Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([CH3:13])([CH3:12])[C:9]([OH:11])=O)=[CH:4][CH:3]=1.[NH2:14][CH2:15][CH2:16][CH2:17][N:18]1[CH2:23][CH2:22][CH:21]([C:24]2[CH:25]=[CH:26][C:27]([F:36])=[C:28]([NH:30][C:31](=[O:35])[CH2:32][CH2:33][CH3:34])[CH:29]=2)[CH2:20][CH2:19]1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]([CH3:13])([CH3:12])[C:9]([NH:14][CH2:15][CH2:16][CH2:17][N:18]2[CH2:19][CH2:20][CH:21]([C:24]3[CH:25]=[CH:26][C:27]([F:36])=[C:28]([NH:30][C:31](=[O:35])[CH2:32][CH2:33][CH3:34])[CH:29]=3)[CH2:22][CH2:23]2)=[O:11])=[CH:6][CH:7]=1
Reactant: CCCC(=O)Nc1cc(C2CCN(CCCN)CC2)ccc1F
Reactant: CC(C)(C(=O)O)c1ccc(Cl)cc1
Product: CCCC(=O)Nc1cc(C2CCN(CCCNC(=O)C(C)(C)c3ccc(Cl)cc3)CC2)ccc1F

Procedure:
Example 110 was prepared from 2-(4-chlorophenyl)-2-methylpropanoic acid and N-{5-[1-(3-aminopropyl)-4-piperidinyl]-2-fluorophenyl}butanamide according to the procedures described in Scheme 10: 1H NMR (400 MHz, CDCl3) δ 8.31–8.12 (m, 1H), 7.44–7.15 (m, 5H), 7.12–6.94 (m, 1H), 6.75–6.61 (br, 1H), 6.61–6.46 (br, 1H), 3.35–3.12 (m, 4H), 2.70–2.47 (m, 3H), 2.46–2.35 (m, 2H), 2.35–2.21 (m, 2H), 1.92–1.67 (m, 8H), 1.54 (s, 6H), 1.02 (t, 3H, J=7.2 Hz); ESMS m/e: 502.3 (M+H)+.
Reaction SMILES: C(C#N)[C:2]1[CH:11]=[CH:10][C:7]([O:8][CH3:9])=[C:4]([O:5][CH3:6])[CH:3]=1.C(Cl)C1C=CC(OC)=C(OC)C=1>C1(C)C=CC=CC=1>[C:7]1([O:8][CH3:9])[C:4](=[CH:3][CH:2]=[CH:11][CH:10]=1)[O:5][CH3:6]
Reactant: COc1ccc(CC#N)cc1OC
Agent: COc1ccc(CCl)cc1OC
Solvent: Cc1ccccc1
Product: COc1ccccc1OC

Procedure:
The present invention relates to a process for the preparation of veratryl cyanide (VCN), wherein the toluene solution of the veratryl chloride obtained by chloromethylation of veratrol is reacted directly with sodium cyanide, with the addition of water, a ketone and a catalyst.
Reaction SMILES: FC(F)(F)S(O[CH2:7][C:8]([F:11])([F:10])[F:9])(=O)=O.[O:14]1[C:19]2([CH2:24][CH2:23][N:22]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:21][CH2:20]2)[CH2:18][NH:17][CH2:16][CH:15]1[C:32]([O:34][CH3:35])=[O:33].C([O-])(O)=O.[Na+]>CCO>[F:9][C:8]([F:11])([F:10])[CH2:7][N:17]1[CH2:18][C:19]2([CH2:24][CH2:23][N:22]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:21][CH2:20]2)[O:14][CH:15]([C:32]([O:34][CH3:35])=[O:33])[CH2:16]1
Reactant: O=S(=O)(OCC(F)(F)F)C(F)(F)F
Reactant: COC(=O)C1CNCC2(CCN(C(=O)OC(C)(C)C)CC2)O1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Product: COC(=O)C1CN(CC(F)(F)F)CC2(CCN(C(=O)OC(C)(C)C)CC2)O1
Temperature: 70 °C
Yield: 70 %

