Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH2:8])[C:5]([N+:9]([O-:11])=[O:10])=[CH:4][CH:3]=1.[NH2:12][CH2:13][CH2:14][N:15]1[CH2:20][CH2:19][CH:18]([NH:21][C:22]2[N:26]([CH2:27][C:28]3[CH:33]=[CH:32][C:31]([F:34])=[CH:30][CH:29]=3)[C:25]3[CH:35]=[CH:36][CH:37]=[CH:38][C:24]=3[N:23]=2)[CH2:17][CH2:16]1.CN1CCCC1=O.N>CO>[F:34][C:31]1[CH:32]=[CH:33][C:28]([CH2:27][N:26]2[C:25]3[CH:35]=[CH:36][CH:37]=[CH:38][C:24]=3[N:23]=[C:22]2[NH:21][CH:18]2[CH2:19][CH2:20][N:15]([CH2:14][CH2:13][NH:12][C:2]3[N:7]=[C:6]([NH2:8])[C:5]([N+:9]([O-:11])=[O:10])=[CH:4][CH:3]=3)[CH2:16][CH2:17]2)=[CH:29][CH:30]=1
Reactant: NCCN1CCC(Nc2nc3ccccc3n2Cc2ccc(F)cc2)CC1
Reactant: Nc1nc(Cl)ccc1[N+](=O)[O-]
Agent: N
Solvent: CO
Solvent: CN1CCCC1=O
Product: Nc1nc(NCCN2CCC(Nc3nc4ccccc4n3Cc3ccc(F)cc3)CC2)ccc1[N+](=O)[O-]
Temperature: 150 °C
Yield: 50 %

Procedure:
A mixture of 3.4 parts of 6-chloro-3-nitro-2-pyridinamine, 7.4 parts of N-[1-(2-aminoethyl)-4-piperidinyl]-1-[(4-fluorophenyl)-methyl]-1H-benzimidazol-2-amine and 10 parts of 1-methyl-2-pyrrolidinone was stirred and heated for 2 hours at 150° C. The reaction mixture was cooled and taken up in methanol saturated with ammonia. The whole was evaporated and water was added to the residue. The product was extracted three times with 4-methyl-2-pentanone. The combined extracts were dried, filtered and evaporated in vacuo. The residue was purified by column chromatography over silica gel using a mixture of trichloromethane and methanol (95:5 by volume) as eluent. The pure fractions were collected and the eluent was evaporated. The residue was crystallized from 4-methyl-2-pentanone, yielding 5 parts (50%) of N6 -[2-[4-[[1-[(4-fluorophenyl)methyl]-1H-benzimidazol-2-yl]-amino]-1-piperidinyl]ethyl]-3-nitro-2,6-pyridinediamine; mp. 205.7° C. (intermediate 150).
Reaction SMILES: [CH3:1][C@@H:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH2:5][C:4](=O)[NH:3]1.Cl>O1CCCC1>[CH3:1][C@@H:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH2:5][CH2:4][NH:3]1
Reactant: C[C@H]1NC(=O)Cc2ccccc21
Agent: Cl
Solvent: C1CCOC1
Product: C[C@H]1NCCc2ccccc21
Temperature: 25 °C
Yield: 96.4 %

Procedure:
10.0 g of the compound(62 mM) prepared by Step 2 above and 20 ml of tetrahydrofuran were mixed, and 9 ml of 10.2M borane-methylsulfide complex was dropwise added thereto. The mixture was reacted under reflux for an hour and cooled to room temperature. By adding 10 ml of 6N HCl to the reaction solution, the remaining borane-methylsulfide complex was destroyed and the resultant was neutralized with 10% NaOH. The reaction solution was extracted from ethyl acetate, dehydrated and concentrated to give 8.8 g of the title compound in oil form.
Reaction SMILES: [NH2:1][C:2]1[CH:19]=[CH:18][C:5]2[CH2:6][CH2:7][N:8]([CH2:11][C@@H:12]([OH:17])[C:13]([F:16])([F:15])[F:14])[CH2:9][CH2:10][C:4]=2[CH:3]=1.Cl[C:21]1[N:26]=[C:25]([NH:27][C:28]2[C:37]([F:38])=[CH:36][CH:35]=[CH:34][C:29]=2[C:30]([NH:32][CH3:33])=[O:31])[C:24]([Cl:39])=[CH:23][N:22]=1>>[Cl:39][C:24]1[C:25]([NH:27][C:28]2[C:37]([F:38])=[CH:36][CH:35]=[CH:34][C:29]=2[C:30]([NH:32][CH3:33])=[O:31])=[N:26][C:21]([NH:1][C:2]2[CH:19]=[CH:18][C:5]3[CH2:6][CH2:7][N:8]([CH2:11][C@@H:12]([OH:17])[C:13]([F:16])([F:14])[F:15])[CH2:9][CH2:10][C:4]=3[CH:3]=2)=[N:22][CH:23]=1
Reactant: Nc1ccc2c(c1)CCN(C[C@@H](O)C(F)(F)F)CC2
Reactant: CNC(=O)c1cccc(F)c1Nc1nc(Cl)ncc1Cl
Product: CNC(=O)c1cccc(F)c1Nc1nc(Nc2ccc3c(c2)CCN(C[C@@H](O)C(F)(F)F)CC3)ncc1Cl

