Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[N:10][C:11](Cl)=[CH:12][C:13]=2O)=[CH:4][CH:3]=1.P(Br)(Br)([Br:18])=O.[BrH:21]>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[N:10][C:11]([Br:18])=[CH:12][C:13]=2[Br:21])=[CH:4][CH:3]=1
Reactant: Oc1cc(Cl)nnc1-c1ccc(Cl)cc1
Reactant: O=P(Br)(Br)Br
Reactant: Br
Solvent: Cc1ccccc1
Product: Clc1ccc(-c2nnc(Br)cc2Br)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 86.1 %

Procedure:
3-(4'-Chlorophenyl)-4-hydroxy-6-chloropyridazine (Compound 1, 24.1 g, 0.09997 mol) was initially introduced into a reaction flask and a solution of phosphorus oxybromide (85.8 g, 0.3 mol) in toluene (150 ml) was added, and the reaction mixture was then stirred for one hour at room temperature. The mixture was then refluxed gently for three hours, during which process gaseous hydrogen bromide was given off. The mixture was decomposed on ice, which gave a pasty reaction product, which solidified on trituration with petroleum ether. The product was then washed thoroughly with water, isolated and dried to constant weight. 30.0 g (0.0861 mol, 86.1% of theory) of 3-(4'-chlorophenyl)-4,6-dibromopyridazine of m.p.=160°-162° C. were obtained. Recrystallized from an ethanol/dioxane mixture (20+3), the sample showed a melting point of 163°-165° C.
Reaction SMILES: [CH:1]([N:4]1[C:8]([C:9]2[N:10]=[C:11]3[C:17]4[CH:18]=[CH:19][C:20]([C:22]5[CH:23]=[N:24][N:25]([C:27]([CH3:33])([CH3:32])[C:28]([O:30]C)=[O:29])[CH:26]=5)=[CH:21][C:16]=4[O:15][CH2:14][CH2:13][N:12]3[CH:34]=2)=[N:7][CH:6]=[N:5]1)([CH3:3])[CH3:2].[OH-].[Li+].[CH3:37]O>O>[CH:1]([N:4]1[C:8]([C:9]2[N:10]=[C:11]3[C:17]4[CH:18]=[CH:19][C:20]([C:22]5[CH:23]=[N:24][N:25]([C:27]([CH3:32])([CH3:33])[C:28]([OH:30])=[O:29])[CH:26]=5)=[CH:21][C:16]=4[O:15][CH2:14][CH2:13][N:12]3[CH:34]=2)=[N:7][C:6]([CH3:37])=[N:5]1)([CH3:3])[CH3:2]
Reactant: CO
Reactant: COC(=O)C(C)(C)n1cc(-c2ccc3c(c2)OCCn2cc(-c4ncnn4C(C)C)nc2-3)cn1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Product: Cc1nc(-c2cn3c(n2)-c2ccc(-c4cnn(C(C)(C)C(=O)O)c4)cc2OCC3)n(C(C)C)n1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
The mixture of methyl 2-(4-(2-(1-isopropyl-1H-1,2,4-triazol-5-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-9-yl)-1H-pyrazol-1-yl)-2-methylpropanoate and corresponding acid (100 mg, 0.22 mmol) was treated with 1 M of lithium hydroxide in water (2 mL) and methanol (0.37 mL). The reaction was stirred at room temp for 12 h. Acidified by 10% aqueous citric acid to pH=5 and extracted with EtOAc twice. The combined organic layers were washed with brine, dried and concentrated to give 2-(4-(2-(1-isopropyl-3-methyl-1H-1,2,4-triazol-5-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-9-yl)-1H-pyrazol-1-yl)-2-methylpropanoic acid 216. 1H NMR (400 MHz, DMSO) δ 8.44 (s, 1H), 8.39 (s, 0H), 8.37 (s, 1H), 7.98 (s, 1H), 7.92 (s, 2H), 7.45 (dd, J=8.4, 1.8, 1H), 7.36 (d, J=1.7, 1H), 5.90 (dt, J=13.2, 6.6, 1H), 4.53 (q, J=6.0, 4H), 1.72 (d, J=42.8, 6H), 1.50 (d, J=6.6, 6H).