Procedure:
2,2,2-Trifluoroethyl trifluoromethanesulfonate (164 μL, 1.06 mmol) was added to a solution of 9-tert-butyl 2-methyl 1-oxa-4,9-diazaspiro[5.5]undecane-2,9-dicarboxylate (222 mg, 0.71 mmol) and NaHCO3 (237 mg, 2.83 mmol) in anhydrous EtOH (6 mL) at room temperature. The reaction mixture was purged with argon, sealed with a cap and heated at 70° C. for 12 hours. The reaction mixture was cooled to room temperature, filtered and concentrated in vacuo. The crude material was purified by silica gel column chromatography using 0 to 30% EtOAc in DCM as eluent to yield 9-tert-butyl 2-methyl 4-(2,2,2-trifluoroethyl)-1-oxa-4,9-diazaspiro[5.5]undecane-2,9-dicarboxylate (197 mg, 68%). ESI-MS m/z calc. 410.4. found 411.5 (M+1)+; Retention time: 2.08 minutes (3 min run).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:62])[NH:4][CH:5]([C:9]([N:11]1[CH:17]([C:18]2[NH:19][C:20]([C:23]3[CH:28]=[CH:27][C:26]([C:29]4[CH:38]=[CH:37][C:36]5[C:31](=[CH:32][CH:33]=[C:34]([C:39]6[NH:40][C:41]([CH:44]7[CH:49]8[CH2:50][CH:46]([CH2:47][CH2:48]8)[N:45]7[C:51](=[O:61])[CH:52]([CH:58]7[CH2:60][CH2:59]7)[NH:53][C:54]([O:56][CH3:57])=[O:55])=[N:42][CH:43]=6)[CH:35]=5)[CH:30]=4)=[CH:25][CH:24]=3)=[CH:21][N:22]=2)[CH2:16][C:13]2([CH2:15][CH2:14]2)[CH2:12]1)=[O:10])[CH:6]([CH3:8])[CH3:7].COC(NC(C(C)C)C(O)=O)=O>>[CH3:57][O:56][C:54](=[O:55])[NH:53][CH:52]([C:51]([N:45]1[CH:44]([C:41]2[NH:40][C:39]([C:34]3[CH:33]=[CH:32][C:31]4[C:36](=[CH:37][CH:38]=[C:29]([C:26]5[CH:25]=[CH:24][C:23]([C:20]6[NH:19][C:18]([CH:17]7[CH2:16][C:13]8([CH2:14][CH2:15]8)[CH2:12][N:11]7[C:9](=[O:10])[CH:5]([NH:4][C:3]([O:2][CH3:1])=[O:62])[CH:6]([CH3:8])[CH3:7])=[N:22][CH:21]=6)=[CH:28][CH:27]=5)[CH:30]=4)[CH:35]=3)=[CH:43][N:42]=2)[CH:49]2[CH2:50][CH:46]1[CH2:47][CH2:48]2)=[O:61])[CH:58]([CH3:59])[CH3:60]
Reactant: COC(=O)NC(C(=O)N1CC2(CC2)CC1c1ncc(-c2ccc(-c3ccc4cc(-c5cnc(C6C7CCC(C7)N6C(=O)C(NC(=O)OC)C6CC6)[nH]5)ccc4c3)cc2)[nH]1)C(C)C
Agent: COC(=O)NC(C(=O)O)C(C)C
Product: COC(=O)NC(C(=O)N1CC2(CC2)CC1c1ncc(-c2ccc(-c3ccc4cc(-c5cnc(C6C7CCC(C7)N6C(=O)C(NC(=O)OC)C(C)C)[nH]5)ccc4c3)cc2)[nH]1)C(C)C
Yield: 65 %

Procedure:
This compound was prepared using the procedure used to prepare [1-(6-{5-[4-(6-{2-[2-(2-Cyclopropyl-2-methoxycarbonylamino-acetyl)-2-aza-bicyclo[2.2.1]hept-3-yl]-3H-imidazol-4-yl}-naphthalen-2-yl)-phenyl]-1H-imidazol-2-yl}-5-aza-spiro[2.4]heptane-5-carbonyl)-2-methyl-propyl]-carbamic acid methyl ester using 2-Methoxycarbonylamino-3-methyl-butyric acid to provide [1-(3-{5-[6-(4-{2-[5-(2-Methoxycarbonylamino-3-methyl-butyryl)-5-aza-spiro[2.4]hept-6-yl]-3H-imidazol-4-yl}-phenyl)-naphthalen-2-yl}-1H-imidazol-2-yl]-2-aza-bicyclo[2.2.1]heptane-2-carbonyl)-2-methyl-propyl]-carbamic acid methyl ester (0.070 g, 65%) as a white powder.
Reaction SMILES: [CH3:1][C:2]1[N:11]=[CH:10][C:9]2[C:4](=[CH:5][C:6]([N+:12]([O-])=O)=[CH:7][CH:8]=2)[N:3]=1.[H][H]>CCOC(C)=O.[Pd]>[NH2:12][C:6]1[CH:5]=[C:4]2[C:9]([CH:10]=[N:11][C:2]([CH3:1])=[N:3]2)=[CH:8][CH:7]=1
Reactant: Cc1ncc2ccc([N+](=O)[O-])cc2n1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCOC(C)=O
Product: Cc1ncc2ccc(N)cc2n1
Reaction time: 6 h
Yield: 92.2 %