Procedure:
2-{5-Chloro-2-[3-((R)-3,3,3-trifluoro-2-hydroxy-propyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-ylamino]-pyrimidin-4-ylamino}-3-fluoro-N-methyl-benzamide was prepared from (R)-3-(7-amino-1,2,4,5-tetrahydro-benzo[d]azepin-3-yl)-1,1,1-trifluoro-propan-2-ol and 2-(2,5-dichloro-pyrimidin-4-ylamino)-3-fluoro-N-methyl-benzamide in an analogous manner to Example 328. Product isolated as a white foam (36 mg, 24%). LCMS (m/e) 553 (M+1); 1H-NMR (CDCl3, 400 MHz) δ 8.78 (s, 1H), 8.09 (s, 1H), 7.38-7.26 (m, 3H), 7.19 (s, 1H), 7.15 (d, 1H, J=8.1 Hz), 6.92 (d, 1H, J=8.1 Hz), 6.86 (s, 1H), 6.15-6.05 (m, 1H), 4.40 (bs, 1H), 4.12-4.00 (m, 1H), 2.94 (d, 3H, J=4.9 Hz), 2.91-2.60 (m, 10H).
Reaction SMILES: CS(C)=O.[CH3:5][NH:6][C@H:7]1[CH2:11][CH2:10][NH:9][CH2:8]1.[C:12]([C:14]1[C:19]2[N:20]=[C:21]([C:23]([N:25]([CH2:27][CH3:28])[CH3:26])=[O:24])[O:22][C:18]=2[C:17](F)=[C:16]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[C:15]=1[CH3:36])#[N:13].C(N(CC)CC)C>[Cl-].[Na+].O>[C:12]([C:14]1[C:19]2[N:20]=[C:21]([C:23]([N:25]([CH2:27][CH3:28])[CH3:26])=[O:24])[O:22][C:18]=2[C:17]([N:9]2[CH2:10][CH2:11][C@H:7]([NH:6][CH3:5])[CH2:8]2)=[C:16]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[C:15]=1[CH3:36])#[N:13]
Reactant: CN[C@H]1CCNC1
Reactant: CCN(C)C(=O)c1nc2c(C#N)c(C)c(-c3ccccc3)c(F)c2o1
Agent: [Cl-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Solvent: CCN(CC)CC
Product: CCN(C)C(=O)c1nc2c(C#N)c(C)c(-c3ccccc3)c(N3CC[C@H](NC)C3)c2o1
Reaction time: 2.67 h
Yield: 32.2 %