Reaction SMILES: [Br:1][CH2:2][C:3]1[CH:11]=[CH:10][CH:9]=[CH:8][C:4]=1[C:5]([OH:7])=[O:6].[CH2:12](O)[C:13]([Cl:16])([Cl:15])[Cl:14].C(Cl)CCl.Cl>CN(C1C=CN=CC=1)C.C(Cl)Cl.O>[Cl:14][C:13]([Cl:16])([Cl:15])[CH2:12][O:6][C:5](=[O:7])[C:4]1[CH:8]=[CH:9][CH:10]=[CH:11][C:3]=1[CH2:2][Br:1]
Reactant: O=C(O)c1ccccc1CBr
Reactant: OCC(Cl)(Cl)Cl
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCCl
Solvent: O
Solvent: ClCCl
Product: O=C(OCC(Cl)(Cl)Cl)c1ccccc1CBr
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 49.7 %

Procedure:
To a suspension of 2-(bromomethyl)benzoic acid (1.0 g, 4.65 mmol), β-trichloroethanol (0.54 mL, 5.58 mmol) and DMAP (0.057 g, 0.465 mmol) in DCM (20 mL) was added EDC×HCl (1.34 g, 6.98 mmol) at 0° C. The solution was stirred at 0° C. for 0.5 h and thereafter allowed to reach rt and stirred overnight. Water was added and the phases were separated through a phase separator. The organic portion was concentrated and the crude was submitted to flash chromatography using heptane and EtOAc (90/10) as eluent to yield the titled compound (0.80 g, 50%) as an oil; 1H NMR (400 MHz, CDCl3): δ 4.99 (s, 2H), 5.08 (s, 2H), 7.46 (m, 1H), 7.60 (m, 2H), 8.13 (d, 1H).
Reaction SMILES: Cl[C:2]1[N:3]=[CH:4][CH:5]=[C:6]2[CH:10]=[CH:9][S:8][C:7]=12.O.[SH2:12].[Na].Cl>CN(C)C=O>[S:8]1[C:7]2[C:2](=[S:12])[NH:3][CH:4]=[CH:5][C:6]=2[CH:10]=[CH:9]1
Reactant: Clc1nccc2ccsc12
Reactant: S
Agent: Cl
Agent: [Na]
Solvent: CN(C)C=O
Solvent: O
Product: S=c1[nH]ccc2ccsc12
Temperature: 0 °C

Procedure:
(adc) 4.85 g of 7-chloro-thieno[2,3-c]pyridine was dissolved in 15 ml of dimethylformamide and 3.18 g of sodium hydrogen sulfide monohydrate were added under argon. The mixture was heated to 110°-115° for one hour, an additional 1.06 g of sodium hydrogen sulfide monohydrate were added and the mixture was held at the temperature indicated above for an additional hour. The mixture was poured on to 150 ml of ice-water and acidified with 1N aqueous hydrochloric acid solution. After stirring at 2° for a short time, the yellowish crystals were removed by filtration. After recrystallization from a toluene/ethyl acetate mixture, there was obtained pure thieno[2,3-c]pyridine-7(6H)-thione, m.p. 187°-189°.