Procedure:
Compound 25A (0.400 g, 2.12 mmol) was dissolved in EtOAc (20 mL) and Pd/C (10% Pd, 0.045 g) was added. Hydrogen was then introduced to the flask with a balloon. After 6 h, the reaction was filtered through celite rinsing with EtOAc. Concentration in vacuo gave compound 25B as a yellow solid (0.311 g). This was taken on without purification to subsequent reactions.
Reaction SMILES: C(S([NH:7][C@H:8]([C:18]1[CH:23]=[C:22]([F:24])[CH:21]=[C:20]([F:25])[CH:19]=1)[CH2:9][S:10][C:11]([CH3:17])([CH3:16])[C:12](OC)=[O:13])=O)(C)(C)C.Cl.C(N(CC)CC)C.C1(C)C=CC=CC=1>CO>[F:25][C:20]1[CH:19]=[C:18]([C@H:8]2[NH:7][C:12](=[O:13])[C:11]([CH3:17])([CH3:16])[S:10][CH2:9]2)[CH:23]=[C:22]([F:24])[CH:21]=1
Reactant: COC(=O)C(C)(C)SC[C@H](NS(=O)C(C)(C)C)c1cc(F)cc(F)c1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CO
Solvent: Cc1ccccc1
Product: CC1(C)SC[C@@H](c2cc(F)cc(F)c2)NC1=O
Temperature: 115 °C

Procedure:
To a solution of methyl 2-{[(2R)-2-[(tert-butylsulfinyl)amino]-2-(3,5-difluorophenyl)ethyl]thio}-2-methylpropanoate from Step C (428 mg, 1.09 mmol) in MeOH (20 mL), cooled to 0° C., was added anhydrous HCl gas for 1 minute. The reaction was sealed and allowed to sit at 0° C. for fifteen minutes, after which nitrogen was bubbled through the reaction for twenty minutes. The reaction was concentrated in vacuo. Additional MeOH (30 mL) was added and it was again concentrated in vacuo. This was repeated with another addition of MeOH and triethylamine (440. mg, 4.35 mmol). To the resulting residue was added toluene (10 mL) and triethylamine (440. mg, 4.35 mmol). A reflux condenser was attached and the mixture stirred at 115° C. After one week of stirring, the reaction was judged to be 90% complete by LCMS. The mixture was cooled to ambient temperature and concentrated in vacuo. The residue was diluted with diethyl ether (50 mL) and washed individually with 20 mL of each of the following aqueous solutions: 1 M HCl (twice), water, and saturated brine. The organic layer was then dried over sodium sulfate, filtered, and concentrated in vacuo to give a residue that was purified by silica gel chromatography, eluting with a gradient of MeOH:CH2Cl2-1:99 to 5:95, to give the title compound. MS: m/z=258 (M+1).
Reaction SMILES: [O:1]1[CH2:5][CH2:4][CH2:3][CH:2]1[CH2:6][NH2:7].[CH3:8][Si:9]([CH3:24])([CH2:18][CH2:19][Si:20]([CH3:23])([CH3:22])[CH3:21])[CH2:10][CH2:11][CH2:12][O:13][CH2:14][CH:15]1[CH2:17][O:16]1>C(O)C>[CH3:24][Si:9]([CH3:8])([CH2:18][CH2:19][Si:20]([CH3:21])([CH3:23])[CH3:22])[CH2:10][CH2:11][CH2:12][O:13][CH2:14][CH:15]([OH:16])[CH2:17][NH:7][CH2:6][CH:2]1[CH2:3][CH2:4][CH2:5][O:1]1
Reactant: C[Si](C)(C)CC[Si](C)(C)CCCOCC1CO1
Reactant: NCC1CCCO1
Solvent: CCO
Product: C[Si](C)(C)CC[Si](C)(C)CCCOCC(O)CNCC1CCCO1
Temperature: 70 °C