Procedure:
Under nitrogen atmosphere, a dimethyl sulfoxide (1 ml) solution of (3S)-3-(methylamino)pyrrolidine (67 μl, 633 μmol) was added at 140 to 150° C. to a dimethyl sulfoxide (10 ml) solution of 4-cyano-N-ethyl-7-fluoro-N,5-dimethyl-6-phenyl-1,3-benzoxazole-2-carboxamide (I-285) (178 mg, 528 μmol) and triethylamine (96 μl, 686 μmol), followed by stirring at the same temperature for 160 minutes. After cooling, saturated brine was added to the reaction liquid, and the reaction liquid was extracted with ethyl acetate. Next, the combined organic layer was washed with saturated brine, then dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated under the reduced pressure. The resulting residue was purified by preparative TLC (eluent, dichloromethane:methanol=10:1, v/v) to obtain the entitled compound (71 mg, 32%) as an amorphous substance.
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:10]=[C:9]([NH:11][C@H:12]([CH2:14][CH3:15])[CH3:13])[N:8]=[C:7]([C:16]([O:18][CH2:19][CH3:20])=[O:17])[CH:6]=1)=[O:4].Cl>C1COCC1.[OH-].[Li+]>[CH3:20][CH2:19][O:18][C:16]([C:7]1[CH:6]=[C:5]([C:3]([OH:4])=[O:2])[CH:10]=[C:9]([NH:11][C@H:12]([CH2:14][CH3:15])[CH3:13])[N:8]=1)=[O:17]
Reactant: CCOC(=O)c1cc(C(=O)OC)cc(N[C@@H](C)CC)n1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CCOC(=O)c1cc(C(=O)O)cc(N[C@@H](C)CC)n1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Dissolve (S)-6-sec-butylaminopyridine-2,4-dicarboxylic acid 2-ethyl ester 4-methyl ester (990 mg, 3.5 mmol) in THF (35 mL) and dropwise add 1 N lithium hydroxide solution (3.5 mL). Stir at room temperature for 2 h and acidify the mixture to about pH=4 by 5 N HCl and concentrate to near dryness. Dilute with ethyl acetate (20 mL) and wash the organic layer with saturated sodium chloride solution, dry (magnesium sulfate) and concentrate to give a 2:1 ratio of crude title compound to starting material which is used in the next step without further purification.
Reaction SMILES: Br[CH2:2][C:3](=O)[C:4]([OH:6])=[O:5].[CH3:8][N:9]([CH3:13])[C:10]([NH2:12])=[S:11]>C1COCC1>[CH3:8][N:9]([CH3:13])[C:10]1[S:11][CH:2]=[C:3]([C:4]([OH:6])=[O:5])[N:12]=1
Reactant: O=C(O)C(=O)CBr
Reactant: CN(C)C(N)=S
Solvent: C1CCOC1
Product: CN(C)c1nc(C(=O)O)cs1
Temperature: 25 °C
Reaction time: 4 h
Yield: 87.1 %

Procedure:
3-Bromopyruvic acid (2.94 g, 17.6 mmol) was added to a stirred solution of 1,1-dimethyl-thiourea (1.87 g, 17.6 mmol) in dry THF (60 mL). The reaction mixture was stirred at rt for 4 hrs. The precipitate that had formed was filtered off, washed with cold THF and dried on high vacuum. LC-MS showed the product peak. The product was obtained as a white solid (2.64 g, 59%).
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][C:8]([NH:10][C:11]3[CH:16]=[N:15][CH:14]=[C:13](Cl)[N:12]=3)=[CH:9][C:4]=2[N:3]=[CH:2]1.[N:18]1[CH:23]=[CH:22][C:21](B(O)O)=[CH:20][CH:19]=1.C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[N:18]1[CH:23]=[CH:22][C:21]([C:13]2[N:12]=[C:11]([NH:10][C:8]3[CH:7]=[CH:6][C:5]4[S:1][CH:2]=[N:3][C:4]=4[CH:9]=3)[CH:16]=[N:15][CH:14]=2)=[CH:20][CH:19]=1
Reactant: OB(O)c1ccncc1
Reactant: Clc1cncc(Nc2ccc3scnc3c2)n1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: c1cc(-c2cncc(Nc3ccc4scnc4c3)n2)ccn1
Yield: 50.3 %

