Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@H:12]1[CH2:17][CH2:16][N:15](C(OC(C)(C)C)=O)[CH2:14][C@H:13]1[F:25])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[F:25][C@H:13]1[C@@H:12]([NH:11][C:9](=[O:10])[O:8][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[CH2:17][CH2:16][NH:15][CH2:14]1
Reactant: CC(C)(C)OC(=O)N1CC[C@H](NC(=O)OCc2ccccc2)[C@H](F)C1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(N[C@H]1CCNC[C@H]1F)OCc1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 78.9 %

Procedure:
(cis)-tert-Butyl 4-(benzyloxycarbonylamino)-3-fluoropiperidine-1-carboxylate (7.5 g, 21.3 mmol) was weighed into a 500 mL 1 neck round bottom and dissolved in 200 mL of DCM, followed by addition of TFA (16.4 mL, 213 mmol) and stirring at ambient temperature for 1 hour, at which time all bubbling had ceased and the reaction appeared complete by TLC. The crude reaction was concentrated in vacuo, followed by aqueous work-up with 2 N NaOH and DCM. The combined organics were dried over Na2SO4, filtered and concentrated in vacuo to afford benzyl(cis)-3-fluoropiperidin-4-ylcarbamate (4.25 g, 16.8 mmol, 79.2% yield) as a white solid.
Reaction SMILES: [CH2:1]([C:5]1([CH3:12])[CH2:10][CH2:9][CH2:8][CH2:7][C:6]1=[O:11])[CH:2]([CH3:4])[CH3:3].[Br:13]C1CC(C(C)C)CCC1=O>>[Br:13][CH:7]1[C:6](=[O:11])[C:5]([CH2:1][CH:2]([CH3:4])[CH3:3])([CH3:12])[CH2:10][CH2:9][CH2:8]1
Reactant: CC(C)C1CCC(=O)C(Br)C1
Reactant: CC(C)CC1(C)CCCCC1=O
Product: CC(C)CC1(C)CCCC(Br)C1=O

Procedure:
The bromination of 2-isobutyl-2-methyl-cyclohexanone takes place in a manner similar to that described above for the preparation of 2-bromo-4-isopropyl-cyclohexanone. The title compound is reacted as a crude product without further characterization.
Reaction SMILES: O[C:2]1[CH:7]=[CH:6][C:5]([C:8]#[C:9][C:10]2[CH:11]=[C:12]3[C:16](=[CH:17][CH:18]=2)[NH:15][C:14](=[O:19])/[C:13]/3=[CH:20]\[C:21]2[NH:22][CH:23]=[CH:24][CH:25]=2)=[CH:4][CH:3]=1.C(C1C=C2C(=CC=1)NC(=O)/C/2=C\C1NC=CC=1)#C.BrC1C=CC=CC=1[N+:51]([O-:53])=[O:52].C(N(CC)CC)C>[Cu]I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.CN(C=O)C>[N+:51]([C:6]1[CH:7]=[CH:2][CH:3]=[CH:4][C:5]=1[C:8]#[C:9][C:10]1[CH:11]=[C:12]2[C:16](=[CH:17][CH:18]=1)[NH:15][C:14](=[O:19])/[C:13]/2=[CH:20]\[C:21]1[NH:22][CH:23]=[CH:24][CH:25]=1)([O-:53])=[O:52]
Reactant: O=[N+]([O-])c1ccccc1Br
Reactant: O=C1Nc2ccc(C#Cc3ccc(O)cc3)cc2/C1=C/c1ccc[nH]1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Agent: C#Cc1ccc2c(c1)/C(=C/c1ccc[nH]1)C(=O)N2
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: O=C1Nc2ccc(C#Cc3ccccc3[N+](=O)[O-])cc2/C1=C/c1ccc[nH]1