Reaction SMILES: C([Si](C)(C)[O:6][C:7]1[C:8](=O)[C:9](=[CH:13]N(C)C)[CH2:10][CH2:11][CH:12]=1)(C)(C)C.[NH:20]([C:24]1[CH:25]=[C:26]([S:30]([NH2:33])(=[O:32])=[O:31])[CH:27]=[CH:28][CH:29]=1)[C:21]([NH2:23])=[NH:22].C(=O)([O-])[O-].[K+].[K+]>CC(N(C)C)=O>[OH:6][C:7]1[C:8]2[N:23]=[C:21]([NH:20][C:24]3[CH:25]=[C:26]([S:30]([NH2:33])(=[O:31])=[O:32])[CH:27]=[CH:28][CH:29]=3)[N:22]=[CH:13][C:9]=2[CH2:10][CH2:11][CH:12]=1
Reactant: N=C(N)Nc1cccc(S(N)(=O)=O)c1
Reactant: CN(C)C=C1CCC=C(O[Si](C)(C)C(C)(C)C)C1=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Product: NS(=O)(=O)c1cccc(Nc2ncc3c(n2)C(O)=CCC3)c1
Temperature: 110 °C
Reaction time: 20 h
Yield: 6.5 %

Procedure:
The crude 2-(tert-butyl-dimethyl-silanyloxy)-6-dimethylaminomethylene-cyclohex-2-enone in DMA (75 mL) was treated with 3-guanidino-benzenesulfonamide as the hydrochloride salt (7.79 g, 31.09 mmol) and potassium carbonate (2.13, g, 15.54 mmol) and the mixture stirred at 110° C. for 20 hours. The mixture was evaporated under high vacuum and triturated with dichloromethane (100 mL) to give a buff coloured precipitate. The precipitate was filtered, the mother liquors concentrated in vacuo and purified by flash chromatography on silica gel eluting with ethyl acetate to give 3-(8-hydroxy-5,6-dihydro-quinazolin-2-ylamino)benzenesulfonamide as a yellow solid (0.63 g, 6.5%). MS (ES+) 319, (ES−) 317. δH (d6 DMSO) 2.04-2.12 (2H, m), 2.66-2.74 (2H, m), 2.84-2.90 (2H, m), 7.33 (2H, s), 7.43 (1H, d), 7.48 (1H, t), 8.16 (1H, d), 8.25 (1H, s), 8.78 (1H, s), 10.25 (1H, s).
Reaction SMILES: ClC(Cl)(OC(=O)OC(Cl)(Cl)Cl)Cl.[Cl:13][C:14]1[C:19]([F:20])=[CH:18][CH:17]=[C:16]([Cl:21])[C:15]=1[C@H:22]([O:24][C:25]1[C:26]2[O:34][CH:33]=[C:32]([C:35]3[CH2:36][CH2:37][NH:38][CH2:39][CH:40]=3)[C:27]=2[CH:28]=[N:29][C:30]=1[NH2:31])[CH3:23].CCN(C(C)C)C(C)C.[N:50]1([C:56](OC(C)(C)C)=[O:57])[CH2:55][CH2:54][NH:53][CH2:52][CH2:51]1>C(Cl)Cl>[NH2:31][C:30]1[N:29]=[CH:28][C:27]2[C:32]([C:35]3[CH2:36][CH2:37][N:38]([C:56]([N:50]4[CH2:55][CH2:54][NH:53][CH2:52][CH2:51]4)=[O:57])[CH2:39][CH:40]=3)=[CH:33][O:34][C:26]=2[C:25]=1[O:24][C@@H:22]([C:15]1[C:16]([Cl:21])=[CH:17][CH:18]=[C:19]([F:20])[C:14]=1[Cl:13])[CH3:23]
Reactant: C[C@@H](Oc1c(N)ncc2c(C3=CCNCC3)coc12)c1c(Cl)ccc(F)c1Cl
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Agent: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: C[C@@H](Oc1c(N)ncc2c(C3=CCN(C(=O)N4CCNCC4)CC3)coc12)c1c(Cl)ccc(F)c1Cl
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A solution of triphosgene (4 mg, 0.01 mmol) in DCM (0.8 mL) was cooled to 0° C. A solution of 7-[(R)-1-(2,6-dichloro-3-fluorophenyl)-ethoxy]-3-(1,2,3,6-tetrahydropyridin-4-yl)-furo[3,2-c]pyridin-6-ylamine (10.0 mg, 0.0237 mmol), DIPEA (0.04 mL, 0.2 mmol) and DCM was added, and the mixture was allowed to warm to rt. A solution of tert-butyl 1-piperazinecarboxylate (8.82 mg, 0.0474 mmol) in DCM was then added, and the mixture was stirred at rt for 30 min. The material was transferred to a separatory funnel and washed with sat. aq. NaHCO3. The organic layer was concentrated in vacuo, redissolved in dioxane and transferred to a sealed tube. 4 M HCl in 1,4-dioxane (0.2 mL) was added, and the solution was heated to 50° C. for 3 h. The material was concentrated in vacuo and redissolved in DMF (0.5 mL). The solution was purified by HPLC. The fractions containing the pure product were concentrated in vacuo to afford the title compound as a brown solid. 1H NMR (CD3OD, 400 MHz): δ=1.89 (d, J=6.8 Hz, 3H), 2.56 (br, s, 2H), 3.21-3.29 (m, 4H), 3.44-3.52 (m, 4H), 3.56 (t, J=5.8 Hz, 2H), 4.08 (d, J=2.5 Hz, 2H), 6.26 (br, s, 1H), 6.50 (q, J=6.7 Hz, 1H), 7.22 (t, J=8.7 Hz, 1H), 7.40 (dd, J=9.0, 4.9 Hz, 1H), 7.66 (s, 1H), 8.19 (s, 1H). MS (ES+): m/z 534.14 [MH+]. HPLC: tR=2.16 min (ZQ2, polar—5 min).