Procedure:
A mixture of benzothiazol-5-yl-(6-chloro-pyrazin-2-yl)-amine (0.06 g, 0.228 mmol), pyridine-4-boronic acid (0.043 g, 0.342 mmol), sodium carbonate (0.124 g, 1.14 mmol) and tetrakis(triphenylphosphine)palladium(0) (0.013 g, 0.0114 mmol) in DME:water (3:2, 5 mL) was heated at reflux for 22 h. The reaction mixture was concentrated under reduced pressure and the residue obtained was extracted with dichloromethane. The organic layer was washed with water, brine, dried over sodium sulfate and concentrated. The crude product was purified by flash chromatography (5% methanol in CH2Cl2 as eluent) to yield N-(6-pyridin-4-ylpyrazin-2-yl)-1,3-benzothiazol-5-amine (0.035 g, 50%) as a yellow solid. 1H NMR (CD3OD) δ 9.31 (s, 1H), 8.98 (d, J=2.02 Hz, 1H), 8.75-8.74 (d, J=5.31 Hz, 2H), 8.64 (s, 1H), 8.31 (s, 1H), 8.24-8.22 (d, J=5.99 Hz, 2H), 8.06-8.04 (d, J=8.77 Hz, 1H), 7.74-7.71 (dd, J=10.73, 2.01 Hz, 1H); MS (API-ES/Positive); m/z: 306 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([CH2:8][C:9]([C:11]2[C:12]([F:24])=[C:13]([NH:17][C:18](=[O:23])[O:19][CH2:20][CH:21]=[CH2:22])[CH:14]=[CH:15][CH:16]=2)=[O:10])[CH:5]=[CH:4][N:3]=1.C1C(=O)N([Br:32])C(=O)C1.O>CC(N(C)C)=O>[Br:32][CH:8]([C:6]1[CH:5]=[CH:4][N:3]=[C:2]([Cl:1])[N:7]=1)[C:9]([C:11]1[C:12]([F:24])=[C:13]([NH:17][C:18](=[O:23])[O:19][CH2:20][CH:21]=[CH2:22])[CH:14]=[CH:15][CH:16]=1)=[O:10]
Reactant: C=CCOC(=O)Nc1cccc(C(=O)Cc2ccnc(Cl)n2)c1F
Reactant: O=C1CCC(=O)N1Br
Solvent: O
Solvent: CC(=O)N(C)C
Product: C=CCOC(=O)Nc1cccc(C(=O)C(Br)c2ccnc(Cl)n2)c1F
Temperature: 25 °C
Reaction time: 8 h
Yield: 99.5 %

Procedure:
To a stirring mixture of 2-propen-1-yl {3-[(2-chloro-4-pyrimidinyl)acetyl]-2-fluorophenyl}carbamate (5 g, 14.30 mmol) in DMA (100 ml) was added NBS (2.54 g, 14.30 mmol) and mixture was stirred at 25° C. overnight. The reaction mixture was poured into water (400 ml) and extracted with EtOAc (100 ml×3). The combined organic layers were dried over Na2SO4 and evaporated to afford the title compound as a yellow oil (6.1 g, 99%). MS (ES): 427 [M+H]+.
Reaction SMILES: Cl.[C:2]([N:5]1[CH2:10][CH2:9][CH:8]([CH2:11][CH2:12][C:13]([OH:15])=[O:14])[CH2:7][CH2:6]1)(=[NH:4])[NH2:3].[C:16]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1O)#[N:17].C1(N=C=NC2CCCCC2)CCCCC1>N1C=CC=CC=1>[C:2]([N:5]1[CH2:10][CH2:9][CH:8]([CH2:11][CH2:12][C:13]([O:15][C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=2[C:16]#[N:17])=[O:14])[CH2:7][CH2:6]1)(=[NH:3])[NH2:4]
Reactant: N=C(N)N1CCC(CCC(=O)O)CC1
Reactant: N#Cc1ccccc1O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Cl
Solvent: c1ccncc1
Product: N#Cc1ccccc1OC(=O)CCC1CCN(C(=N)N)CC1
Yield: 41.6 %

