Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(O[C:4]([C:6]1[C:7]([CH3:12])=[CH:8][CH:9]=[CH:10][CH:11]=1)=[NH:5])C.[CH3:13][N:14]([C:16](=O)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[NH2:15]>C(OCC)C>[CH3:13][N:14]1[C:16]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[N:5][C:4]([C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=2[CH3:12])=[N:15]1
Reactant: CCOC(=N)c1ccccc1C
Reactant: CN(N)C(=O)c1ccccc1
Solvent: CCOCC
Product: Cc1ccccc1-c1nc(-c2ccccc2)n(C)n1
Reaction time: 5 h
Yield: 32 %

Procedure:
A mixture of 1.14 g. of o-toluimidic acid ethyl ester, 1.14 g. of 1-methyl-1-benzoylhydrazine and 0.1 g. of o-toluimidic acid ester hydrochloride, as a catalyst, is heated at about 100° C for 3 hours under reduced pressure (about 200 mm Hg) and then at about 120° C for 5 hours. The raw material is taken up with diethyl ether and the organic solution is washed with aqueous sodium bicarbonate and then dried over Na2SO4. After evaporation of the solvent, the product is distilled at 170° C/0.1 mm Hg. Yield 32%.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][C@@H:11]([CH2:13][N:14]([CH:31]([CH3:33])[CH3:32])[C:15](=[O:30])[C:16]2[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[C:18]([O:24][CH2:25][CH2:26][CH2:27][O:28][CH3:29])[CH:17]=2)[C@H:10]([CH2:34][OH:35])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CCN(CC)CC.[CH3:43][S:44](Cl)(=[O:46])=[O:45]>C(Cl)Cl>[C:1]([O:5][C:6]([N:8]1[CH2:9][C@@H:10]([CH2:34][O:35][S:44]([CH3:43])(=[O:46])=[O:45])[C@H:11]([CH2:13][N:14]([CH:31]([CH3:32])[CH3:33])[C:15](=[O:30])[C:16]2[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[C:18]([O:24][CH2:25][CH2:26][CH2:27][O:28][CH3:29])[CH:17]=2)[CH2:12]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CS(=O)(=O)Cl
Reactant: COCCCOc1cc(C(=O)N(C[C@@H]2CN(C(=O)OC(C)(C)C)C[C@H]2CO)C(C)C)ccc1OC
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COCCCOc1cc(C(=O)N(C[C@@H]2CN(C(=O)OC(C)(C)C)C[C@H]2COS(C)(=O)=O)C(C)C)ccc1OC
Reaction time: 0.33 h

Procedure:
To a solution of (3S,4R)-3-hydroxymethyl-4-({isopropyl-[4-methoxy-3-(3-methoxy-propoxy)-benzoyl]-amino}-methyl)-pyrrolidine-1-carboxylic acid tert-butyl ester (2.32 g, 4.69 mmol; Example 10, reaction step H) is subsequently added at −20° C. with stirring NEt3 (1.95 mL, 14.1 mmol) and in a dropwise fashion methane sulfonylchloride (0.423 mL, 5.39 mmol). Stirring is continued for 20 min at −20° C., the mixture is then diluted with CH2Cl2 and the organic layer is washed with 2N HCl, dried (Na2SO4) and evaporated to dryness to give the crude title compound as yellowish oil. TLC, Rf (hexane/AcOEt 1:3)=0.13.
Reaction SMILES: [NH2:1][C:2]1[CH2:6][CH2:5][CH:4]([CH2:7][CH3:8])[C:3]=1[C:9]([O:11]C)=O.C([O-])=O.[NH4+].[CH:17]([NH2:19])=O>>[CH2:7]([CH:4]1[C:3]2[C:9]([OH:11])=[N:19][CH:17]=[N:1][C:2]=2[CH2:6][CH2:5]1)[CH3:8]
Reactant: NC=O
Reactant: CCC1CCC(N)=C1C(=O)OC
Agent: O=C[O-]
Agent: [NH4+]
Product: CCC1CCc2ncnc(O)c21
Temperature: 150 °C
Yield: 71.9 %