Reaction SMILES: C([O:4][C:5]1[C:6]([O:24][CH3:25])=[CH:7][C:8]2[NH:9][C:10]3[C:15]([S:16](=[O:21])(=[O:20])[C:17]=2[C:18]=1[Br:19])=[CH:14][C:13]([O:22][CH3:23])=[CH:12][CH:11]=3)(=O)C.[OH-].[Na+].C(O)(=O)C>CO.O>[Br:19][C:18]1[C:17]2[S:16](=[O:20])(=[O:21])[C:15]3[C:10](=[CH:11][CH:12]=[C:13]([O:22][CH3:23])[CH:14]=3)[NH:9][C:8]=2[CH:7]=[C:6]([O:24][CH3:25])[C:5]=1[OH:4]
Reactant: COc1ccc2c(c1)S(=O)(=O)c1c(cc(OC)c(OC(C)=O)c1Br)N2
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: CC(=O)O
Solvent: O
Product: COc1ccc2c(c1)S(=O)(=O)c1c(cc(OC)c(O)c1Br)N2
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 106.4 %

Procedure:
To a suspension of 3-acetoxy-4-bromo-2,7-dimethoxy-10H-phenothiazine-5,5-dioxide (10.0 g) in methanol (105 ml) there was added 2N aqueous sodium hydroxide solution (74 ml) and the resulting mixture was stirred at room temperature for 20 minutes. There was then added 10% aqueous acetic acid solution (250 ml) and a thick precipitate was formed. The mixture was diluted with water (105 ml) and filtered, the solid washed with water and ether, and dried in a desiccator, affording the title compound (9.6 g). Further purification of a small sample was achieved through chromatography on a short column of silica gel, eluting with acetone. m.p.: 252°-260° (dec).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:10])[CH:4](Cl)[CH2:5][CH2:6][CH2:7][CH3:8].[O-:11][C:12]#[N:13].[K+].[CH3:15][OH:16]>CN(C=O)C>[CH3:1][O:2][C:3](=[O:10])[CH:4]([NH:13][C:12]([O:16][CH3:15])=[O:11])[CH2:5][CH2:6][CH2:7][CH3:8]
Reactant: N#C[O-]
Reactant: CCCCC(Cl)C(=O)OC
Reactant: CO
Agent: [K+]
Solvent: CN(C)C=O
Product: CCCCC(NC(=O)OC)C(=O)OC
Yield: 67 %

Procedure:
11.52 grams of 2-chlorohexanoic acid methyl ester were heated with 8.52 grams of potassium cyanate and 7.85 grams of methanol in 70 ml of DMF. After a reaction time of 30 hours the reaction mixture was worked up as described in Example 1. There were obtained 9.53 grams (67%) of 2-methoxycarbonylaminohexanoic acid methyl ester with a purity of 99% (determined gas chromatographically).