Procedure:
A mixture of 4.0 g of 1-amidino-4-piperidinepropionic acid hydrochloride, 2.0 g of o-cyanophenol and 3.5 g of dicyclohexylcarbodiimide was stirred at room temperature for 24 hours in 20 ml of dry pyridine. Any insoluble materials were filtered and washed with dry pyridine. The filtrate and washings were combined together, and the solvent was removed under reduced pressure. Ethyl acetate was added to the residue to give crystals which were then recrystallized from water to obtain 2.1 g (yield: 37%) of o-cyanophenyl 1-amidino-4-piperidinepropionate as colorless crystals having a melting point of 159.5° to 162.5° C.
Reaction SMILES: [OH:1][C:2]1[C:7]2[C@@:8]3([OH:45])[C@@:21]([O:25][CH3:26])([C@H:22]([OH:24])[CH2:23][C:6]=2[CH:5]=[C:4]([CH3:46])[C:3]=1[C:47]([O:49][CH3:50])=[O:48])[C:20](=[O:27])[C:19]1[C:10](=[CH:11][C:12]2[C:13](=[O:43])[C:14]([NH:30][C@@H:31]4[C@H:36]([O:37][CH3:38])[C@H:35]([OH:39])[C@@H:34]([O:40][CH3:41])[C@H:33]([CH3:42])[O:32]4)=[CH:15][C:16](=[NH:29])[C:17]=2[C:18]=1[OH:28])[C:9]3=[O:44].[Br-].[CH2:52]([O:54][C:55](=[O:59])[CH2:56][CH2:57][Zn+])[CH3:53]>C1COCC1>[CH2:52]([O:54][C:55](=[O:59])[CH2:56][CH2:57][C:13]1([OH:43])[C:12]2[CH:11]=[C:10]3[C:19]([C:20](=[O:27])[C@@:21]4([O:25][CH3:26])[C@@:8]([OH:45])([C:9]3=[O:44])[C:7]3[C:2]([OH:1])=[C:3]([C:47]([O:49][CH3:50])=[O:48])[C:4]([CH3:46])=[CH:5][C:6]=3[CH2:23][C@H:22]4[OH:24])=[C:18]([OH:28])[C:17]=2[C:16](=[NH:29])[CH:15]=[C:14]1[NH:30][C@@H:31]1[C@H:36]([O:37][CH3:38])[C@H:35]([OH:39])[C@@H:34]([O:40][CH3:41])[C@H:33]([CH3:42])[O:32]1)[CH3:53]
Reactant: COC(=O)c1c(C)cc2c(c1O)[C@]1(O)C(=O)c3cc4c(c(O)c3C(=O)[C@]1(OC)[C@H](O)C2)C(=N)C=C(N[C@H]1O[C@@H](C)[C@H](OC)[C@@H](O)[C@H]1OC)C4=O
Reactant: CCOC(=O)CC[Zn+]
Agent: [Br-]
Solvent: C1CCOC1
Product: CCOC(=O)CCC1(O)C(N[C@H]2O[C@@H](C)[C@H](OC)[C@@H](O)[C@H]2OC)=CC(=N)c2c1cc1c(c2O)C(=O)[C@]2(OC)[C@H](O)Cc3cc(C)c(C(=O)OC)c(O)c3[C@]2(O)C1=O
Temperature: -78 °C
Reaction time: 2 h
Yield: 12 %

Procedure:
To a −78° C. solution of (6R,6aS,14aR)-methyl 1,6,8,14a-tetrahydroxy-11-((2S,3R,4R,5R,6S)-4-hydroxy-3,5-dimethoxy-6-methyltetrahydro-2H-pyran-2-ylamino)-9-imino-6a-methoxy-3-methyl-7,12,14-trioxo-5,6,6a,7,9,12,14,14a-octahydrobenzo[a]tetracene-2-carboxylate (50 mg, 0.072 mmol) in THF (2 mL) was added a solution of 3-ethoxy-3-oxopropylzinc bromide in THF (0.5 M, 1.15 mL, 0.58 mmol) dropwise. The reaction mixture was stirred at −78° C. for 2 h, and then quenched with a saturated solution of ammonium chloride. The mixture was extracted with chloroform (3×10 mL). The combined organics were dried (Na2SO4), filtered and concentrated. The crude was purified by preparative TLC (silica gel, 85:15 chloroform/methanol) to afford (6R,6aS,14aR)-methyl 12-(3-ethoxy-3-oxopropyl)-1,6,8,12,14a-pentahydroxy-11-((2S,3R,4R,5R,6S)-4-hydroxy-3,5-dimethoxy-6-methyltetrahydro-2H-pyran-2-ylamino)-9-imino-6a-methoxy-3-methyl-7,14-dioxo-5,6,6a,7,9,12,14,14a-octahydrobenzo[a]tetracene-2-carboxylate (7 mg, 12%) as an orange solid and as a mixture of diastereomers: 1H NMR (500 MHz, CD3OD) δ 7.18 (s, 1H), 6.57 (s, 1H), 5.54 (s, 1H), 4.96 (s, 1H), 4.88-4.83 (m, 2H), 3.84 (s, 3H), 3.76 (s, 3H), 3.75-3.66 (m, 3H), 3.57 (s, 3H), 3.34 (s, 3H), 3.25-3.16 (m, 2H), 3.03 (t, J=9.0 Hz, 1H), 2.39 (s, 3H), 2.15-1.85 (m, 4H), 1.45-1.26 (m, 1H), 1.25 (d, J=5.5 Hz, 3H), 1.09 (t, J=7.0 Hz, 3H); MS (ESI+) m/z 799 (M+H); HPLC >99% (AUC), tR 10.04 min.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[C:4]([Cl:12])[C:3]=1[NH:13][NH:14][CH:15]([CH2:18][C:19]#[N:20])[C:16]#[N:17]>ClC1C=CC=CC=1>[NH2:20][C:19]1[N:13]([C:3]2[C:2]([Cl:1])=[CH:7][C:6]([C:8]([F:10])([F:11])[F:9])=[CH:5][C:4]=2[Cl:12])[N:14]=[C:15]([C:16]#[N:17])[CH:18]=1
Reactant: N#CCC(C#N)NNc1c(Cl)cc(C(F)(F)F)cc1Cl
Solvent: Clc1ccccc1
Product: N#Cc1cc(N)n(-c2c(Cl)cc(C(F)(F)F)cc2Cl)n1

