Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C:4]1[N:8]([CH2:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]3[C:17]([C:22]([O:24]C(C)(C)C)=[O:23])=[CH:18][CH:19]=[CH:20][CH:21]=3)=[CH:12][CH:11]=2)[C:7]2[CH:29]=[C:30]([C:34]3O[C:36](C)=[C:37](C)[N:38]=3)[CH:31]=[C:32]([CH3:33])[C:6]=2[N:5]=1)[CH2:2][CH3:3].CN(C)C[CH2:44][NH:45][CH:46]=O>>[CH2:1]([C:4]1[N:8]([CH2:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]3[C:17]([C:22]([OH:24])=[O:23])=[CH:18][CH:19]=[CH:20][CH:21]=3)=[CH:12][CH:11]=2)[C:7]2[CH:29]=[C:30]([C:34]3[N:38]([CH2:37][CH2:36][N:45]([CH3:44])[CH3:46])[C:7]([CH3:29])=[C:6]([CH3:32])[N:5]=3)[CH:31]=[C:32]([CH3:33])[C:6]=2[N:5]=1)[CH2:2][CH3:3]
Reactant: CN(C)CCNC=O
Reactant: CCCc1nc2c(C)cc(-c3nc(C)c(C)o3)cc2n1Cc1ccc(-c2ccccc2C(=O)OC(C)(C)C)cc1
Product: CCCc1nc2c(C)cc(-c3nc(C)c(C)n3CCN(C)C)cc2n1Cc1ccc(-c2ccccc2C(=O)O)cc1

Procedure:
Prepared analogously to Example 146 from tert.butyl 4'-[[2-n-propyl-4-methyl-6-(4,5-dimethyl-oxazol-2-yl)-1H-benzimidazol-1-yl]-methyl]-biphenyl-2-carboxylate and N-(2-dimethylaminoethyl)formamide/-2-dimethylamino-ethylamine.
Reaction SMILES: [CH3:1][C:2]1([CH3:27])[CH:7]2[CH2:8][CH:3]1[CH2:4][CH2:5][CH:6]2[CH2:9][CH2:10][N:11]1[CH2:16][CH2:15][C:14]([NH:19][C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([F:26])[CH:21]=2)([C:17]#[N:18])[CH2:13][CH2:12]1.C(OC(=O)C)(=[O:30])C.[OH-].[Na+]>C(O)=O>[CH3:1][C:2]1([CH3:27])[CH:7]2[CH2:8][CH:3]1[CH2:4][CH2:5][CH:6]2[CH2:9][CH2:10][N:11]1[CH2:16][CH2:15][C:14]([NH:19][C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([F:26])[CH:21]=2)([C:17]([NH2:18])=[O:30])[CH2:13][CH2:12]1
Reactant: CC1(C)C2CCC(CCN3CCC(C#N)(Nc4cccc(F)c4)CC3)C1C2
Reactant: CC(=O)OC(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: O=CO
Product: CC1(C)C2CCC(CCN3CCC(Nc4cccc(F)c4)(C(N)=O)CC3)C1C2
Temperature: 25 °C
Reaction time: 24 h
Yield: 98 %

Procedure:
A mixture of 28.7 g (78 mmol) (28a), 135 ml of formic acid and 135 ml of acetic anhydride was stirred at room temperature for 1 day. The reaction was monitored by 1H-NMR and MS. After completed reaction the reaction mixture was poured into ice-water (800 ml). The pH was adjusted to 10 by the addition of 33% NaOH (aq). The aqueous layer was extracted with DCM (3×1 l). The combined organic layers were dried over Na2SO4 and concentrated in vacuo. The residue was dissolved in 550 ml tert.-butylalcohol, 45 ml water and 45 ml concentrated aqueous ammonia. The 90 ml of 35% hydrogen peroxide were added drop wise at room temperature. The mixture was stirred overnight. The reaction was monitored by TLC. 900 ml of water were added and the mixture was extracted with DCM (3×500 ml). The combined organic layers were dried over Na2SO4 and concentrated in vacuo to give 29.3 g (76 mmol, 98%) of (29a) as a yellow solid, which was used in the next step without purification.
Reaction SMILES: [C:1]1([N:7]2[C:12](=[O:13])[C:11]3[S:14][CH:15]=[C:16]([C:17]4[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=4)[C:10]=3[N:9]=[CH:8]2)C=[CH:5][CH:4]=[CH:3][CH:2]=1.NC1C(C2C=CC=CC=2)=CSC=1C(OC)=[O:36].C(OCC)(OCC)OCC.O1CCC[C@@H]1CN>C(O)(=O)C>[C:17]1([C:16]2[C:10]3[N:9]=[CH:8][N:7]([CH2:1][C@H:2]4[CH2:3][CH2:4][CH2:5][O:36]4)[C:12](=[O:13])[C:11]=3[S:14][CH:15]=2)[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: COC(=O)c1scc(-c2ccccc2)c1N
Reactant: O=c1c2scc(-c3ccccc3)c2ncn1-c1ccccc1
Agent: NC[C@H]1CCCO1
Solvent: CC(=O)O
Solvent: CCOC(OCC)OCC
Product: O=c1c2scc(-c3ccccc3)c2ncn1C[C@H]1CCCO1
Yield: 72.4 %