Procedure:
This compound was also prepared in a manner analogous to the preparation of (Z)-1,3-dihydro-5-(4-hydroxyphenyl)ethynyl-3-[(1H-pyrrol-2-yl)methylene]-2H-indol-2-one in Example 83 above. In this example, (Z)-1,3-dihydro-5-ethynyl-3-[(1H-pyrrol-2-yl)methylene]-2H-indol-2-one (150 mg, 0.64 mmol) (from Example 82) was coupled with 1-bromo-2-nitrobenzene (150 mg, 0.74 mmol) (Aldrich) using CuI (13 mg, 0.068 mmol) (Aldrich) and (Ph3P)2PdCl2 (22 mg, 0.031 mmol) (Aldrich) as catalyst in 2 mL DMF and 4 mL triethylamine at 70° C. for 15 hours to give (Z)-1,3-dihydro-5-(2-nitrophenyl)ethynyl-3-[(1H-pyrrol-2-yl)methylene]-2H-indol-2-one as a red powder. (Yield 115 mg, 51%).
Reaction SMILES: Cl.[CH:2]1[C:12]2[CH2:11][CH2:10][C:9]3[CH:13]=[CH:14][CH:15]=[CH:16][C:8]=3[N:7]([CH2:17][CH2:18][CH2:19]C3(C(O)=O)CCCNC3)[C:6]=2[CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.CS(Cl)(=O)=O.[CH3:41][O:42][C:43](=[O:50])[CH2:44][CH:45]1[CH2:49][CH2:48][NH:47][CH2:46]1>C1COCC1>[CH3:41][O:42][C:43](=[O:50])[CH2:44][CH:45]1[CH2:49][CH2:48][N:47]([CH2:19][CH2:18][CH2:17][N:7]2[C:8]3[CH:16]=[CH:15][CH:14]=[CH:13][C:9]=3[CH2:10][CH2:11][C:12]3[CH:2]=[CH:3][CH:4]=[CH:5][C:6]2=3)[CH2:46]1
Reactant: O=C(O)C1(CCCN2c3ccccc3CCc3ccccc32)CCCNC1
Reactant: COC(=O)CC1CCNC1
Agent: CS(=O)(=O)Cl
Agent: Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: COC(=O)CC1CCN(CCCN2c3ccccc3CCc3ccccc32)C1
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 30.1 %

Procedure:
3-(10,11-Dihydro-5H-dibenzo[b,f]azepin-5-yl)-1-propanol (2.0 g, 0.0079 mol, prepared as described in example 10) was dissolved in dry THF (25 ml) under an atmosphere of nitrogen, and triethylamine (2.75 ml) was added. Methanesulfonyl chloride (0.61 ml, 0.0079 mol) was added dropwise and when addition was complete the reaction mixture was stirred for 45 minutes. The mixture was filtered and 3-pyrrolidinacetic acid methyl ester (2.4 g, 0.012 mol) was added to the filtrate. The mixture was heated at reflux temperature for 4 h and then stirred at room temperature for 48 h. Triethylamine (2.2 ml) was added and the mixture was heated at reflux temperature for 24 h. After cooling to room temperature the solvent was removed by evaporation in vacuo. The residue was purified by column chromatography on silica gel (125 g) using a mixture of dichloromethane and methanol (9:1) as eluent, affording 0.9 g (27%) of 1-(3-(10,11-dihydro-5H-dibenzo[b,f]azepin-5yl)-1-propyl)-3-pyrrolidinacetic acid methyl ester as an oil. Rf : 0.15 (SiO2 ; dichloromethane/methanol/acetic acid=20:2:1).
Reaction SMILES: C(=O)([O-])[O-].[Ca+2:5].[P:6](=[O:10])([OH:9])([OH:8])[OH:7]>O>[P:6]([O-:10])([O-:9])([O-:8])=[O:7].[Ca+2:5].[P:6]([O-:10])([O-:9])([O-:8])=[O:7].[Ca+2:5].[Ca+2:5]
Reactant: O=P(O)(O)O
Agent: O=C([O-])[O-]
Agent: [Ca+2]
Solvent: O
Product: O=P([O-])([O-])[O-]