Procedure:
A mixture of 2-(2,6-dichloro-4-trifluoromethylphenylhydrazino)succinonitrile (0.323 g) and cupric chloride (0.175 g) was heated in chlorobenzene at 60° C. for 6 hours. After filtration and evaporation the title compound and 5-amino-3-cyano-1-(2,6-dichloro-4-trifluoromethylphenyl)pyrazole were obtained as a 7:1 mixture. Column chromatography on silica gel eluting with dichloromethane gave the pure title compound, obtained as a mixture of syn and anti isomers, NMR (anti isomer) 3.6(s,2H), 7.57(s,2H), 8.82(s,1H, exchangeable with D2O), NMR (syn isomer) 3.56(s,2H), 7.59(s,2H), 8.27(s,1H,exchangeable with D2O).
Reaction SMILES: [C-:1]#[N:2].[Na+].Cl[C:5]1[CH:6]=[C:7]([C:11]2[N:12]=[N:13][C:14]([NH:17][CH2:18][C:19]([C:22]3[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=3)([CH3:21])[CH3:20])=[CH:15][N:16]=2)[CH:8]=[CH:9][CH:10]=1>CN1C(=O)CCC1>[F:28][C:25]1[CH:26]=[CH:27][C:22]([C:19]([CH3:21])([CH3:20])[CH2:18][NH:17][C:14]2[N:13]=[N:12][C:11]([C:7]3[CH:6]=[C:5]([CH:10]=[CH:9][CH:8]=3)[C:1]#[N:2])=[N:16][CH:15]=2)=[CH:23][CH:24]=1
Reactant: CC(C)(CNc1cnc(-c2cccc(Cl)c2)nn1)c1ccc(F)cc1
Reactant: [C-]#N
Agent: [Na+]
Solvent: CN1CCCC1=O
Product: CC(C)(CNc1cnc(-c2cccc(C#N)c2)nn1)c1ccc(F)cc1
Temperature: 200 °C
Yield: 48.7 %

Procedure:
To a microwave vial containing NiBr2 (280 mg, 1.3 mmol) and NaCN (120 mg, 2.5 mmol) was added a solution of 3-(3-chlorophenyl)-N-(2-(4-fluorophenyl)-2-methylpropyl)-1,2,4-triazin-6-amine (450 mg, 1.3 mmol) in NMP (4.0 mL). The vial was purged with nitrogen and sealed. The mixture was heated to 200° C. in a microwave for 25 min and allowed to cool to room temperature. The solution was diluted with EtOAc/ether (1:1), washed with water (3×), dried over Na2SO4 and evaporated to dryness. Purification using silica gel chromatography (0-65% EtOAc/hexanes) gave the desired product (220 mg) as an off white foam.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:10]=[CH:9][C:6]([CH2:7][NH2:8])=[CH:5][CH:4]=1.C([O-])([O-])=O.[K+].[K+].[Br:17][C:18]1[S:26][C:25]2[C:24]([C:27]#[N:28])=[CH:23][N:22]=[C:21](Cl)[C:20]=2[CH:19]=1>CN1CCCC1=O>[Br:17][C:18]1[S:26][C:25]2[C:24]([C:27]#[N:28])=[CH:23][N:22]=[C:21]([NH:8][CH2:7][C:6]3[CH:9]=[CH:10][C:3]([O:2][CH3:1])=[CH:4][CH:5]=3)[C:20]=2[CH:19]=1
Reactant: N#Cc1cnc(Cl)c2cc(Br)sc12
Reactant: COc1ccc(CN)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN1CCCC1=O
Product: COc1ccc(CNc2ncc(C#N)c3sc(Br)cc23)cc1
Temperature: 130 °C
Yield: 66.5 %