Procedure:
In the same manner as the synthesis of Compound 1, methyl 3-amino-4-phenylthiophene-2-carboxylate (100 mg, 0.43 mmol), triethyl orthoformate (1.0 ml), (R)-(tetrahydrofuran-2-yl)methanamine (0.102 ml, 0.99 mmol), and acetic acid (0.1 ml) were used to give 97.3 mg (0.31 mmol, 72.4% yield) of the title compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([C:9](O)=[O:10])[CH:6]=[CH:5][C:4]=1[C:12]1[NH:20][C:19]2[C:18](=[O:21])[NH:17][C:16](=[O:22])[NH:15][C:14]=2[N:13]=1.[NH3:23].O.C(O)(=O)C>S(Cl)(Cl)=O.CN(C)C=O>[CH3:1][O:2][C:3]1[CH:8]=[C:7]([C:9]([NH2:23])=[O:10])[CH:6]=[CH:5][C:4]=1[C:12]1[NH:20][C:19]2[C:18](=[O:21])[NH:17][C:16](=[O:22])[NH:15][C:14]=2[N:13]=1
Reactant: N
Reactant: COc1cc(C(=O)O)ccc1-c1nc2[nH]c(=O)[nH]c(=O)c2[nH]1
Solvent: O
Solvent: O=S(Cl)Cl
Solvent: CC(=O)O
Product: COc1cc(C(N)=O)ccc1-c1nc2[nH]c(=O)[nH]c(=O)c2[nH]1

Procedure:
A quantity of 2.3 gm of 8-(2-methoxy-4-carboxy-phenyl)-1H,-3H-purin-2,6-dione are refluxed for one hour in 50 ml of thionyl chloride with the addition of 1 drop of dimethylformamide. The excess thionyl chloride is drawn off, and the residue is stirred for 16 hours at ambient temperature with a solution of ammonia in dimethylformamide. The dimethylformamide is drawn off, the remainder is mixed with water and acidified with glacial acetic acid, and the product precipitated is filtered off.
Reaction SMILES: [C:1]([O:5][C:6](=[O:33])[N:7]([CH3:32])[CH2:8][C:9]#[C:10][C:11]1[CH:16]=[CH:15][C:14]([C:17](=[O:31])[C:18]2[CH:23]=[CH:22][C:21]([O:24][CH:25]3[CH2:30][CH2:29][CH2:28][CH2:27][O:26]3)=[CH:20][CH:19]=2)=[CH:13][N:12]=1)([CH3:4])([CH3:3])[CH3:2]>[Ni].CO>[CH3:32][N:7]([CH2:8][CH2:9][CH2:10][C:11]1[CH:16]=[CH:15][C:14]([C:17](=[O:31])[C:18]2[CH:23]=[CH:22][C:21]([O:24][CH:25]3[CH2:30][CH2:29][CH2:28][CH2:27][O:26]3)=[CH:20][CH:19]=2)=[CH:13][N:12]=1)[C:6](=[O:33])[O:5][C:1]([CH3:4])([CH3:2])[CH3:3]
Reactant: CN(CC#Cc1ccc(C(=O)c2ccc(OC3CCCCO3)cc2)cn1)C(=O)OC(C)(C)C
Agent: [Ni]
Solvent: CO
Product: CN(CCCc1ccc(C(=O)c2ccc(OC3CCCCO3)cc2)cn1)C(=O)OC(C)(C)C
Reaction time: 1 h
Yield: 55 %