Procedure:
C-(Tetrahydro-furan-2-yl)-methylamine (3.68 g; 36.4 mMol) and 40 mL of ethanol were charged to a 100 mL RB flask equipped with a magnetic stirrer. The mixture was stirred and heated to 70° C. 2-{3-[Dimethyl-(2-trimethylsilanyl-ethyl)-silanyl]-propoxymethyl}-oxirane 8 (2 g; 7.28 mMol) mixed with 10 g ethanol was placed in an addition funnel and added dropwise to the flask. The mixture was stirred and maintained at 70° C. for an additional 4 hours. Ethanol was stripped off on the rotovap. The mixture was distilled under vacuum to remove impurities and excess C-(Tetrahydro-furan-2-yl)-methylamine.
Reaction SMILES: [CH2:1]([O:8][CH2:9][C@@:10]1([N:37]2[CH:45]=[C:43]([CH3:44])[C:41](=[O:42])[NH:40][C:38]2=[O:39])[O:33][C@H:13]([CH2:14][O:15][Si:16]([C:29]([CH3:32])([CH3:31])[CH3:30])([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C@@H:12]([CH2:34][CH:35]=[O:36])[CH2:11]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[BH4-].[Na+]>>[CH2:1]([O:8][CH2:9][C@@:10]1([N:37]2[CH:45]=[C:43]([CH3:44])[C:41](=[O:42])[NH:40][C:38]2=[O:39])[O:33][C@H:13]([CH2:14][O:15][Si:16]([C:29]([CH3:30])([CH3:31])[CH3:32])([C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C@@H:12]([CH2:34][CH2:35][OH:36])[CH2:11]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cc1cn([C@@]2(COCc3ccccc3)C[C@H](CC=O)[C@@H](CO[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)O2)c(=O)[nH]c1=O
Agent: [BH4-]
Agent: [Na+]
Product: Cc1cn([C@@]2(COCc3ccccc3)C[C@H](CCO)[C@@H](CO[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)O2)c(=O)[nH]c1=O

Procedure:
Compound 55 will be treated with NaBH4 to furnish the title compound 56.
Reaction SMILES: C([OH:3])C.[C:4]([OH:13])(=[O:12])[C@@H:5]([C@H:7]([C:9]([OH:11])=[O:10])[OH:8])[OH:6]>O>[C:9]([CH:7]([CH:5]([C:4]([O-:13])=[O:12])[OH:6])[OH:8])([O-:11])=[O:10].[OH2:3]
Reactant: O=C(O)[C@H](O)[C@@H](O)C(=O)O
Reactant: CCO
Solvent: O
Product: O=C([O-])C(O)C(O)C(=O)[O-]
Temperature: 70 °C
Reaction time: 72 h

Procedure:
In 50 volume parts of water are dissolved 19 parts of TRH monohydrate and 7.5 parts of L-tartaric acid, and while the solution is warmed to 70°C, ethanol is added in installments. Immediately after a slight turbidity is observed, the temperature is gradually brought down to room temperature, at which temperature the solution is allowed to stand for 3 days. Then, the solution is cooled to 10°C and allowed to stand for 2 days to allow crystallization to be completed. The crystals thus obtained are harvested by filtration, washed with hot ethanol and dried under reduced pressure at 50°C for 1 hour and at 80°C for 5 hours. The described procedure yields 18 parts of TRH tartrate-water as crystals melting at 127°C-130°C. [α]D 24 =-49.90°(c=1.05 in water)
Reaction SMILES: [N+:1]([O-:4])(O)=[O:2].[Cl:5][C:6]1[CH:11]=[C:10]([Cl:12])[CH:9]=[CH:8][C:7]=1[CH3:13]>O>[Cl:5][C:6]1[CH:11]=[C:10]([Cl:12])[C:9]([N+:1]([O-:4])=[O:2])=[CH:8][C:7]=1[CH3:13]
Reactant: O=[N+]([O-])O
Reactant: Cc1ccc(Cl)cc1Cl
Solvent: O
Product: Cc1cc([N+](=O)[O-])c(Cl)cc1Cl
Reaction time: 1 h

Procedure:
To stirred fuming nitric acid (200 ml) at 0° C. was added slowly 2,4-dichlorotoluene (50 g, 0.3mole). Upon completion of addition, the reaction mixture was stirred for one hour, then was poured into water (100 ml). A yellow precipitate was collected by filtration to yield 62.0 g of 2,4-dichloro-5-nitrotoluene, m.p. 40°-44° C.
Reaction SMILES: [CH2:1]1[CH2:6][C@@H:5]([C:7]([OH:9])=[O:8])[NH:4]C[CH2:2]1.[CH2:10](NC(=O)[C@H]([C@H](CC)C)N)C1C=CC=CC=1.C(N(CC)CC)C.BrCC(C12CC3CC(CC(C3)C1)C2)=O>C1COCC1>[NH2:4][C@H:5]([C:7]([OH:9])=[O:8])[C@H:6]([CH2:1][CH3:2])[CH3:10]
Reactant: O=C(O)[C@@H]1CCCCN1
Reactant: CC[C@H](C)[C@H](N)C(=O)NCc1ccccc1
Agent: O=C(CBr)C12CC3CC(CC(C3)C1)C2
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC[C@H](C)[C@H](N)C(=O)O
Yield: 221.8 %