Procedure:
To a stirred solution of 4-methoxybenzylamine (1.2 equiv., 2.4 mmol) and K2CO3 (2.4 equiv., 4.8 mmol) in 5 mL anhydrous 1-methyl-2-pyrrolidinone was added 15 (1 equiv., 2 mmol). The mixture was heated at 130° C. under N2 for 1.5 h, allowed to cool, and the product precipitated by the addition of H2O (5 mL). The mixture was filtered, washed with water, and dried, yielding 16 (1.33 mmol) as a brown solid. 1H NMR (400 MHz, d6-DMSO) δ: 8.75 (1H, t, broad), 8.56 (1H, s), 8.21 (1H, s), 7.43 (2H, d, J=8.6 Hz), 7.04 (2H, d, J=8.6), 4.84 (2H, d, J=5.8), 3.88 (3H, s).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C@H:8]([NH:10][C:11](=[O:13])[CH3:12])[CH3:9])[CH:5]=[N:6][CH:7]=1.[H-].[Na+].I[CH3:17]>C1COCC1.C(Cl)Cl>[Br:1][C:2]1[CH:3]=[C:4]([C@H:8]([N:10]([CH3:17])[C:11](=[O:13])[CH3:12])[CH3:9])[CH:5]=[N:6][CH:7]=1
Reactant: CC(=O)N[C@H](C)c1cncc(Br)c1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: ClCCl
Solvent: C1CCOC1
Product: CC(=O)N(C)[C@H](C)c1cncc(Br)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 87.1 %

Procedure:
To a vial is added N-[(R)-1-(5-bromo-pyridin-3-yl)-ethyl]-acetamide (111 mg, 0.46 mmol) in 3 ml of THF, followed by the addition of 60% NaH (35 mg, 0.92 mmol). Then iodomethane (130 mg, 0.91 mmol) is added. The reaction mixture is stirred at room temperature for 18 hours. The reaction mixture is diluted with DCM, washed with water, brine, dried over anhydrous Na2SO4, filtered and concentrated to give the crude product. Purification by the flash column chromatography affords 103 mg of N-[(R)-1-(5-bromo-pyridin-3-yl)-ethyl]-N-methyl-acetamide.
Reaction SMILES: [C:1]([O:5][C:6](=[O:18])[N:7]([C:9]1[CH:14]=[CH:13][C:12]([C:15](Cl)=[O:16])=[CH:11][N:10]=1)[CH3:8])([CH3:4])([CH3:3])[CH3:2].[CH3:19][CH:20]1[CH2:32][C:24]2[N:25]=[C:26]([NH:28][C:29](=[O:31])[CH3:30])[S:27][C:23]=2[C:22](=[O:33])[CH2:21]1>>[C:1]([O:5][C:6](=[O:18])[N:7]([C:9]1[CH:14]=[CH:13][C:12]([C:15]([CH:21]2[CH:20]([CH3:19])[CH2:32][C:24]3[N:25]=[C:26]([NH:28][C:29](=[O:31])[CH3:30])[S:27][C:23]=3[C:22]2=[O:33])=[O:16])=[CH:11][N:10]=1)[CH3:8])([CH3:4])([CH3:3])[CH3:2]
Reactant: CN(C(=O)OC(C)(C)C)c1ccc(C(=O)Cl)cn1
Reactant: CC(=O)Nc1nc2c(s1)C(=O)CC(C)C2
Product: CC(=O)Nc1nc2c(s1)C(=O)C(C(=O)c1ccc(N(C)C(=O)OC(C)(C)C)nc1)C(C)C2

Procedure:
A-13 is prepared via general procedure A1 starting from (5-chlorocarbonyl-pyridin-2-yl)-methyl-carbamic acid tert-butyl ester (A-10) (7.24 g, 26.8 mmol) and N-(5-methyl-7-oxo-4,5,6,7-tetrahydro-benzothiazol-2-yl)-acetamide (A-06) (5.00 g, 22.3 mmol). After evaporation of the solvent 7.72 g of A-13 is obtained that is used without further purification in the next step.
Reaction SMILES: [OH-].[Na+].[Br:3][CH2:4][C:5](Br)=[O:6].[CH3:8][NH:9][C:10]1[C:11](=[CH:16][CH:17]=[CH:18][CH:19]=1)[C:12]([O:14][CH3:15])=[O:13]>ClCCl>[Br:3][CH2:4][C:5]([N:9]([C:10]1[CH:19]=[CH:18][CH:17]=[CH:16][C:11]=1[C:12]([O:14][CH3:15])=[O:13])[CH3:8])=[O:6]
Reactant: CNc1ccccc1C(=O)OC
Reactant: O=C(Br)CBr
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Product: COC(=O)c1ccccc1N(C)C(=O)CBr
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 73.2 %