Procedure:
Raney nickel (2.4 mg, 0.04 mmol, 10 mol %) was added to a solution of tert-butylmethyl(3-(5-(4-(tetrahydro-2H-pyran-2-yloxy)benzoyl)pyridin-2-yl)prop-2-ynyl)carbamate (180 mg, 0.4 mmol) in 3 mL methanol at room temperature, and the reaction mixture was stirred for 1 h under hydrogen atmosphere. The nickel was filtered off and the filtrate was concentrated in vacuo to afford the desired product as a yellow solid (100 mg, 55.6% yield).
Reaction SMILES: [NH:1]1[CH2:16][CH2:15][CH2:14][CH2:13][C@H:2]1[C:3]([O:5][CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)=[O:4].[CH3:17][O:18][C:19]1[CH:29]=[CH:28][C:22]([CH:23]=[CH:24][C:25](O)=[O:26])=[CH:21][CH:20]=1.Cl.CN(C)CCCN=C=NCC.C(N(C(C)C)CC)(C)C>C(Cl)Cl>[CH3:17][O:18][C:19]1[CH:29]=[CH:28][C:22]([CH:23]=[CH:24][C:25]([N:1]2[CH2:16][CH2:15][CH2:14][CH2:13][C@H:2]2[C:3]([O:5][CH2:6][C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=2)=[O:4])=[O:26])=[CH:21][CH:20]=1
Reactant: O=C(OCc1ccccc1)[C@@H]1CCCCN1
Reactant: COc1ccc(C=CC(=O)O)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COc1ccc(C=CC(=O)N2CCCC[C@H]2C(=O)OCc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 12 h
Yield: 64.8 %

Procedure:
To a solution of 145 mg (0.37 mmol) of (S)-Benzyl pipecolate salt (134) (described in Example 1) in 8.0 mL of methylene chloride was added 102 mg (0.57 mmol) of 4-methoxycinnamic acid, 107 mg (0.55 mmol) of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDC) and 130 μL (0.74 mmol) of diisopropylethylamine. The resulting solution was stirred at ambient temperature for 12 h and was then concentrated under reduced pressure. Flash chromatography (slution with 1:1 ethyl acetate-hexane) gave 91 mg (65%) of the amide (112) as a colorless oil. 1H NMR (300 MHz, CDCl3) δ 7.66 (d), 7.50 (d), 7.35 (m), 6.90 (d), 6.82 (d), 6.63 (d), 5.55 (d), 5.20 (br s), 4.86 (br s), 4.67 (brd) 4.03 (br d), 3.83 (s), 3.37 (dr), 2.78 (dt) 2.33 (br d), 1.74 (m), 1.43(m). Rf 0.40 (1:1 ether-hexane).
Reaction SMILES: [CH3:1][C:2]1[N:6]=[C:5]([C:7]2[CH:12]=[CH:11][C:10]([NH2:13])=[CH:9][CH:8]=2)[S:4][N:3]=1.C([N:22]=[C:23]=[S:24])(=O)C1C=CC=CC=1.C(=O)([O-])[O-].[K+].[K+]>O1CCCC1.O>[CH3:1][C:2]1[N:6]=[C:5]([C:7]2[CH:12]=[CH:11][C:10]([NH:13][C:23]([NH2:22])=[S:24])=[CH:9][CH:8]=2)[S:4][N:3]=1
Reactant: O=C(N=C=S)c1ccccc1
Reactant: Cc1nsc(-c2ccc(N)cc2)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Product: Cc1nsc(-c2ccc(NC(N)=S)cc2)n1
Temperature: 25 °C
Reaction time: 3 h
Yield: 71.3 %

Procedure:
To a solution of 4-(3-methyl-[1,2,4]thiadiazol-5-yl)-phenylamine (81 mg, 0.42 mmol) in tetrahydrofurane (6.4 mL) was added benzoyl isothiocyanate (76 mg, 0.44 mmol). The reaction was stirred at room temperature for 3 hours. The solvent was removed under reduced pressure and the residue was suspended in methanol (10.6 mL). Potassium carbonate (175 mg, 1.27 mmol) dissolved in water (5.3 mL) was added drop wise to the suspension. The reaction was stirred at room temperature over night. The resulting solution was evaporated and the residue was stirred with water. The precipitate was filtered off, washed with water and with diethyl ether to yield the title compound as a yellow solid (75 mg, 71%). MS ISP (m/e): 251.0 (100) [(M+H)+], 501.1 (83) [(2M+H)+]. 1H NMR (DMSO-D6, 300 MHz): δ (ppm)=10.04 (br s, 1H), 7.94 (d, 2H), 7.72 (d, 2H), 2.63 (s, 3H).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([S:8][CH3:9])[N:5]=[C:4]2[N:10]([C:15]3[C:20]([F:21])=[CH:19][CH:18]=[CH:17][C:16]=3[F:22])[C:11](=[O:14])[NH:12][CH2:13][C:3]=12.[CH3:23][N:24]([CH3:43])[C:25](=[O:42])[C:26]1[CH:31]=[CH:30][C:29]([CH3:32])=[C:28](B2OC(C)(C)C(C)(C)O2)[CH:27]=1.C([O-])([O-])=O.[K+].[K+]>O1CCOCC1.O>[F:22][C:16]1[CH:17]=[CH:18][CH:19]=[C:20]([F:21])[C:15]=1[N:10]1[C:4]2[N:5]=[C:6]([S:8][CH3:9])[N:7]=[C:2]([C:28]3[CH:27]=[C:26]([CH:31]=[CH:30][C:29]=3[CH3:32])[C:25]([N:24]([CH3:43])[CH3:23])=[O:42])[C:3]=2[CH2:13][NH:12][C:11]1=[O:14]
Reactant: CSc1nc(Cl)c2c(n1)N(c1c(F)cccc1F)C(=O)NC2
Reactant: Cc1ccc(C(=O)N(C)C)cc1B1OC(C)(C)C(C)(C)O1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: CSc1nc(-c2cc(C(=O)N(C)C)ccc2C)c2c(n1)N(c1c(F)cccc1F)C(=O)NC2
Temperature: 95 °C