Procedure:
Using the procedure described in Example 5 and Example 17, L-homoproline-L-isoleucine benzylamide (75 mg, 0.22 mmol), was treated with triethylamine (0.15 mL, 1.12 mmol, 5 eq), 1-adamantyl bromomethyl ketone (92 mg, 0.36 mmol, 1.6 eq), and THF (10 mL), to provide 64 mg (56%) of L-isoleucine, N-[1-(2-adamantan-1-yl-2-oxoethyl)-L-homoproline] benzylamide.
Reaction SMILES: C([NH:9][C:10]([NH:12][C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([C:19]2[N:20]([CH2:32][CH3:33])[C:21]3[C:26]([C:27]=2[C:28]#[N:29])=[CH:25][CH:24]=[C:23]([O:30][CH3:31])[CH:22]=3)[CH:14]=1)=[S:11])(=O)C1C=CC=CC=1.[OH-].[Na+]>CO.O>[C:28]([C:27]1[C:26]2[C:21](=[CH:22][C:23]([O:30][CH3:31])=[CH:24][CH:25]=2)[N:20]([CH2:32][CH3:33])[C:19]=1[C:15]1[CH:14]=[C:13]([NH:12][C:10]([NH2:9])=[S:11])[CH:18]=[CH:17][CH:16]=1)#[N:29]
Reactant: CCn1c(-c2cccc(NC(=S)NC(=O)c3ccccc3)c2)c(C#N)c2ccc(OC)cc21
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CCn1c(-c2cccc(NC(N)=S)c2)c(C#N)c2ccc(OC)cc21
Temperature: 50 °C
Yield: 96.4 %

Procedure:
A suspension of 1-benzoyl-3-[3-(3-cyano-1-ethyl-6-methoxy-1H-indol-2-yl)-phenyl]-thiourea (241 mg, 0.530 mmol) in methyl alcohol (2.0 ml) and water (0.5 mL) was stirred at room temperature as sodium hydroxide (31 mg, 0.78 mmol) was added. The reaction mixture was heated to 50° C. for 17 h. The reaction mixture was concentrated to remove methyl alcohol. Water was added to the mixture and the solid was filtered, washed with water and dried to give 179 mg of [3-(3-cyano-1-ethyl-6-methoxy-1H-indol-2-yl)-phenyl]-thiourea, compound 767 (96% yield) as a white solid.
Reaction SMILES: Br[C:2]1[C:10]2[N:9]3[CH2:11][CH2:12][CH2:13][NH:14][C:15](=[O:16])[C:8]3=[C:7]([CH3:17])[C:6]=2[CH:5]=[C:4]([C:18]#[N:19])[CH:3]=1.[CH3:20][O:21][C:22]1[CH:27]=[CH:26][C:25](B(O)O)=[CH:24][CH:23]=1>>[CH3:20][O:21][C:22]1[CH:27]=[CH:26][C:25]([C:2]2[C:10]3[N:9]4[CH2:11][CH2:12][CH2:13][NH:14][C:15](=[O:16])[C:8]4=[C:7]([CH3:17])[C:6]=3[CH:5]=[C:4]([C:18]#[N:19])[CH:3]=2)=[CH:24][CH:23]=1
Reactant: Cc1c2n(c3c(Br)cc(C#N)cc13)CCCNC2=O
Reactant: COc1ccc(B(O)O)cc1
Product: COc1ccc(-c2cc(C#N)cc3c(C)c4n(c23)CCCNC4=O)cc1