Reaction SMILES: [CH3:1][CH:2]([CH3:28])[CH:3]([NH:15][C:16]([CH:18]1[CH2:22][CH:21]([CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])[CH2:20][NH:19]1)=[O:17])[CH:4]1[CH:9]([OH:10])[CH:8]([OH:11])[CH:7]([OH:12])[CH:6]([S:13][CH3:14])[O:5]1.[CH2:29]([N:31](CC)CC)[CH3:30].BrCC#N>C(#N)C>[CH3:1][CH:2]([CH3:28])[CH:3]([NH:15][C:16]([CH:18]1[CH2:22][CH:21]([CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])[CH2:20][N:19]1[CH2:30][C:29]#[N:31])=[O:17])[CH:4]1[CH:9]([OH:10])[CH:8]([OH:11])[CH:7]([OH:12])[CH:6]([S:13][CH3:14])[O:5]1
Reactant: CCCCCC1CNC(C(=O)NC(C(C)C)C2OC(SC)C(O)C(O)C2O)C1
Reactant: CCN(CC)CC
Agent: N#CCBr
Solvent: CC#N
Product: CCCCCC1CC(C(=O)NC(C(C)C)C2OC(SC)C(O)C(O)C2O)N(CC#N)C1
Temperature: 25 °C
Reaction time: 18 h
Yield: 4.9 %

Procedure:
A stirred solution of crude 4-pentyl-pyrrolidine-2-carboxylic acid [2-methyl-1-(3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl)-propyl]-amide (210 mg, 0.50 mmol, 1 equiv) and triethylamine (0.21 mL, 1.51 mmol, 3 equiv), in anhydrous acetonitrile (3 mL) was treated with bromoacetonitrile (42 μl, 0.60 mmol, 1.2 equiv), at rt and under nitrogen. The resulting reaction mixture was stirred at rt for 18 h, evaporated to dryness and purified by chromatography over silica gel, with an eluant of 2.5% methanol in dichloromethane. The desired fractions were pooled, evaporated to dryness, and lyophilized to furnish the title compound (11.2 mg, 10%) as a fluffy white powder: TLC Rf=0.2 (5% methanol in dichloromethane); 1H NMR (300 MHz, CD3OD) δ 5.44 (d, J=5.49, 1), 4.38-4.23 (m, 4), 2.29 (s, 3), 1.52 (m, 11), 1.16-1.09 (m, 12); MS (ESPOS): 458.5 [M+H]+, MS (ESNEG): 456.5 [M−H]−.
Reaction SMILES: [OH:1][CH:2]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[CH2:6][CH2:5][N:4]([S:13]([C:16]2[CH:21]=[CH:20][C:19]([CH3:22])=[CH:18][CH:17]=2)(=[O:15])=[O:14])[CH2:3]1.[C:23]1(O)[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>C1C=CC=CC=1>[O:1]([CH:2]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[CH2:6][CH2:5][N:4]([S:13]([C:16]2[CH:17]=[CH:18][C:19]([CH3:22])=[CH:20][CH:21]=2)(=[O:15])=[O:14])[CH2:3]1)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: Cc1ccc(S(=O)(=O)N2CCc3ccccc3C(O)C2)cc1
Reactant: Oc1ccccc1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: c1ccccc1
Product: Cc1ccc(S(=O)(=O)N2CCc3ccccc3C(Oc3ccccc3)C2)cc1
Temperature: 25 °C
Yield: 54 %

Procedure:
To a solution of 1-hydroxy-2,3,4,5-tetrahydro-3-(p-toluenesulfonyl)-3-benzazepine (10 g, 32 mmole), phenol (3.4 g, 36 mmole) and triphenylphosphine (9.5 g, 36 mmole) in benzene (300 ml), cooled with an ice bath, was slowly dropped a solution of diethyl azodicarboxylate (6.3 g, 36 mmole) in benzene (100 ml). After stirred twenty hours at ambient temperature, the reaction mixture was filtered to remove sym-dicarbethoxyhydrazine. The filtrate was concentrated to an oil which was dissolved in ether and cooled to precipitate the product and triphenylphosphine oxide. The desired product was crystallized from methanol to give a solid of 1-phenoxy-2,3,4,5-tetrahydro-3-(p-toluenesulfonyl)-3-benzazepine (6.8 g, 33%, m.p. 155°-156° C.).
Reaction SMILES: [H-].[Na+].[NH2:3][C:4]1[N:9]=[C:8]([CH3:10])[C:7]([Cl:11])=[C:6]([CH3:12])[N:5]=1.[CH3:13][N:14]([CH3:18])[C:15](Cl)=[O:16].O>C1(C)C=CC=CC=1>[CH3:13][N:14]([CH3:18])[C:15]([NH:3][C:4]1[N:9]=[C:8]([CH3:10])[C:7]([Cl:11])=[C:6]([CH3:12])[N:5]=1)=[O:16]
Reactant: Cc1nc(N)nc(C)c1Cl
Reactant: CN(C)C(=O)Cl
Agent: [H-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: O
Product: Cc1nc(NC(=O)N(C)C)nc(C)c1Cl
Reaction time: 1 h

Procedure:
Sodium hydride (6 g, 55%, 0.137 mole) is added to a mixture of 2-amino-4,6-dimethyl-5-chloropyrimidine (19.5 g, 0.125 mole) in 250 ml of toluene. The mixture, under a nitrogen atmosphere is heated to reflux and stirred for one hour. Another portion of sodium hydride (6 g, 55%, 0.137 mole) is added and after two hours of reflux, dimethyl carbamoyl chloride (13.9 g, 0.125 mole) is added. After one hours of reflux the reaction is cooled, water is added, the toluene is removed by vacuum concentration and the product is extracted into petroleum ether from which it is crystallized by evaporation. N,N-Dimethyl-N'-(4,6-dimethyl-5-chloro-2-pyrimidinyl)urea melting at 127°-129° C. is obtained.