Procedure:
5-chloro-1-(2,6-difluorophenyl)-7-(methylthio)-3,4-dihydropyrimido[4,5-d]pyrimidin-2(1H)-one (0.102 g, 0.298 mmol), N,N,4-trimethyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide from above, (0.129 g, 0.447 mmol), and K2CO3 (0.123 g, 0.894 mmol), were taken up in dioxane (6 mL) and water (1.2 mL). The mixture was degassed with argon for 30 min and tetrakis(triphenyl-phosphine)palladium(0) (0.026 g, 0.022 mmol) was added. The mixture was then heated under argon at 95°C. for 18 h. The solvents were pumped off, and after aqueous workup, the crude material was flashed on silica gel (15 g), eluted with a EtOAc/CH2Cl2 gradient to give the title compound as a white amorphous solid. mp 144-147° C. LC-MS m/z 470 (M+H)+, 2.02 min (ret time).
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][N:11]=[C:10]([CH3:13])[N:9]=2)=[CH:4][CH:3]=1.[CH3:14][C:15]1[CH:20]=[CH:19][C:18]([NH:21][C:22]([C:24]2[CH:28]=[CH:27][S:26][CH:25]=2)=[O:23])=[CH:17][C:16]=1B1OC(C)(C)C(C)(C)O1>CN(C=O)C>[CH3:14][C:15]1[C:16]([C:2]2[CH:7]=[CH:6][C:5]([C:8]3[O:12][N:11]=[C:10]([CH3:13])[N:9]=3)=[CH:4][CH:3]=2)=[CH:17][C:18]([NH:21][C:22]([C:24]2[CH:28]=[CH:27][S:26][CH:25]=2)=[O:23])=[CH:19][CH:20]=1
Reactant: Cc1ccc(NC(=O)c2ccsc2)cc1B1OC(C)(C)C(C)(C)O1
Reactant: Cc1noc(-c2ccc(I)cc2)n1
Solvent: CN(C)C=O
Product: Cc1noc(-c2ccc(-c3cc(NC(=O)c4ccsc4)ccc3C)cc2)n1

Procedure:
Example 26 was prepared using 5-(4-iodophenyl)-3-methyl-[1,2,4]oxadiazole (Intermediate 12) and N-[4-methyl-3-(4,4,5,5, -tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]thiophene-3-amide (Intermediate 27) using DMF as the solvent.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[F:9].[Br:10]N1C(=O)CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(#N)C>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][Br:10])=[CH:4][C:3]=1[F:9]
Reactant: Cc1ccc(Br)c(F)c1
Reactant: O=C1CCC(=O)N1Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: CC#N
Product: Fc1cc(CBr)ccc1Br
Temperature: 25 °C
Yield: 90 %