Procedure:
For example, an aqueous-suspension of calcium carbonate as a support and a dilute aqueous solution of phosphoric acid are mixed in water so that an atomic ratio of Ca/P becomes not more than 33.3 under the following mixing conditions. The mixture is then aged under the following conditions to obtain an aqueous slurry of a calcium phosphate compound, followed by dehydration or without dehydration, drying under drying conditions at not higher than 700° C., and crushing.
Reaction SMILES: [OH-].[Na+].Cl.Cl.[CH3:5][C:6]1[N:11]=[C:10]([CH2:12][S:13]C(=N)N)[CH:9]=[CH:8][CH:7]=1>O>[CH3:5][C:6]1[N:11]=[C:10]([CH2:12][SH:13])[CH:9]=[CH:8][CH:7]=1
Reactant: Cc1cccc(CSC(=N)N)n1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: Cc1cccc(CS)n1
Temperature: 20 °C
Reaction time: 0.58 h
Yield: 88.2 %

Procedure:
A solution of sodium hydroxide pellets (37 g) in distilled water (140 cc) is added dropwise, in the course of 15 minutes, to a solution, cooled to 15° C., of 2-(6-methylpyrid-2-ylmethyl)isothiourea dihydrochloride (114.7 g) in distilled water (280 cc). The reaction mixture is heated to the boil and is then stirred for 35 minutes. After cooling to 20° C., the reaction mixture is extracted three times with diethyl ether (480 cc in total). The combined ether extracts are washed three times with distilled water (300 cc in total), dried over anhydrous sodium sulphate and concentrated under reduced pressure (20 mm Hg) at 30° C. 6-Methylpyrid-2-ylmethanethiol (55.4 g) is thus obtained in the form of a yellow oil.
Reaction SMILES: C1(O[C:8](=[O:25])[NH:9][CH:10]2[CH2:15][CH2:14][C:13]([N:22]([CH3:24])[CH3:23])([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[CH2:12][CH2:11]2)C=CC=CC=1.[F:26][C:27]1[CH:28]=[C:29]2[C:33](=[CH:34][CH:35]=1)[NH:32][CH:31]=[C:30]2[CH:36]1[CH2:41][CH2:40][NH:39][CH2:38][CH2:37]1>O1CCOCC1>[CH3:24][N:22]([CH3:23])[C:13]1([C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH2:12][CH2:11][CH:10]([NH:9][C:8]([N:39]2[CH2:40][CH2:41][CH:36]([C:30]3[C:29]4[C:33](=[CH:34][CH:35]=[C:27]([F:26])[CH:28]=4)[NH:32][CH:31]=3)[CH2:37][CH2:38]2)=[O:25])[CH2:15][CH2:14]1
Reactant: CN(C)C1(c2ccccc2)CCC(NC(=O)Oc2ccccc2)CC1
Reactant: Fc1ccc2[nH]cc(C3CCNCC3)c2c1
Solvent: C1COCCO1
Product: CN(C)C1(c2ccccc2)CCC(NC(=O)N2CCC(c3c[nH]c4ccc(F)cc34)CC2)CC1

Procedure:
The polar diastereoisomer of (4-dimethylamino-4-phenylcyclohexyl)-carbamic acid phenyl ester (322 mg, 0.95 mmole) was added to a solution of 5-fluoro-3-piperidine-4-yl-1H-indole (208 mg, 0.95 mmole) in dioxane (10 ml). The reaction mixture was then boiled under reflux for 32 hours. The reaction mixture was worked up by distilling off dioxane and diluting with water (10 ml). The reaction mixture was adjusted to pH 11 with 5M NaOH and extracted with EE (3×15 ml). The organic phase was dried with Na2SO4 and concentrated by evaporation. The polar diastereoisomer of 4-(5-fluoro-1H-indol-3-yl)piperidine-1-carboxylic acid-(4-dimethylamino-4-phenylcyclohexyl)-amide was recrystallised from methanol (5 ml). It was obtained in a yield of 230 mg (52%) as a colourless solid.
Reaction SMILES: [F:1][C:2]1[C:3]([CH2:10][CH2:11][OH:12])=[C:4]([OH:9])[CH:5]=[CH:6][C:7]=1[F:8].C([O-])([O-])=O.[K+].[K+].Br[CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.O>CC(C)=O>[CH2:20]([O:9][C:4]1[C:3]([CH2:10][CH2:11][OH:12])=[C:2]([F:1])[C:7]([F:8])=[CH:6][CH:5]=1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: OCCc1c(O)ccc(F)c1F
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: O
Product: OCCc1c(OCc2ccccc2)ccc(F)c1F
Temperature: 25 °C
Reaction time: 16 h
Yield: 83.1 %