Reaction SMILES: [H-].[Na+].[CH2:3]([N:10]1[C@@H:15]2[C@@H:16]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:17][C@@:11]1([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[C@H:12]([OH:25])[CH2:13][CH2:14]2)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[F:32][C:33]([F:47])([F:46])[C:34]1[CH:35]=[C:36]([CH:39]=[C:40]([C:42]([F:45])([F:44])[F:43])[CH:41]=1)[CH2:37]Br>CN(C)C=O>[CH2:3]([N:10]1[C@@H:15]2[C@@H:16]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:17][C@@:11]1([C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1)[C@H:12]([O:25][CH2:37][C:36]1[CH:39]=[C:40]([C:42]([F:44])([F:45])[F:43])[CH:41]=[C:34]([C:33]([F:32])([F:46])[F:47])[CH:35]=1)[CH2:13][CH2:14]2)[C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: CC(C)(C)OC(=O)[C@H]1C[C@@]2(c3ccccc3)[C@H](O)CC[C@@H]1N2Cc1ccccc1
Reactant: FC(F)(F)c1cc(CBr)cc(C(F)(F)F)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)[C@H]1C[C@@]2(c3ccccc3)[C@H](OCc3cc(C(F)(F)F)cc(C(F)(F)F)c3)CC[C@@H]1N2Cc1ccccc1
Reaction time: 20 h
Yield: 121.2 %

Procedure:
Sodium hydride (60% in oil, 110 mg, 2.75 mmol) was added to a stirred mixture of (1R*,2R*,5S*,6S*)-8-benzyl-6-(tert-butoxycarbonyl)-1-phenyl-8-azabicyclo[3.2.1]octan-2-ol (Description 21a; 670 mg, 1.1 mmol), 3,5-bis(trifluoromethyl)benzyl bromide (1 ml, 5.45 mmol) in N,N-dimethylformamide (5 ml) at room temperature. The reaction mixture was stirred for 20 hours, quenched with saturated aqueous NH4Cl and extracted into a 1:1 mixture of iso-hexane:diethyl ether. The combined organic extracts were washed with water, dried (Na2SO4) and concentrated. The residue was purified by chromatography on silica gel (iso-hexane:diethyl ether 0-5%) to give the title compound (826 mg, 78%).