Procedure:
A solution of 4-bromo-3-fluorotoluene (21.5 g, 0.114 moles) in acetonitrile (200 ml) is added with N-bromosuccinimide, (NBS; 21.2 g, 0.119 moles). The mixture is refluxed, added with dibenzoyl peroxide (1.4 g, 0.004 moles), refluxed for 3 hour, then cooled at room temperature, and extracted with water. The aqueous phase is discarded, and the organic phase is washed with brine, dried over sodium sulphate, and concentrated under vacuum to give an oil (27.1 g, 90% yield).
Reaction SMILES: [CH2:1]([C:3]1[C:8]([C:9]2[S:10][C:11]([C:14]3[CH:19]=[CH:18][C:17]([O:20][CH:21]([CH3:23])[CH3:22])=[C:16]([C:24]([F:27])([F:26])[F:25])[CH:15]=3)=[N:12][N:13]=2)=[CH:7][CH:6]=[CH:5][C:4]=1[CH2:28][CH:29]=O)[CH3:2].[NH:31]1[CH2:34][CH:33]([C:35]([O:37][CH3:38])=[O:36])[CH2:32]1.C([O-])(=O)C.[Na+].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>CO.ClCCl.O.CC(O)=O>[CH2:1]([C:3]1[C:8]([C:9]2[S:10][C:11]([C:14]3[CH:19]=[CH:18][C:17]([O:20][CH:21]([CH3:22])[CH3:23])=[C:16]([C:24]([F:26])([F:27])[F:25])[CH:15]=3)=[N:12][N:13]=2)=[CH:7][CH:6]=[CH:5][C:4]=1[CH2:28][CH2:29][N:31]1[CH2:34][CH:33]([C:35]([O:37][CH3:38])=[O:36])[CH2:32]1)[CH3:2]
Reactant: CCc1c(CC=O)cccc1-c1nnc(-c2ccc(OC(C)C)c(C(F)(F)F)c2)s1
Reactant: COC(=O)C1CNC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(=O)O
Solvent: O
Product: CCc1c(CCN2CC(C(=O)OC)C2)cccc1-c1nnc(-c2ccc(OC(C)C)c(C(F)(F)F)c2)s1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 50.9 %

Procedure:
To a solution of (2-ethyl-3-{5-[4-[(1-methylethyl)oxy]-3-(trifluoromethyl)phenyl]-1,3,4-thiadiazol-2-yl}phenyl)acetaldehyde (D19) (40 mg) and methyl 3-azetidinecarboxylate (53.0 mg) in methanol (10 mL) stirred at room temperature was added sodium acetate (37.8 mg) and AcOH (0.026 mL). The reaction mixture was stirred at room temperature for 10 min. The residue was dissolved in dichloromethane (DCM) (10 mL), and sodium triacetoxyborohydride (58.5 mg) was added. Stirring continued for overnight. Water was added to quench the reaction, and DCM was removed by evaporation. The mixture was extracted by EA for 3 times. The combined organic solution was washed by brine, dried over anhydrous Na2SO4. The dried solution was filtered and concentrated to afford methyl 1-[2-(2-ethyl-3-{5-[4-[(1-methylethyl)oxy]-3-(trifluoromethyl)phenyl]-1,3,4-thiadiazol-2-yl}phenyl)ethyl]-3-azetidinecarboxylate (D20) (25 mg), which was used for the next without further purification. MS (ES): C27H30F3N3O3S requires 533. found 534.2 (M+H+).
Reaction SMILES: C([O:5][C:6](=[O:25])[CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][C:10]=1[C:16]#[C:17][C:18]1[CH:19]=[N:20][CH:21]=[CH:22][C:23]=1[CH3:24])(C)(C)C.Cl>C(Cl)Cl>[Cl:15][C:12]1[CH:13]=[CH:14][C:9]([O:8][CH2:7][C:6]([OH:25])=[O:5])=[C:10]([C:16]#[C:17][C:18]2[CH:19]=[N:20][CH:21]=[CH:22][C:23]=2[CH3:24])[CH:11]=1
Reactant: Cc1ccncc1C#Cc1cc(Cl)ccc1OCC(=O)OC(C)(C)C
Agent: Cl
Solvent: ClCCl
Product: Cc1ccncc1C#Cc1cc(Cl)ccc1OCC(=O)O
Reaction time: 20 h
Yield: 90.9 %

Procedure:
A solution of tert-butyl{4-chloro-2-[(4-methylpyridin-3-yl)ethynyl]phenoxy}acetate (Intermediate 19, 138 mg; 0.39 mmol) in DCM (1.4 mL) was treated with an HCl solution (4 N in dioxane, 2.7 mL). After stirring for 20 hours, the solvents were removed under vacuum to afford the title compound as a beige solid (107 mg, 82%).
Reaction SMILES: [Br:1][C:2]1[C:3](F)=[C:4]2[C:10]([NH2:11])=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1.[CH3:13][N:14]([C@@H:22]1[CH2:27][CH2:26][CH2:25][NH:24][CH2:23]1)[C:15](=[O:21])[O:16][C:17]([CH3:20])([CH3:19])[CH3:18].C(N(C(C)C)C(C)C)C>CN1C(=O)CCC1>[NH2:11][C:10]1[C:4]2[C:5](=[N:6][CH:7]=[C:2]([Br:1])[C:3]=2[N:24]2[CH2:25][CH2:26][CH2:27][C@@H:22]([N:14]([CH3:13])[C:15](=[O:21])[O:16][C:17]([CH3:18])([CH3:19])[CH3:20])[CH2:23]2)[NH:8][CH:9]=1
Reactant: CN(C(=O)OC(C)(C)C)[C@@H]1CCCNC1
Reactant: Nc1c[nH]c2ncc(Br)c(F)c12
Solvent: CN1CCCC1=O
Solvent: CCN(C(C)C)C(C)C
Product: CN(C(=O)OC(C)(C)C)[C@@H]1CCCN(c2c(Br)cnc3[nH]cc(N)c23)C1
Temperature: 125 °C
Reaction time: 20 h