Procedure:
Sodium hydroxide solution (1.5M, 50 ml) was added dropwise to an ice cooled mixture of bromoacetyl bromide (11 g) and methyl N-methylanthranilate (8.2 g) in dichloromethane (250 ml). After the addition was complete (15 min) stirring was continued at room temperature for 20 min. The organic phase was then separated, washed with 1N HCl (50 ml), brine (50 ml), NaHCO3 solution (50 ml), dried (MgSO4) and evaporated to give a colourless oil which crystallised on standing. Trituration with pet-ether (bp 60°-80°) followed by filtration afforded 10.4 g of product as a colourless solid. 1H NMR (360 MHz, CDCl3) δ: 3.23 (3H, s), 3.54 and 3.60 (2H, ABq J=11 Hz), 3.90 (3H, s), 7.40 (1H, d, J=8 Hz), 7.51 (1H, t, J=8 Hz), 7.65 (1H, t, J=8 Hz), 8.04 (1H, d, J=8 Hz).
Reaction SMILES: [OH:1][C@@H:2]1[CH2:7][CH2:6][C@H:5]([NH:8][C:9]2[N:14]3[N:15]=[C:16]([NH:18][C:19]4[CH:27]=[C:26]5[C:22]([C:23](=O)[C:24](=[O:29])[N:25]5[CH3:28])=[C:21]([CH3:31])[CH:20]=4)[N:17]=[C:13]3[CH:12]=[CH:11][CH:10]=2)[CH2:4][CH2:3]1.BrC1C=C2C(C(=O)C(=O)N2C)=C(C)C=1.NC1N=C2C=CC=C(N[C@@H]3CC[C@H](O)CC3)N2N=1.C(=O)([O-])[O-].[Cs+].[Cs+].C1(P(C2C=CC=CC=2)C2C3OC4C(=CC=CC=4P(C4C=CC=CC=4)C4C=CC=CC=4)C(C)(C)C=3C=CC=2)C=CC=CC=1>O1CCOCC1.[Pd].[Pd].C(=CC(C=CC1C=CC=CC=1)=O)C1C=CC=CC=1.C(=CC(C=CC1C=CC=CC=1)=O)C1C=CC=CC=1.C(=CC(C=CC1C=CC=CC=1)=O)C1C=CC=CC=1>[OH:1][C@@H:2]1[CH2:7][CH2:6][C@H:5]([NH:8][C:9]2[N:14]3[N:15]=[C:16]([NH:18][C:19]4[CH:27]=[C:26]5[C:22]([CH2:23][C:24](=[O:29])[N:25]5[CH3:28])=[C:21]([CH3:31])[CH:20]=4)[N:17]=[C:13]3[CH:12]=[CH:11][CH:10]=2)[CH2:4][CH2:3]1
Reactant: Cc1cc(Nc2nc3cccc(N[C@H]4CC[C@@H](O)CC4)n3n2)cc2c1C(=O)C(=O)N2C
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: Cc1cc(Br)cc2c1C(=O)C(=O)N2C
Solvent: C1COCCO1
Product: Cc1cc(Nc2nc3cccc(N[C@H]4CC[C@@H](O)CC4)n3n2)cc2c1CC(=O)N2C
Temperature: 90 °C
Reaction time: 17 h

Procedure:
cis-6-(5-(4-Hydroxycyclohexylamino)-[1,2,4]triazolo[1,5-a]pyridin-2-ylamino)-1,4-dimethylindoline-2,3-dione. A mixture of 6-bromo-1,4-dimethylindoline-2,3-dione (0.34 g, 1.338 mmol), cis-4-(2-amino-[1,2,4]triazolo[1,5-a]pyridin-5-ylamino)cyclohexanol (0.446 g, 1.804 mmol), cesium carbonate (1.308 g, 4.01 mmol), tris(dibenzylideneacetone) dipalladium(0) (0.245 g, 0.268 mmol) and 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (0.310 g, 0.535 mmol) in 1,4-dioxane (6 mL) was degassed for 2 min and then stirred at 90° C. for 17 h. The cooled reaction solution was filtered through Celite and the filter cake was washed with dichloromethane and methanol. The solvent was removed under reduced pressure. Purification by column chromatography (eluting with 0-10% methanol in dichloromethane) provided the title compound as a yellow solid (0.22 g, 39.1% yield). MS (ESI) m/z 421.5 [M+H]+.