:15][CH2:18][CH2:19][CH2:20][CH3:21])[CH2:9][N:10]2[CH:14]=[N:13][CH:12]=[N:11]2)=[CH:4][CH:3]=1
Reactant: OC(Cn1cncn1)c1ccc(Cl)cc1
Reactant: CCCCBr
Agent: [H-]
Agent: [Na+]
Product: CCCCOC(Cn1cncn1)c1ccc(Cl)cc1

Procedure:
Following the procedure of Example 9, Step 2, 1-p-chlorophenyl-2-(1,2,4-triazol-1-yl)-ethanol (2.23 g), sodium hydride (440 mg; 50%) and n-butyl bromide (1.37 g) were reacted to give the title compound as an oil.
Reaction SMILES: [CH3:1][C:2]1[C:39]([CH3:40])=[CH:38][CH:37]=[CH:36][C:3]=1[O:4][CH2:5][CH2:6][CH2:7][C:8]([N:10]1[C:19]2[C:14](=[C:15]([C:20]3[CH:21]=[N:22][N:23]([CH2:25][C:26]4[CH:31]=[CH:30][CH:29]=[C:28]([O:32][CH2:33][CH2:34]O)[CH:27]=4)[CH:24]=3)[CH:16]=[CH:17][CH:18]=2)[CH2:13][CH2:12][CH2:11]1)=[O:9].[C:41]([O:45][C:46]([NH:48][C:49]([NH:51][C:52]([O:54][C:55]([CH3:58])([CH3:57])[CH3:56])=[O:53])=[NH:50])=[O:47])([CH3:44])([CH3:43])[CH3:42].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CCOC(/N=N/C(OCC)=O)=O>C(Cl)Cl>[C:55]([O:54][C:52]([NH:51][C:49](=[N:48][C:46](=[O:47])[O:45][C:41]([CH3:44])([CH3:43])[CH3:42])[NH:50][CH2:34][CH2:33][O:32][C:28]1[CH:29]=[CH:30][CH:31]=[C:26]([CH2:25][N:23]2[CH:24]=[C:20]([C:15]3[CH:16]=[CH:17][CH:18]=[C:19]4[C:14]=3[CH2:13][CH2:12][CH2:11][N:10]4[C:8](=[O:9])[CH2:7][CH2:6][CH2:5][O:4][C:3]3[CH:36]=[CH:37][CH:38]=[C:39]([CH3:40])[C:2]=3[CH3:1])[CH:21]=[N:22]2)[CH:27]=1)=[O:53])([CH3:58])([CH3:57])[CH3:56]
Reactant: CC(C)(C)OC(=O)NC(=N)NC(=O)OC(C)(C)C
Reactant: Cc1cccc(OCCCC(=O)N2CCCc3c(-c4cnn(Cc5cccc(OCCO)c5)c4)cccc32)c1C
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: Cc1cccc(OCCCC(=O)N2CCCc3c(-c4cnn(Cc5cccc(OCCNC(=NC(=O)OC(C)(C)C)NC(=O)OC(C)(C)C)c5)c4)cccc32)c1C
Temperature: 25 °C
Reaction time: 1 h
Yield: 90 %