Procedure:
A 250 mL round bottom flask was charged with 5-bromo-4-fluoro-1H-pyrrolo[2,3-b]pyridin-3-amine (1.00 g, 4.35 mmol; Example 1, Step H), (R)-tert-butyl methyl(piperidin-3-yl)carbamate (1.86 g, 8.69 mmol), N-ethyl-N-isopropylpropan-2-amine (2.27 mL, 13.0 mmol), and NMP (10.8 mL). Nitrogen was bubbled through the mixture for 5 minutes. The reaction was stirred at 125° C. (oil bath) under positive nitrogen atmosphere for 20 hours to provide the crude (R)-tert-butyl 1-(3-amino-5-bromo-1H-pyrrolo[2,3-b]pyridin-4-yl)piperidin-3-yl(methyl)carbamate.
Reaction SMILES: C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl.[CH2:23]([O:25][C:26]1[CH:27]=[C:28]([CH:32]=[C:33]([O:42][CH2:43][CH3:44])[C:34]=1[C:35]1[CH:36]=[N:37][C:38]([F:41])=[CH:39][CH:40]=1)[C:29]([OH:31])=O)[CH3:24].Cl.[NH:46]1[C:50]([C:51]2[CH:52]=[C:53]3[C:63](=[CH:64][CH:65]=2)[O:62][C:56]2([CH2:61][CH2:60][NH:59][CH2:58][CH2:57]2)[CH2:55][C:54]3=[O:66])=[N:49][N:48]=[N:47]1>O.CN(C=O)C.CCN(CC)CC>[CH2:43]([O:42][C:33]1[CH:32]=[C:28]([C:29]([N:59]2[CH2:60][CH2:61][C:56]3([CH2:55][C:54](=[O:66])[C:53]4[C:63](=[CH:64][CH:65]=[C:51]([C:50]5[NH:49][N:48]=[N:47][N:46]=5)[CH:52]=4)[O:62]3)[CH2:57][CH2:58]2)=[O:31])[CH:27]=[C:26]([O:25][CH2:23][CH3:24])[C:34]=1[C:35]1[CH:36]=[N:37][C:38]([F:41])=[CH:39][CH:40]=1)[CH3:44]
Reactant: CCOc1cc(C(=O)O)cc(OCC)c1-c1ccc(F)nc1
Reactant: O=C1CC2(CCNCC2)Oc2ccc(-c3nnn[nH]3)cc21
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: O
Product: CCOc1cc(C(=O)N2CCC3(CC2)CC(=O)c2cc(-c4nnn[nH]4)ccc2O3)cc(OCC)c1-c1ccc(F)nc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Et3N (200 μL), HOBT (110 mg) and WSC hydrochloride (138 mg) were added to a DMF (4 mL) solution of 3,5-diethoxy-4-(6-fluoropyridin-3-yl)benzoic acid (186 mg) and 6-(tetrazol-5-yl)spiro[chroman-2,4′-piperidin]-4-one hydrochloride (231 mg), and stirred overnight at room temperature. Water was added to the reaction liquid, the formed solid was taken out through filtration, and the solid was washed with water and ether. The solid was dried under reduced pressure to obtain the title compound. 1H-NMR (400 MHz, DMSO-d6) δ: 8.42 (1H, d, J=4.0 Hz), 8.24 (1H, dd, J=8.0, 4.0 Hz), 8.13 (1H, s), 7.89 (1H, dt, J=8.0, 4.0 Hz), 7.32 (1H, d, J=8.0 Hz), 7.18 (1H, dd, J=8.0, 4.0 Hz), 6.75 (2H, s), 4.32-4.18 (1H, m), 4.08 (4H, q, J=8.0 Hz), 3.64-3.20 (3H, m), 2.98 (2H, s), 2.10-1.75 (4H, m), 1.17 (6H, t, J=8.0 Hz). MS [M+H]+=573.
Reaction SMILES: ClS([N:5]=[C:6]=O)(=O)=O.[N:8]1([C:13]2[CH:14]=[C:15]([CH:20]=[CH:21][CH:22]=2)[C:16]([O:18][CH3:19])=[O:17])[CH:12]=[CH:11][CH:10]=[CH:9]1.CN(C)C=O.O>ClCCl>[C:6]([C:12]1[N:8]([C:13]2[CH:14]=[C:15]([CH:20]=[CH:21][CH:22]=2)[C:16]([O:18][CH3:19])=[O:17])[CH:9]=[CH:10][CH:11]=1)#[N:5]
Reactant: O=C=NS(=O)(=O)Cl
Reactant: COC(=O)c1cccc(-n2cccc2)c1
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)c1cccc(-n2cccc2C#N)c1
Reaction time: 1 h