Procedure:
The title compound, white solid (55 mg, 64%), MS (ISP) m/z=346.5 [(M+H)+], mp 277° C., was prepared in accordance with the general method of example 1 from 7-bromo-11-methyl-1-oxo-2,3,4,5-tetrahydro-[1,4]diazepino[1,2-a]indole-9-carbonitrile (intermediate 17) (79.5 mg, 0.25 mmol) and commercially available 4-methoxy-phenylboronic acid (49.4 mg, 0.325 mmol).
Reaction SMILES: [C:1]([O:5][C:6]([C@@H:8]1[CH2:12][S:11][CH:10]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[F:19])[NH:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:20][C:21]1[CH:22]=[C:23]([NH:27][C:28](=[O:34])[NH:29][CH2:30][C:31](O)=[O:32])[CH:24]=[CH:25][CH:26]=1.C1(N=C=NC2CCCCC2)CCCCC1.[K+].[Br-]>CCCCCCC.CN(C=O)C>[CH3:20][C:21]1[CH:22]=[C:23]([NH:27][C:28](=[O:34])[NH:29][CH2:30][C:31]([N:9]2[C@H:8]([C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])[CH2:12][S:11][C@@H:10]2[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[F:19])=[O:32])[CH:24]=[CH:25][CH:26]=1
Reactant: Cc1cccc(NC(=O)NCC(=O)O)c1
Reactant: CC(C)(C)OC(=O)[C@@H]1CSC(c2ccccc2F)N1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: [Br-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCCCCCC
Product: Cc1cccc(NC(=O)NCC(=O)N2[C@@H](c3ccccc3F)SC[C@H]2C(=O)OC(C)(C)C)c1
Yield: 20.1 %

Procedure:
The operation is carried out in a fashion similar to that described in Example 33, but starting from 3.5 g of tert-butyl-(2RS,4R)-2-(2-fluorophenyl)-4-thiazolidinecarboxylate, 2.3 g of 2-[3-(3-methylphenyl)ureido]acetic acid and 2.3 g of N,N'-dicyclohexylcarbodiimide. After vigorous stirring in heptane, 1.05 g of tert-butyl (2R,4R)-3-{2-[3-(3-methylphenyl)ureido]acetyl}-2-(2-fluorophenyl)-4-thiazolidinecarboxylate are thus obtained in the form of a white solid, melting at 107° C. ([α]D20 =+61.8°±1.5° (C=0.66%; DMF)) [proton NMR (200 MHz, DMSO D6, δ in ppm), 2 rotamers at room temperature, peak coalescence at 120° C., characteristic chemical shifts at 120° C.: 2.2 (bs, 3H, CH3); 6.7 (bd, 1H, N--C6H4 --C in position 4 or 6); 7.1 to 7.40 (m, 6H, aromatic); 7.9 (bm, 1H, C6H4F in position 3). Infrared spectrum (KBr), characteristics bands in cm-1 : 3370, 2975, 2925, 1735, 1645, 1615, 1590, 1560, 1490, 1460, 1370, 1150, 775, 760, 690].
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([C:8]2[CH:15]=[CH:14][C:11]([C:12]#[N:13])=[C:10](F)[CH:9]=2)[CH:5]=[C:4]([N:17]2[CH2:20][CH2:19][CH2:18]2)[N:3]=1.O.[NH2:22][NH2:23]>CO>[NH2:1][C:2]1[N:7]=[C:6]([C:8]2[CH:9]=[C:10]3[C:11]([C:12]([NH2:13])=[N:22][NH:23]3)=[CH:14][CH:15]=2)[CH:5]=[C:4]([N:17]2[CH2:20][CH2:19][CH2:18]2)[N:3]=1
Reactant: NN
Reactant: N#Cc1ccc(-c2cc(N3CCC3)nc(N)n2)cc1F
Solvent: CO
Solvent: O
Product: Nc1nc(-c2ccc3c(N)n[nH]c3c2)cc(N2CCC2)n1
Temperature: 95 °C
Reaction time: 8 h
Yield: 44.5 %

Procedure:
In a 25 mL sealable tube were combined 4-[2-amino-6-(1-azetidinyl)-4-pyrimidinyl]-2-fluorobenzonitrile (0.21 g, 0.79 mmol), hydrazine monohydrate (0.77 mL, 15.8 mmol) and CH3OH (10 mL). The vial was sealed, and the reaction mixture was stirred overnight at 95° C. The reaction was concentrated, and the resulting yellow solid was diluted with EtOH (2 mL) and water (5 mL). The mixture was sonicated, and the solid was filtered, washed with water, and dried under vacuum to afford the title compound (99 mg, 43%) as a light yellow solid. LC-MS (ES) m/z=282 [M+H]+. 1H NMR (400 MHz, DMSO-d6): δ 2.33 (m, 2H), 4.02 (m, 4H), 5.38 (s, 2H), 6.13 (bs, 2H), 6.14 (s, 1H), 7.51 (dd, J=8.3, 1.3 Hz, 1H), 7.70 (d, J=8.3 Hz, 1H), 7.91 (s, 1H), 11.50 (s, 1H).
Reaction SMILES: F[C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10].CC(C)=O.C(=O)=O.[NH3:19]>>[F:8][C:6]1[CH:5]=[CH:4][C:3]([N+:9]([O-:11])=[O:10])=[C:2]([NH2:19])[CH:7]=1
Reactant: O=[N+]([O-])c1ccc(F)cc1F
Reactant: N
Agent: O=C=O
Solvent: CC(C)=O
Product: Nc1cc(F)ccc1[N+](=O)[O-]
Reaction time: 7 h