Procedure:
To a solution of 4-(2,3-dimethylphenoxy)-1-(5-(1-(3-(2-hydroxyethoxy)benzyl)-1H-pyrazol-4-yl)-3,4-dihydroquinolin-1(2H)-yl)butan-1-one (0.02 g, 0.037 mmol), 1,3-bis(tert-butoxycarbonyl)-guanidine (0.024 g, 0.093 mmol), triphenylphosphine (0.024 g, 0.093 mmol) in DCM (0.1 mL) was added DEAD (0.040 g, 0.093 mmol, 40% wt in toluene). The reaction mixture was stirred at room temperature for 1 h and then concentrated. The resulting residue was purified by flash chromatography (0-100% ethyl acetate:hexanes) to afford the title compound (0.026 g, 90% yield) as a white powder. LCMS, [M+H]+=781.3.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH:21]([CH3:23])[CH3:22])[C:6]2[O:10][C:9]([C:11]3[CH:19]=[CH:18][C:14]([C:15](O)=[O:16])=[CH:13][CH:12]=3)=[N:8][C:7]=2[CH:20]=1)#[N:2].[C:24]([O:28][C:29]([N:31]1[CH2:36][CH2:35][CH:34]([CH:37]([NH2:42])[C:38]([O:40][CH3:41])=[O:39])[CH2:33][CH2:32]1)=[O:30])([CH3:27])([CH3:26])[CH3:25].F[P-](F)(F)(F)(F)F.Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1.C(N(CC)C(C)C)(C)C>CN(C)C=O>[C:24]([O:28][C:29]([N:31]1[CH2:36][CH2:35][CH:34]([CH:37]([NH:42][C:15](=[O:16])[C:14]2[CH:13]=[CH:12][C:11]([C:9]3[O:10][C:6]4[C:5]([CH:21]([CH3:23])[CH3:22])=[CH:4][C:3]([C:1]#[N:2])=[CH:20][C:7]=4[N:8]=3)=[CH:19][CH:18]=2)[C:38]([O:40][CH3:41])=[O:39])[CH2:33][CH2:32]1)=[O:30])([CH3:27])([CH3:26])[CH3:25]
Reactant: CC(C)c1cc(C#N)cc2nc(-c3ccc(C(=O)O)cc3)oc12
Reactant: COC(=O)C(N)C1CCN(C(=O)OC(C)(C)C)CC1
Agent: Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)C(NC(=O)c1ccc(-c2nc3cc(C#N)cc(C(C)C)c3o2)cc1)C1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
At room temperature, a 2-dram vial equipped with a magnetic stirrer was charged with 4-(5-cyano-7-isopropyl-1,3-benzoxazol-2-yl)benzoic acid (INTERMEDIATE 2), 4-(amino-methoxycarbonyl-methyl)-piperidine-1-carboxylic acid tert-butyl ester, bromo-tris-pyrrolidino phosphonium hexafluorophosphate, and dimethylformamide (5 ml). To this mixture was added of N,N-diisopropylethylamine, dropwise. The reaction mixture was allowed to stir at room temperature for 3 d. The residue was purified by flash chromatography using a Biotage SP 1, 40M silica cartridge, eluting with a linear gradient of 20% to 100% hexanes in ethyl acetate over 15 column volumes to provide the title compound. Mass spectrum (ESI) 559.3 (M+1).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH:7]=[CH:8][C:9]1[C:17]2[C:12](=[CH:13][C:14]([NH:18][C:19]3[CH:27]=[CH:26][CH:25]=[CH:24][C:20]=3[C:21](O)=[O:22])=[CH:15][CH:16]=2)[NH:11][N:10]=1.[CH:28]1([NH2:31])[CH2:30][CH2:29]1.C(N(CC)CC)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[CH:28]1([NH:31][C:21](=[O:22])[C:20]2[CH:24]=[CH:25][CH:26]=[CH:27][C:19]=2[NH:18][C:14]2[CH:13]=[C:12]3[C:17]([C:9](/[CH:8]=[CH:7]/[C:2]4[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=4)=[N:10][NH:11]3)=[CH:16][CH:15]=2)[CH2:30][CH2:29]1
Reactant: NC1CC1
Reactant: O=C(O)c1ccccc1Nc1ccc2c(C=Cc3ccccn3)n[nH]c2c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: O=C(NC1CC1)c1ccccc1Nc1ccc2c(/C=C/c3ccccn3)n[nH]c2c1
Reaction time: 8 h
Yield: 35.2 %

Procedure:
A solution of 2-[3-(2-Pyridin-2-yl-vinyl)-1H-indazol-6-ylamino]-benzoic acid (50.0 mg, 0.084 mmol), cyclopropyl amin (11.6 μL, 0.17 mmol), triethylamine (58 μl, 0.25 mmol), dissolved in DMF (0.8 mL), was treated with HATU (48 mg, 0.13 mmol). The mixture was stirred overnight, then purified by reverse phase HPLC yielding 11.7 mg (35%) of the title compound as a yellow solid. 1H NMR (DMSO-d6): δ 9.81 (1H, s), 8.68 (1H, d, J=1.7), 8.51 (1H, s), 8.01 (4H, m), 7.50 (5H, m), 7.24 (1H, s), 7.03 (1H, d, J=5.3), 6.89 (1H, t, J=4.2), 2.84 (1H, m), 0.72 (2H, m), 0.56 (2H, m). ESIMS (M+H+): 396.1.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]([OH:11])([CH3:10])[CH3:9])=[N:6][CH:7]=1.[H-].[Na+].[CH3:14]I>CN(C=O)C>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]([O:11][CH3:14])([CH3:9])[CH3:10])=[N:6][CH:7]=1
Reactant: CI
Reactant: CC(C)(O)c1ccc(Br)cn1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(C)(C)c1ccc(Br)cn1
Reaction time: 0.5 h
Yield: 108.6 %

Procedure:
2-(5-bromopyridin-2-yl)propan-2-ol (50 mg, 0.2 mmol, from Example 184, Step 3) was added to a mixture of NaH in mineral oil (10 mg, 0.5 mmol) in DMF (5 mL). The reaction was stirred for 30 min and the methyl iodide (30 μL, 0.5 mmol) was added and stirred for 2 hours. The reaction was partitioned between EtOAc and water. The combined organic layer was washed with brine, dried over MgSO4, filtered and concentrated to give crude product 5-bromo-2-(1-methoxy-1-methylethyl)pyridine as an oil (0.05 g, 90%). LCMS calculated for C9H13BrNO (M+H)+: m/z=230.0, 232.0. found: 230.0, 231.8.