Procedure:
To a solution of 3,4-difluoro-2-(2-hydroxyethyl)phenol (460 mg, 2.64 mmol) in Acetone (10 mL) was added K2CO3 (730 mg, 5.28 mmol) followed by (bromomethyl)benzene (0.471 mL, 3.96 mmol) and the resulting mixture was stirred at room temp for 16 h. Water was then added and the mixture was extracted with ethyl acetate, dried (Na2SO4), filtered and concentrated. The residue was then purified by Biotage (5-30% EtOAc/hexane) to afford 2-(6-(benzyloxy)-2,3-difluorophenyl)ethanol (580 mg, 2.195 mmol, 83% yield) as viscous oil. 1H NMR (500 MHz, CDCl3) δ 7.46-7.34 (m, 5H), 6.99 (q, J=9.1 Hz, 1H), 6.67-6.59 (m, 1H), 5.09 (s, 2H), 3.86 (q, J=6.4 Hz, 2H), 3.05 (td, J=6.5, 1.7 Hz, 2H).
Reaction SMILES: C(OC([N:11]1[CH:17]([C:18]2[NH:19][C:20]([C:23]3[CH:28]=[CH:27][C:26]([Br:29])=[CH:25][CH:24]=3)=[CH:21][N:22]=2)[CH2:16][C:13]2([CH2:15][CH2:14]2)[CH2:12]1)=O)C1C=CC=CC=1.Br.[CH3:31][O:32][C:33]([NH:35][CH:36]([CH:40]([CH3:42])[CH3:41])[C:37](O)=[O:38])=[O:34].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CCOC(C)=O.CN(C=O)C.C(Cl)Cl>[CH3:31][O:32][C:33](=[O:34])[NH:35][CH:36]([C:37]([N:11]1[CH:17]([C:18]2[NH:19][C:20]([C:23]3[CH:28]=[CH:27][C:26]([Br:29])=[CH:25][CH:24]=3)=[CH:21][N:22]=2)[CH2:16][C:13]2([CH2:15][CH2:14]2)[CH2:12]1)=[O:38])[CH:40]([CH3:42])[CH3:41]
Reactant: O=C(OCc1ccccc1)N1CC2(CC2)CC1c1ncc(-c2ccc(Br)cc2)[nH]1
Reactant: COC(=O)NC(C(=O)O)C(C)C
Agent: Br
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: COC(=O)NC(C(=O)N1CC2(CC2)CC1c1ncc(-c2ccc(Br)cc2)[nH]1)C(C)C
Temperature: 25 °C
Reaction time: 2.67 h
Yield: 60.1 %

Procedure:
6-[5-(4-Bromo-phenyl)-1H-imidazol-2-yl]-5-aza-spiro[2.4]heptane-5-carboxylic acid benzyl ester (478 mg, 1.04 mmol) was treated with DCM (5 mL) then HBr (33 wt % in AcOH, 5 mL). The mixture was stirred for 160 minutes at room temperature, concentrated under reduced pressure then coevaporated 2× with toluene to remove excess AcOH. The crude residue was treated with 2-Methoxycarbonylamino-3-methyl-butyric acid (274 mg, 1.56 mmol), HATU (435 mg, 1.14 mmol) and DMF (10 mL) The stirred mixture was cooled to 0° C. and DIPEA (0.91 mL, 5.2 mmol) was added before the warming to room temperature. After 1 h, the reaction mixture was diluted with EtOAc and washed with saturated aqueous NaHCO3 and brine. The organic layer was dried over MgSO4, filtered and concentrated and the crude residue was purified by silica column chromatography (75% to 100% EtOAc/hexane) to yield (1-{6-[5-(4-Bromo-phenyl)-1H-imidazol-2-yl]-5-aza-spiro[2.4]heptane-5-carbonyl}-2-methyl-propyl)-carbamic acid methyl ester (297 mg, 60%).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([NH2:8])[C:3]=1[NH2:9].Cl[C:11]1[N:19]=[C:18]([C:20]([F:23])([F:22])[F:21])[CH:17]=[CH:16][C:12]=1[C:13](O)=[O:14]>C(OCCO)CCC>[CH3:1][C:2]1[C:3]2[NH:9][C:13](=[O:14])[C:12]3[CH:16]=[CH:17][C:18]([C:20]([F:23])([F:21])[F:22])=[N:19][C:11]=3[NH:8][C:4]=2[CH:5]=[CH:6][CH:7]=1
Reactant: Cc1cccc(N)c1N
Reactant: O=C(O)c1ccc(C(F)(F)F)nc1Cl
Solvent: CCCCOCCO
Product: Cc1cccc2c1NC(=O)c1ccc(C(F)(F)F)nc1N2
Temperature: 145 °C