Procedure:
2,4-Difluoronitrobenzene (1.0 eq) was placed in a dry round-bottomed flask equipped with a dry ice condenser charged with acetone/dry ice. Ammonia was condensed into the flask and the resulting solution was stirred at reflux for 7 hours. A yellow precipitate was formed within 1 hours. After 7 hours, the condenser was removed and the liquid ammonia was allowed to evaporate over several hours. The crude product was purified by flash chromatography on silica gel (85:15 hexanes:EtOAc, product at Rf=0.32, contaminant at Rf=0.51). GC/MS m/z 156.1 (M+), Rt 11.16 minutes.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]2[N:13]=[CH:12][N:11]=[C:10]([NH:14][C:15]3[CH:20]=[C:19]([O:21][CH3:22])[C:18]([O:23][CH3:24])=[C:17]([O:25][CH3:26])[CH:16]=3)[N:9]=2)=[CH:6][CH:5]=[CH:4][N:3]=1.[NH2:27][C:28]1[CH:29]=[C:30]([CH:47]=[CH:48][CH:49]=1)[C:31]([NH:33][C:34]1[CH:39]=[CH:38][C:37]([O:40][C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=2)=[CH:36][CH:35]=1)=[O:32].CS(C)=O>CO>[O:40]([C:37]1[CH:36]=[CH:35][C:34]([NH:33][C:31](=[O:32])[C:30]2[CH:47]=[CH:48][CH:49]=[C:28]([NH:27][C:2]3[C:7]([C:8]4[N:9]=[C:10]([NH:14][C:15]5[CH:20]=[C:19]([O:21][CH3:22])[C:18]([O:23][CH3:24])=[C:17]([O:25][CH3:26])[CH:16]=5)[N:11]=[CH:12][N:13]=4)=[CH:6][CH:5]=[CH:4][N:3]=3)[CH:29]=2)=[CH:39][CH:38]=1)[C:41]1[CH:42]=[CH:43][CH:44]=[CH:45][CH:46]=1
Reactant: COc1cc(Nc2ncnc(-c3cccnc3Cl)n2)cc(OC)c1OC
Reactant: Nc1cccc(C(=O)Nc2ccc(Oc3ccccc3)cc2)c1
Solvent: CO
Solvent: CS(C)=O
Product: COc1cc(Nc2ncnc(-c3cccnc3Nc3cccc(C(=O)Nc4ccc(Oc5ccccc5)cc4)c3)n2)cc(OC)c1OC
Temperature: 90 °C

Procedure:
To [4-(2-chloro-pyridin-3-yl)-[1,3,5]triazin-2-yl]-(3,4,5-trimethoxy-phenyl)amine (Example 2, Step 4)(103 mg, 0.275 mmol) was added 3-amino-N-(4-phenoxyphenyl)-benzamide (297 mg, 0.975 mmol) and DMSO (150 ml), and the mixture was heated overnight at 90° C. The residue was treated with IpOH and MeOH, triturated, sonicated, and filtered to obtain N-(4-phenoxy-phenyl)-3-{3-[4-(3,4,5-trimethoxy-phenylamino)-[1,3,5]triazin-2-yl]-pyridin-2-ylamino}benzamide as a yellow solid: MS m/z 642.5=[M+H]+. Calc'd for C36H31N7O5: 641.24.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([Cl:8])[N:5]=[CH:4][C:3]=1[C:9]([O:11][CH3:12])=[O:10].C(N(CC)CC)C.[NH2:20][NH2:21].O>C(O)C>[Cl:8][C:6]1[CH:7]=[C:2]([NH:20][NH2:21])[C:3]([C:9]([O:11][CH3:12])=[O:10])=[CH:4][N:5]=1
Reactant: COC(=O)c1cnc(Cl)cc1Cl
Reactant: NN
Solvent: CCN(CC)CC
Solvent: O
Solvent: CCO
Product: COC(=O)c1cnc(Cl)cc1NN
Temperature: 25 °C