Procedure:
Chlorosulfonyl isocyanate (18.2 ml) was dropwise added to a solution of methyl 3-(pyrrol-1-yl)benzoate (35.0 g) in dichloromethane (350 ml) at -10°~20° C. and the mixture was stirred for 1 hour at the same temperature. To the mixture was dropwise added N,N-dimethylformamide (105 ml) at the same temperature and the mixture was stirred for 1 hour at 0°-5° C. The reaction mixture was poured into water. The separated organic layer was washed with saturated aqueous sodium bicarbonate solution and water. The organic solution was dried over magnesium sulfate and evaporated in vacuo to give methyl 3-(2-cyanopyrrol-1-yl)benzoate (30.67 g).
Reaction SMILES: [CH:1]1([C:6]2([CH3:19])[CH2:14][C:13]3[C:8](=[C:9]([Cl:17])[C:10]([Cl:16])=[C:11]([OH:15])[CH:12]=3)[CH:7]2[OH:18])[CH2:5][CH2:4][CH2:3][CH2:2]1.[OH-:20].[Na+].C(Cl)(Cl)Cl>CC(C)=O>[CH3:1][C:6]([O:15][C:11]1[CH:12]=[C:13]2[C:8](=[C:9]([Cl:17])[C:10]=1[Cl:16])[C:7](=[O:18])[C:6]([CH:1]1[CH2:2][CH2:3][CH2:4][CH2:5]1)([CH3:19])[CH2:14]2)([CH3:14])[C:7]([OH:18])=[O:20]
Reactant: [OH-]
Reactant: CC1(C2CCCC2)Cc2cc(O)c(Cl)c(Cl)c2C1O
Agent: [Na+]
Solvent: CC(C)=O
Solvent: ClC(Cl)Cl
Product: CC(C)(Oc1cc2c(c(Cl)c1Cl)C(=O)C(C)(C1CCCC1)C2)C(=O)O

Procedure:
To a refluxing solution of 2-cyclopentyl-2-methyl-6,7-dichloro-1,5-indandiol (Example 5, Step C), (15.6 g., 0.05 mole) in acetone (500 ml.) in an inert atmosphere is added solid sodium hydroxide (12.6 g., 0.25 mole). Chloroform (7.6 g., 0.69 mole) in acetone (50 ml.) is added dropwise during a ten-minute period. The reaction mixture is refluxed for 5 hours, then evaporated to dryness at reduced pressure. The residue is dissolved in water, filtered and acidified with hydrochloric acid affording α,α-dimethyl-(1-oxo-2-cyclopentyl-2-methyl-6,7-dichloro-5-indanyloxy)acetic acid.
Reaction SMILES: C(OC([N:8]1[C@@H:12]([CH2:13][N:14]([CH2:25][CH3:26])[C:15]2[CH:20]=[CH:19][N:18]=[C:17]([C:21]([F:24])([F:23])[F:22])[N:16]=2)[CH2:11][O:10]C1(C)C)=O)(C)(C)C.Cl>O1CCOCC1>[NH2:8][C@@H:12]([CH2:13][N:14]([CH2:25][CH3:26])[C:15]1[CH:20]=[CH:19][N:18]=[C:17]([C:21]([F:24])([F:23])[F:22])[N:16]=1)[CH2:11][OH:10]
Reactant: CCN(C[C@H]1COC(C)(C)N1C(=O)OC(C)(C)C)c1ccnc(C(F)(F)F)n1
Agent: Cl
Solvent: C1COCCO1
Product: CCN(C[C@H](N)CO)c1ccnc(C(F)(F)F)n1
Temperature: 60 °C
Reaction time: 3 h