Procedure:
A well-stirred mixture of 3-methyl-1,2-benzenediamine (4.0 g, 33 mmol) and 2-chloro-6-(trifluoromethyl)nicotinic acid (7.3 g, 33 mmol) in 2-butoxyethanol (60 ml) was heated at 140-150° C. for 6 h. The dark solution was then poured over crushed ice, and the resulting dark brown solid was collected, washed with water, and dried. Recrystallization from 50% dioxane/water afforded 7-methyl-2-(trifluoromethyl)-6,11-dihydro-5H-pyrido[2,3-b][1,5]benzodiazepin-5-one.
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]1[CH:4]=[CH:5][C:6]([C:9]([OH:11])=O)=[N:7][CH:8]=1.[CH3:14][C:15]1[C:16]([NH2:30])=[N:17][C:18]2([C:28]3[C:23](=[CH:24][CH:25]=[C:26]([NH2:29])[CH:27]=3)[O:22][CH2:21][CH2:20]2)[N:19]=1>>[NH2:30][C:16]1[C:15]([CH3:14])=[N:19][C:18]2([C:28]3[C:23](=[CH:24][CH:25]=[C:26]([NH:29][C:9](=[O:11])[C:6]4[CH:5]=[CH:4][C:3]([C:2]([F:1])([F:13])[F:12])=[CH:8][N:7]=4)[CH:27]=3)[O:22][CH2:21][CH2:20]2)[N:17]=1
Reactant: O=C(O)c1ccc(C(F)(F)F)cn1
Reactant: CC1=NC2(CCOc3ccc(N)cc32)N=C1N
Product: CC1=NC2(CCOc3ccc(NC(=O)c4ccc(C(F)(F)F)cn4)cc32)N=C1N
Yield: 47.4 %

Procedure:
The title compound (44 mg, 46% yield) was prepared as described for Example 13a starting from 5-(trifluoromethyl)picolinic acid (45 mg, 0.23 mmol) and 5′-methylspiro[chroman-4,2′-imidazole]-4′,6-diamine (Intermediate 30, 54 mg, 0.23 mmol): 1H NMR (400 MHz, DMSO-d6) δ ppm 1.85-1.98 (m, 2H), 2.24 (s, 3H), 4.30-4.50 (m, 2H), 6.56 (s, 2H), 6.81 (d, 1H), 7.02-7.10 (m, 1H), 7.62-7.71 (m, 1H), 8.28 (d, 1H), 8.46 (dd, 1H), 9.01-9.10 (m, 1H), 10.57 (s, 1H); MS (APCI+) m/z 404 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([CH:13]3[CH2:15][CH2:14]3)[C:11](=[O:16])[N:10]([CH2:17][C:18]([NH:20][CH2:21][C:22](=O)[CH2:23][C:24]3[CH:29]=[CH:28][CH:27]=[C:26]([C:30]([F:33])([F:32])[F:31])[CH:25]=3)=O)[N:9]=2)=[CH:4][CH:3]=1.C([O-])(=O)C.[NH4+:39]>CN(C=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([CH:13]3[CH2:15][CH2:14]3)[C:11](=[O:16])[N:10]([CH2:17][C:18]3[NH:39][C:22]([CH2:23][C:24]4[CH:29]=[CH:28][CH:27]=[C:26]([C:30]([F:33])([F:32])[F:31])[CH:25]=4)=[CH:21][N:20]=3)[N:9]=2)=[CH:4][CH:3]=1
Reactant: O=C(CNC(=O)Cn1nc(-c2ccc(Cl)cc2)n(C2CC2)c1=O)Cc1cccc(C(F)(F)F)c1
Reactant: [NH4+]
Agent: CC(=O)[O-]
Solvent: CN(C)C=O
Product: O=c1n(Cc2ncc(Cc3cccc(C(F)(F)F)c3)[nH]2)nc(-c2ccc(Cl)cc2)n1C1CC1
Temperature: 200 °C
Reaction time: 0.25 h