Reaction SMILES: Cl.Cl.[NH2:3][C:4]1[CH:5]=[CH:6][C:7]([N:11]2[CH2:16][CH2:15][CH2:14][C@@H:13]([C:17]([N:19]3[CH2:23][CH2:22][CH2:21][CH2:20]3)=[O:18])[CH2:12]2)=[N:8][C:9]=1[NH2:10].C(O)(=O)C.C(N(CC)CC)C.Cl.C(O[C:39](=N)[C:40]1[CH:41]=[C:42]([CH:48]=[C:49]([CH2:51][CH3:52])[N:50]=1)[C:43]([O:45][CH2:46][CH3:47])=[O:44])C>C(O)C>[CH2:51]([C:49]1[CH:48]=[C:42]([CH:41]=[C:40]([C:39]2[NH:10][C:9]3=[N:8][C:7]([N:11]4[CH2:16][CH2:15][CH2:14][C@@H:13]([C:17]([N:19]5[CH2:23][CH2:22][CH2:21][CH2:20]5)=[O:18])[CH2:12]4)=[CH:6][CH:5]=[C:4]3[N:3]=2)[N:50]=1)[C:43]([O:45][CH2:46][CH3:47])=[O:44])[CH3:52]
Reactant: CCOC(=N)c1cc(C(=O)OCC)cc(CC)n1
Reactant: Nc1ccc(N2CCC[C@@H](C(=O)N3CCCC3)C2)nc1N
Agent: Cl
Solvent: CC(=O)O
Solvent: CCO
Solvent: CCN(CC)CC
Product: CCOC(=O)c1cc(CC)nc(-c2nc3ccc(N4CCC[C@@H](C(=O)N5CCCC5)C4)nc3[nH]2)c1
Temperature: 110 °C

Procedure:
To a solution (R)-(1-(5,6-diaminopyridin-2-yl)piperidin-3-yl)(pyrrolidin-1-yl)methanone dihydrochloride (116 mg, 0.595 mmol) in anhydrous ethanol (5.0 mL) was added acetic acid (0.293 mL, 5.12 mmol) followed by triethylamine (0.179 mL, 1.28 mmol). Ethyl 2-(ethoxy(imino)methyl)-6-ethylisonicotinate hydrochloride (80 mg, 0.32 mmol) was added and the reaction mixture was heated to 110° C. for 30 min. The reaction mixture was cooled to room temperature and the solvent was removed under reduced pressure. The residue was partitioned between a saturated aqueous solution of ammonium chloride (50 mL) and ethyl acetate (50 mL). The pH of the aqueous layer was adjusted to 3 using an aqueous solution of hydrochloric acid (1N). The aqueous layer was extracted with ethyl acetate (50 mL×2). The combined organic layers were washed with brine, dried over sodium sulfate, filtered and concentrated under reduced pressure. The crude material was purified via HPLC to afford the title compound. MS (ESI+) (M+H) 477.2; HPLC retention time 2.7 min (Method A).
Reaction SMILES: C([O:8][C:9]([C@H:11]1[CH2:15][CH2:14][CH2:13][N:12]1[C:16](=[O:37])[CH2:17][CH2:18][CH2:19][C:20]([N:22]1[CH2:26][CH2:25][CH2:24][C@@H:23]1[C:27]([O:29]CC1C=CC=CC=1)=[O:28])=[O:21])=[O:10])C1C=CC=CC=1>C(O)C.[Pd]>[C:27]([C@H:23]1[CH2:24][CH2:25][CH2:26][N:22]1[C:20](=[O:21])[CH2:19][CH2:18][CH2:17][C:16]([N:12]1[CH2:13][CH2:14][CH2:15][C@@H:11]1[C:9]([OH:10])=[O:8])=[O:37])([OH:29])=[O:28]
Reactant: O=C(OCc1ccccc1)[C@H]1CCCN1C(=O)CCCC(=O)N1CCC[C@@H]1C(=O)OCc1ccccc1
Agent: [Pd]
Solvent: CCO
Product: O=C(O)[C@H]1CCCN1C(=O)CCCC(=O)N1CCC[C@@H]1C(=O)O
Yield: 45.8 %

Procedure:
440 mg (0.87 mmol) (R)-1-[5-[(R)-2-benzyloxycarbonyl-pyrrolidin-1-yl]-5-oxo-pentanoyl]-pyrrolidine-2-carboxylic acid benzyl ester in 100 ml ethanol were hydrogenated in the presence of 40 mg 5% Pd on carbon. Filtration and evaporation of the solvent yielded 130 mg (46%) (R)-1-[5-[(R)-2-carboxy-pyrrolidin-1-yl]-5-oxo-pentanoyl]-pyrrolidine-2-carboxylic acid as colorless oil.