Procedure:
(S)-4-{[Ethyl-(2-trifluoromethyl-pyrimidin-4-yl)-amino]-methyl}-2,2-dimethyl-oxazolidine-3-carboxylic acid tert-butyl ester (0.339 g, 0.84 mmol) was dissolved in dioxane (6 ml), aqueous hydrochloric acid (4N, 6 ml) was added and the mixture was stirred at 60° C. for 3 hours. The solvent was evaporated and the residue was dissolved in dichloromethane. A solution of ammonia in methanol (2N, 2 ml) was added and the mixture was evaporated over Isolute® Flash-NH2 silicagel. Chromatography (column: Isolute® Flash-NH2 from Separtis; eluent: ethyl acetate/MeOH=95:5) yielded a light yellow liquid, (0.19 g, 86%); MS (ISP): 265.3 ((M+H)+).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([C:8]([NH:21][S:22]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=2[N+:31]([O-:33])=[O:32])(=[O:24])=[O:23])([CH3:20])[CH2:9][O:10][C@@:11]([CH3:19])([C:15]([F:18])([F:17])[F:16])[C:12]([NH2:14])=O)[C:5]([F:34])=[CH:4][N:3]=1.CCN(CC)CC.FC(F)(F)C(OC(=O)C(F)(F)F)=O>C(Cl)Cl.C([O-])([O-])=O.[Na+].[Na+]>[Br:1][C:2]1[CH:7]=[C:6]([C:8]([NH:21][S:22]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=2[N+:31]([O-:33])=[O:32])(=[O:23])=[O:24])([CH3:20])[CH2:9][O:10][C@@:11]([C:12]#[N:14])([CH3:19])[C:15]([F:18])([F:17])[F:16])[C:5]([F:34])=[CH:4][N:3]=1
Reactant: CC(CO[C@](C)(C(N)=O)C(F)(F)F)(NS(=O)(=O)c1ccccc1[N+](=O)[O-])c1cc(Br)ncc1F
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Solvent: ClCCl
Product: CC(CO[C@](C)(C#N)C(F)(F)F)(NS(=O)(=O)c1ccccc1[N+](=O)[O-])c1cc(Br)ncc1F
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To a dry solution of (R)-2-[(RS)-2-(2-bromo-5-fluoro-pyridin-4-yl)-2-(2-nitro-benzenesulfonyl-amino)-propoxy]-3,3,3-trifluoro-2-methyl-propionamide (860 mg, 1.35 mmol) in DCM (9 ml) was added at rt NEt3 (0.470 ml, 342 mg, 3.38 mmol). At 0° C., trifluoroacetic anhydride (0.229 ml, 340 mg, 1.62 ml) was added dropwise. The reaction mixture was allowed to warm to rt and to stir for 1.5 h. The reaction mixture was diluted with 1M aq. Na2CO3 soln. and DCM. The phases were separated and the aq. phase was twice reextracted with DCM. The combined org. phases were dried over Na2SO4, filtered and concentrated to yield the crude title compound as an orange solid that was used in the next step without further purification (diastereomer mixture). RtH4=1.19 min; ESIMS: 555, 557 [(M+H)+]; 1H NMR (400 MHz, CDCl3): δ 8.01-7.93 (m, 2H), 7.79-7.63 (m, 3H), 7.59 (m, 1H), 4.26-4.16 (m, 2H), 1.85-1.84 (2d, 3H), 1.78-1.76 (2d, 3H).
Reaction SMILES: [CH3:1][N:2]1[C:11](=[O:12])[C:10]2[C:5](=[C:6]([N+:13]([O-])=O)[CH:7]=[CH:8][CH:9]=2)[N:4]=[C:3]1[C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([C:22]([F:25])([F:24])[F:23])[CH:17]=1>C1COCC1.[Pd]>[NH2:13][C:6]1[CH:7]=[CH:8][CH:9]=[C:10]2[C:5]=1[N:4]=[C:3]([C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([C:22]([F:25])([F:24])[F:23])[CH:17]=1)[N:2]([CH3:1])[C:11]2=[O:12]
Reactant: Cn1c(-c2cccc(C(F)(F)F)c2)nc2c([N+](=O)[O-])cccc2c1=O
Agent: [Pd]
Solvent: C1CCOC1
Product: Cn1c(-c2cccc(C(F)(F)F)c2)nc2c(N)cccc2c1=O
Reaction time: 12 h
Yield: 93.1 %

Procedure:
Pd/C 10 wt % (100 mg) was added to a degassed solution of 3-methyl-8-nitro-2-(3-(trifluoromethyl)phenyl)quinazolin-4(3H)-one 4 (1.3 g, 3.7 mmol) in THF (35 mL). The mixture was hydrogenated under balloon pressure for 12 h. The catalyst was removed by filtration and the solvent evaporated. The residue was purified by MPLC eluting with pentane/EtOAc (0-50%) to give 5 (1.1 g, 90% yield) as a yellow solid.