Procedure:
50 mg (0.10 mmol) of the compound from Example 27A were dissolved in 1 ml of DMF and mixed with 23 mg (0.30 mmol) of ammonium acetate, and the mixture was stirred in a microwave oven at 200° C. for 15 min. After cooling, a further 30 mg (0.39 mmol) of ammonium acetate were added, and the mixture was stirred in a microwave oven at 200° C. for another 30 min. After cooling to RT, the mixture was partitioned between 10 ml of ethyl acetate and 10 ml of water. The organic phase was separated off, washed with in each case 10 ml of water and saturated sodium chloride solution, dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by preparative HPLC [Method 19]. This gave 17 mg (35% of theory) of the target compound as a yellowish resin.
Reaction SMILES: C([Li])CCC.C[Si](C)(C)[C:8]1[S:9][CH:10]=[CH:11][N:12]=1.[C:15]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)(=[O:17])[CH3:16].O>C(OCC)C>[C:18]1([C:15]([C:10]2[S:9][CH:8]=[N:12][CH:11]=2)([OH:17])[CH3:16])[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: CC(=O)c1ccccc1
Reactant: C[Si](C)(C)c1nccs1
Agent: [Li]CCCC
Solvent: CCOCC
Solvent: O
Product: CC(O)(c1ccccc1)c1cncs1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
n-Butyllithium (2.5M solution in hexane, 7ml) in diethyl ether (30ml) was stirred at -70° C. under a nitrogen atmosphere and 2-trimethylsilylthiazole (2.5g) in diethyl ether (10 ml) was added dropwise. After 30 minutes, acetophenone (2.3g) in diethyl ether (10 ml) was added dropwise. After a further 45 minutes the mixture was allowed to warm to room temperature and was then left overnight. Water was added and the mixture was extracted with diethyl ether. The material thus obtained was purified by flash chromatography to give the title compound.
Reaction SMILES: Cl.[O:2]=[C:3]([N:13]1[CH2:18][CH2:17][CH2:16][C@@H:15]([NH:19][C:20]2[CH:25]=[N:24][CH:23]=[C:22]([C:26]3[CH:27]=[N:28][N:29]4[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=34)[N:21]=2)[CH2:14]1)[CH2:4][NH:5]C(=O)OC(C)(C)C>O1CCOCC1.CO>[NH2:5][CH2:4][C:3]([N:13]1[CH2:18][CH2:17][CH2:16][C@@H:15]([NH:19][C:20]2[CH:25]=[N:24][CH:23]=[C:22]([C:26]3[CH:27]=[N:28][N:29]4[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=34)[N:21]=2)[CH2:14]1)=[O:2]
Reactant: CC(C)(C)OC(=O)NCC(=O)N1CCC[C@@H](Nc2cncc(-c3cnn4ccccc34)n2)C1
Agent: Cl
Solvent: CO
Solvent: C1COCCO1
Product: NCC(=O)N1CCC[C@@H](Nc2cncc(-c3cnn4ccccc34)n2)C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 94 %