Reaction SMILES: Br[C:2]1[C:3]([F:17])=[C:4]2[O:8][C:7]([CH:9]3[CH2:11][CH2:10]3)=[N:6][C:5]2=[C:12]([C:15]#[N:16])[C:13]=1[CH3:14].C([Sn](CCCC)(CCCC)[C:23]1[S:24][CH:25]=[CH:26][N:27]=1)CCC>C1C=CC=CC=1.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.C(C1(C)C(O)=C(C(C)(C)C)C=CC1)(C)(C)C>[CH:9]1([C:7]2[O:8][C:4]3[C:5](=[C:12]([C:15]#[N:16])[C:13]([CH3:14])=[C:2]([C:23]4[S:24][CH:25]=[CH:26][N:27]=4)[C:3]=3[F:17])[N:6]=2)[CH2:11][CH2:10]1
Reactant: Cc1c(Br)c(F)c2oc(C3CC3)nc2c1C#N
Reactant: CCCC[Sn](CCCC)(CCCC)c1nccs1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: CC(C)(C)C1=C(O)C(C)(C(C)(C)C)CC=C1
Solvent: c1ccccc1
Product: Cc1c(-c2nccs2)c(F)c2oc(C3CC3)nc2c1C#N
Temperature: 25 °C
Reaction time: 30 h
Yield: 32.4 %

Procedure:
6-Bromo-2-cyclopropyl-7-fluoro-5-methyl-1,3-benzoxazole-4-carbonitrile (I-77) (100 mg, 0.34 mmol) was dissolved in benzene (3 ml), then 2-tributylstannylthiazole (140 μl, 0.37 mmol) and 2,6-di-tert-butylcresol (1 mg) and bis(triphenylphosphine)palladium(II) dichloride (3 mg, 0.003 mmol) were added, followed by heating under reflux for 20 hours under nitrogen atmosphere. The reaction liquid was cooled, the insoluble matter was separated by filtration through Celite, the solvent was concentrated under reduced pressure. The resulting residue was fractionated with ethyl acetate and water, followed by washing with saturated brine. The obtained organic layer was dried over anhydrous sodium sulfate, the solvent was evaporated away under reduced pressure. The resulting residue was dissolved in methylene chloride, potassium fluoride (20 mg) and water (0.1 ml) were added, followed by vigorously stirring at room temperature for 30 hours. The insoluble matter was separated by filtration through Celite, followed by fractionation with methylene chloride and water and by washing with saturated brine. The obtained organic layer was dried over anhydrous sodium sulfate, the solvent was evaporated away under reduced pressure. The resulting residue was subjected to preparative silica gel column chromatography, eluted with a mixed solvent of n-hexane/ethyl acetate (3:1, v/v) to obtain 2-cyclopropyl-7-fluoro-5-methyl-6-(1,3-thiazol-2-yl)-1,3-benzoxazole-4-carbonitrile (31 mg, 0.11 mmol, 31%) as a white solid. This was dissolved in dimethyl sulfoxide (0.7 ml), triethylamine (37 μl, 0.26 mmol) and (3S)-3-(dimethylamino)pyrrolidine (17 μl, 0.14 mmol) were added, followed by stirring at 90° C. under nitrogen atmosphere for 22 hours. After cooling to room temperature, ethyl acetate was added, followed by fractionation with water. The organic layer was washed with saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated away, the resulting residue was subjected to preparative thin-layer silica gel column chromatography and eluted with a mixed solvent of chloroform/methanol (20:1, v/v) to obtain the entitled compound (13 mg, 32%) as a white solid.
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[C:9]([N+:11]([O-])=O)[CH:8]=[C:7]2[C:3]=1[CH:4]=[N:5][NH:6]2.Br[CH:15]1[CH2:18][CH2:17][CH2:16]1>>[CH:15]1([N:6]2[C:7]3[C:3](=[C:2]([CH3:1])[CH:10]=[C:9]([NH2:11])[CH:8]=3)[CH:4]=[N:5]2)[CH2:18][CH2:17][CH2:16]1.[CH:15]1([N:5]2[CH:4]=[C:3]3[C:7]([CH:8]=[C:9]([NH2:11])[CH:10]=[C:2]3[CH3:1])=[N:6]2)[CH2:18][CH2:17][CH2:16]1
Reactant: BrC1CCC1
Reactant: Cc1cc([N+](=O)[O-])cc2[nH]ncc12
Product: Cc1cc(N)cc2c1cnn2C1CCC1
Product: Cc1cc(N)cc2nn(C3CCC3)cc12

Procedure:
In accordance with Example 24 (Steps 1 and 2), 4-methyl-6-nitro-1H-indazole was used instead of 6-nitro-1H-indazole, and bromocyclobutane was used instead of chlorodifluoroacetic acid sodium to obtain 1-cyclobutyl-4-methyl-1H-indazol-6-amine and 2-cyclobutyl-4-methyl-2H-indazol-6-amine.