Procedure:
Into a 20-L 4-necked round-bottom flask was placed methyl 4,6-dichloropyridine-3-carboxylate (1200 g, 5.82 mol), ethanol (10 L), and triethylamine (1182 g, 11.68 mol). NH2NH2.H2O (351 g, 7.02 mol) was then added drop-wise to the reaction mixture at 0° C. The resulting solution was heated to reflux for 1 h. The reaction mixture was cooled to room temperature. The solid was collected by filtration to give methyl 6-chloro-4-hydrazinylnicotinate, which was carried onto the next step without further purification.
Reaction SMILES: C(O[C:4]([C:6]1[N:11]=[CH:10][C:9]2[N:12]=[C:13]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][N:16]=3)[S:14][C:8]=2[C:7]=1[OH:21])=[O:5])C.[NH2:22][CH2:23][C:24]([OH:26])=[O:25].C[O-].[Na+].CO>>[OH:21][C:7]1[C:8]2[S:14][C:13]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][N:16]=3)=[N:12][C:9]=2[CH:10]=[N:11][C:6]=1[C:4]([NH:22][CH2:23][C:24]([OH:26])=[O:25])=[O:5]
Reactant: NCC(=O)O
Reactant: CCOC(=O)c1ncc2nc(-c3ccccn3)sc2c1O
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: O=C(O)CNC(=O)c1ncc2nc(-c3ccccn3)sc2c1O
Temperature: 25 °C
Yield: 75.7 %

Procedure:
A mixture of 7-hydroxy-2-pyridin-2-yl-thiazolo[4,5-c]pyridine-6-carboxylic acid ethyl ester (43 mg, 0.14 mmol) and glycine (214 mg, 2.86 mmol) in 0.5 M sodium methoxide/methanol (5.4 mL, 1.29 mmol) was refluxed for 2 days before it was cooled to room temperature and concentrated in vacuo. The residue was dissolved in water and extracted with methyl tert-butyl ether (2×25 mL). The remaining aqueous layer was acidified to pH=3 with 1N HCl (4 mL). The precipitate was filtered, washed with water and dried in vacuo to give the title compound as a white solid (35 mg): 1H NMR (DMSO-d6, 200 MHz): δ=13.16 (br s, 1H), 9.47 (br s, 1H), 8.92 (s, 1H), 8.75 (d, J=4.3 Hz, 1H), 8.32 (d, J=7.8, 1H), 8.05 (m, 1H), 7.65 (m, 1H), 4.03 (d, J=6.3 Hz, 2H); MS: (+) m/z 331.00 (M+1); (−) m/z 329.00 (M−1).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:9]([CH:10]([CH3:12])[CH3:11])=[C:8]([C:13](O)=[O:14])[N:7]([C:16]2[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=2)[N:6]=1)=[O:4].B.C1COCC1.CO>C1COCC1>[CH3:1][O:2][C:3]([C:5]1[C:9]([CH:10]([CH3:12])[CH3:11])=[C:8]([CH2:13][OH:14])[N:7]([C:16]2[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=2)[N:6]=1)=[O:4]
Reactant: COC(=O)c1nn(-c2ccc(F)cc2)c(C(=O)O)c1C(C)C
Agent: B
Solvent: CO
Solvent: C1CCOC1
Product: COC(=O)c1nn(-c2ccc(F)cc2)c(CO)c1C(C)C
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 89.8 %

Procedure:
(Reference: J. Med. Chem. 1996, 549-555) To a solution of 1-(4-fluoro-phenyl)-4-isopropyl-1H-pyrazole-3,5-dicarboxylic acid 3-methyl ester (15.9 g, 51.8 mmol) in THF (300 mL) at 0° C. was slowly added BH3.THF (1.0 M solution in THF, 104 mL, 104 mmol; commercially available from Sigma Aldrich). The reaction was allowed to warm to 25° C. for 30 min and then heated to 65° C. for 3 hr. After cooling to 25° C., MeOH (50 mL) was slowly added. Subsequently, the solvent was removed under reduced pressure and a second portion of MeOH (100 mL) was slowly added and the solution was stirred at 25° C. for an additional 20 min. The MeOH was then evaporated and EtOAc was added and the organic layer was washed with 1N NaOH and brine prior to drying over Na2SO4. The organic layer was concentrated and purified by silica gel chromatography (15-35% EtOAc/Hex) to provide 1-(4-fluoro-phenyl)-5-hydroxymethyl-4-isopropyl-1H-pyrazole-3-carboxylic acid methyl ester (13.6 g, 90%): H-NMR (CDCl3) δ 7.59-7.56 (m, 2 H), 7.15-7.11 (m, 2 H), 4.57 (s, 2 H), 3.89 (s, 3 H), 3.66-3.62 (m, 1 H), 1.36 (d, 6 H).