Procedure:
A solution of hydrochloric acid in dioxane (4M, 10 mL) was added to a solution of tert-butyl (2-oxo-2-{(3R)-3-[(6-pyrazolo[1,5-a]pyridin-3-ylpyrazin-2-yl)amino]piperidin-1-yl}ethyl)carbamate (Preparation 38, 88 mg, 0.23 mmol) in methanol (3 mL) and the resulting mixture was stirred at ambient temperature for one hour. The solvents were then evaporated to half of their volume and the yellow solid that precipitated was filtered, washed with diethyl ether and dried to give the title compound (76 mg, 95%).
Reaction SMILES: ClC1C(Cl)=NC2C(=CC=C([N+]([O-])=O)C=2)N=1.Cl[C:17]1[C:26](Cl)=[N:25][C:24]2[C:19](=[CH:20][C:21]([N+:31]([O-:33])=[O:32])=[C:22]([N+:28]([O-:30])=[O:29])[CH:23]=2)[N:18]=1.[K][S:35][C:36](=[C:39]([C:42]#[N:43])[C:40]#[N:41])[S:37][K]>>[N+:31]([C:21]1[CH:20]=[C:19]2[C:24](=[CH:23][C:22]=1[N+:28]([O-:30])=[O:29])[N:25]=[C:26]1[S:35][C:36](=[C:39]([C:42]#[N:43])[C:40]#[N:41])[S:37][C:17]1=[N:18]2)([O-:33])=[O:32]
Reactant: O=[N+]([O-])c1cc2nc(Cl)c(Cl)nc2cc1[N+](=O)[O-]
Reactant: N#CC(C#N)=C(S[K])S[K]
Agent: O=[N+]([O-])c1ccc2nc(Cl)c(Cl)nc2c1
Product: N#CC(C#N)=C1Sc2nc3cc([N+](=O)[O-])c([N+](=O)[O-])cc3nc2S1
Yield: 82 %

Procedure:
The process of Example 13 is followed except that the 2,3-dichloro-6-nitroquinoxaline is replaced by 1.25 g of 2,3-dichloro-6,7-dinitroquinoxaline and 1.13 g of the di(potassiomercapto)methylenemalononitrile is used. The recovered material is a dark brown powder weighing 1.26 g with a calculated overall yield of 82 percent and has a melting point greater than 300° C.
Reaction SMILES: [NH2:1][C:2]1[C:7]([CH3:8])=[CH:6][N:5]=[C:4]([C:9]([O:11]C)=[O:10])[CH:3]=1.[OH-].[Na+]>CO>[NH2:1][C:2]1[C:7]([CH3:8])=[CH:6][N:5]=[C:4]([C:9]([OH:11])=[O:10])[CH:3]=1
Reactant: COC(=O)c1cc(N)c(C)cn1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: Cc1cnc(C(=O)O)cc1N
Yield: 64.8 %

Procedure:
A solution of methyl 4-amino-5-methylpicolinate (compound 349.3, 1.50 g, 8.12 mmol, 1.00 equiv, 90%) and 5N sodium hydroxide (aq., 15 mL) in methanol (15 mL) was stiffed overnight at room temperature, then concentrated under reduced pressure. The residue was diluted with 20 mL of H2O and the pH was adjusted to 3-4 with 2 M aqueous hydrogen chloride. The resulting precipitate was collected by filtration and dried to yield 0.8 g (58%) of the title compound as a yellow solid.
Reaction SMILES: C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.[CH3:34][N:35]([CH2:43][C:44]1[CH:45]=[C:46]2[C:51](=[CH:52][CH:53]=1)[CH:50]=[C:49]([C:54]([OH:56])=O)[CH:48]=[CH:47]2)[S:36]([C:39]([F:42])([F:41])[F:40])(=[O:38])=[O:37].C([O:59][C:60](=[O:68])[C:61]1[CH:66]=[CH:65][CH:64]=[C:63]([NH2:67])[CH:62]=1)C.[OH-].[Na+]>C(Cl)Cl.CN(C1C=CN=CC=1)C.CO.O>[CH3:34][N:35]([CH2:43][C:44]1[CH:45]=[C:46]2[C:51](=[CH:52][CH:53]=1)[CH:50]=[C:49]([C:54]([NH:67][C:63]1[CH:62]=[C:61]([CH:66]=[CH:65][CH:64]=1)[C:60]([OH:68])=[O:59])=[O:56])[CH:48]=[CH:47]2)[S:36]([C:39]([F:41])([F:40])[F:42])(=[O:38])=[O:37]
Reactant: CCOC(=O)c1cccc(N)c1
Reactant: CN(Cc1ccc2cc(C(=O)O)ccc2c1)S(=O)(=O)C(F)(F)F
Agent: CN(C)c1ccncc1
Agent: F[P-](F)(F)(F)(F)F
Agent: [Na+]
Solvent: O
Solvent: CO
Solvent: ClCCl
Product: CN(Cc1ccc2cc(C(=O)Nc3cccc(C(=O)O)c3)ccc2c1)S(=O)(=O)C(F)(F)F
Temperature: 25 °C
Reaction time: 8 h
Yield: 37 %

Procedure:
PyBOP (604 mg, 1.16 mmol) was added to the mixture of 6-[(Methyl-trifluoromethanesulfonyl-amino-)-methyl]-naphthalene-2-carboxylic acid (200 mg, 0.58 mmol), ethyl-3-amino-benzoate (86 ul, 0.58 mmol) in DCM (5 ml), followed by addition of DMAP (106 mg, 0.87 mmol). Allowed the mixture stirred at room temperature for overnight. Added more DCM, washed with 1N HCl, NaHCO3(sat.), and brine. Evaporated the solvent to give a white solid which was dissolved in 10 ml of methanol, added NaOH (5 eq, 116 mg) in H2O (10 ml), stirred at room temperature for overnight. Added more H2O and NaOH, then washed with DCM. Separated the DCM, the aqueous layer was acidified with 6N HCl, the resulting white solid was collected by vacuum filtration, washed with H2O, vacuum dry to get 100 mg of 3-({6-[(Methyl-trifluoromethanesulfonyl-amino)-methyl]-naphthalene-2-carbonyl}-amino)-benzoic acid.
Reaction SMILES: [C:1]12([CH2:11][CH2:12][O:13][C:14]3[CH:15]=[C:16]([CH2:20][CH2:21][NH2:22])[CH:17]=[CH:18][CH:19]=3)[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.[CH2:23]([O:30][C:31]1[CH:32]=[CH:33][C:34]([C@@H:42]([O:45][Si:46]([C:49]([CH3:52])([CH3:51])[CH3:50])([CH3:48])[CH3:47])[CH2:43]Br)=[C:35]2[C:40]=1[NH:39][C:38](=[O:41])[CH:37]=[CH:36]2)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.C(=O)([O-])O.[Na+].[I-].[Na+]>CS(C)=O.O>[C:1]12([CH2:11][CH2:12][O:13][C:14]3[CH:15]=[C:16]([CH2:20][CH2:21][NH:22][CH2:43][C@@H:42]([C:34]4[CH:33]=[CH:32][C:31]([O:30][CH2:23][C:24]5[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=5)=[C:40]5[C:35]=4[CH:36]=[CH:37][C:38](=[O:41])[NH:39]5)[O:45][Si:46]([C:49]([CH3:52])([CH3:51])[CH3:50])([CH3:48])[CH3:47])[CH:17]=[CH:18][CH:19]=3)[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2
Reactant: NCCc1cccc(OCCC23CC4CC(CC(C4)C2)C3)c1
Reactant: CC(C)(C)[Si](C)(C)O[C@@H](CBr)c1ccc(OCc2ccccc2)c2[nH]c(=O)ccc12
Agent: O=C([O-])O
Agent: [I-]
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: CC(C)(C)[Si](C)(C)O[C@@H](CNCCc1cccc(OCCC23CC4CC(CC(C4)C2)C3)c1)c1ccc(OCc2ccccc2)c2[nH]c(=O)ccc12
Temperature: 120 °C
Reaction time: 2 h

Procedure:
To a solution of Intermediate 31 (0.51 g, 1.7 mmol) in dimethyl sulfoxide (1.5 mL) and (R)-8-(benzyloxy)-5-(2-bromo-1-(tert-butyldimethylsilyloxy)ethyl)quinolin-2(1H)-one (1.06 g, 2.17 mmol) in dimethyl sulfoxide (2 mL) was added sodium hydrogen carbonate (0.53 g, 6.37 mmol) and sodium iodide (0.970 g, 6.47 mmol). The reaction mixture was stirred at 120° C. for 2 hours. The reaction was poured into water and filtered. The crude was purified by column chromatography with silica gel, eluting by methylen chloride giving the title compound as a solid (0.84 g, 63%). MS (M+): 708.