Procedure:
Methyl 2-amino-5-ethylcyclopent-1-enecarboxylate (1.62 g, 9.57 mmol) was combined with ammonium formate (3.02 g, 47.9 mmol) and formamide (3.80 mL, 95.7 mmol), and the reaction mixture was heated to 150° C. for 16 hours. Conversion was confirmed by LCMS. The reaction was cooled to room temperature and partitioned between a 5:1 DCM/i-PrOH solution and water. The aqueous layer was extracted multiple times with the same DCM/i-PrOH solution. The combined extracts were concentrated to dryness and partitioned between DCM and brine. The organic portion was concentrated to provide 5-ethyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-ol (1.13 g, 6.88 mmol, 71.9% yield) as an oil, which was taken to the next step without purification. MS (APCI+) [M+H]: 165.0.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]2[CH:16]=[C:15]([N:17]([CH3:19])[CH3:18])[S:14][C:13]=2[CH:20]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:21][C:22]1[CH:30]=[CH:29][C:25]([C:26](Cl)=[O:27])=[CH:24][C:23]=1[C:31]([F:34])([F:33])[F:32]>>[F:21][C:22]1[CH:30]=[CH:29][C:25]([C:26]([C:16]2[C:12]3[CH:11]=[CH:10][C:9]([O:8][CH2:1][C:2]4[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=4)=[CH:20][C:13]=3[S:14][C:15]=2[N:17]([CH3:18])[CH3:19])=[O:27])=[CH:24][C:23]=1[C:31]([F:32])([F:33])[F:34]
Reactant: O=C(Cl)c1ccc(F)c(C(F)(F)F)c1
Reactant: CN(C)c1cc2ccc(OCc3ccccc3)cc2s1
Product: CN(C)c1sc2cc(OCc3ccccc3)ccc2c1C(=O)c1ccc(F)c(C(F)(F)F)c1
Yield: 93 %

Procedure:
The title compound was prepared in 93% yield from 6-benzyloxy-2-(dimethylamino)benzo[b]thiophene and 4-fluoro-3-(trifluoromethyl)benzoyl chloride by essentially following the procedure outlined in Example 81, Part C, and Example 85, Part B.
Reaction SMILES: [Cl:1][C:2]1[C:7](I)=[C:6]([CH3:9])[N:5]=[C:4]([NH2:10])[N:3]=1.[C:11]([C:13]1[N:17]([CH3:18])[CH:16]=[N:15][CH:14]=1)#[CH:12].C(N(CC)CC)C>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>[Cl:1][C:2]1[C:7]([C:12]#[C:11][C:13]2[N:17]([CH3:18])[CH:16]=[N:15][CH:14]=2)=[C:6]([CH3:9])[N:5]=[C:4]([NH2:10])[N:3]=1
Reactant: C#Cc1cncn1C
Reactant: Cc1nc(N)nc(Cl)c1I
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CCN(CC)CC
Product: Cc1nc(N)nc(Cl)c1C#Cc1cncn1C

Procedure:
The title compound is synthesized according to general procedure GP2 starting from 1.4 g (5.3 mmol) 4-chloro-5-iodo-6-methyl-pyrimidin-2-ylamine (A-3) and 900 mg (8.5 mmol) 5-ethynyl-1-methyl-1H-imidazole using 10 mg (0.05 mmol) CuI, 112 mg (0.03 mmol) PdCl2(PPh3)2, 5.3 mL (5.3 mmol) of 9-methoxy-9-BBN and 1.3 mL (9.5 mmol) triethylamine in 125 mL degassed and dry acetonitril. The product precipitates from the reaction mixture and is filtered off. Yield: 780 mg (54%).
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[C:8]([N:9]([CH2:18][CH3:19])[C:10](=[O:17])[CH2:11][CH:12]2[CH2:15][NH:14][C:13]2=[O:16])=[CH:7][N:6]([C:20]2[CH:21]=[N:22][CH:23]=[CH:24][CH:25]=2)[N:5]=1.[CH3:26]I>CN(C=O)C>[Cl:3][C:4]1[C:8]([N:9]([CH2:18][CH3:19])[C:10](=[O:17])[CH2:11][CH:12]2[CH2:15][N:14]([CH3:26])[C:13]2=[O:16])=[CH:7][N:6]([C:20]2[CH:21]=[N:22][CH:23]=[CH:24][CH:25]=2)[N:5]=1
Reactant: CI
Reactant: CCN(C(=O)CC1CNC1=O)c1cn(-c2cccnc2)nc1Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCN(C(=O)CC1CN(C)C1=O)c1cn(-c2cccnc2)nc1Cl
Reaction time: 0.02 h

Procedure:
To a suspension of NaH (60% dispersion in oil, 0.029 g, 0.72 mmol) in DMF (2 mL) was added N-(3-chloro-1-(pyridin-3-yl)-1H-pyrazol-4-yl)-N-ethyl-2-(2- oxoazetidin-3-yl)acetamide (0.20 g, 0.60 mmol) in DMF (0.5 mL), dropwise, at a temperature of about −10° C. over one minute. The reaction mixture was charged with methyl iodide (0.093 g, 0.66 mmol) in DMF (0.5 mL), dropwise, and stirred for 5 minutes. The reaction mixture was quenched with ice water (10 mL) and extracted with EtOAc (3×15 mL). The organic layers were combined and washed with water (3×10 mL) and brine (10 mL), dried over Na2SO4, and concentrated under reduced pressure. The residue was purified by flash chromatography eluting with 1%-8% MeOH/CH2Cl2 to afford the title compound F32 as a gum (0.065 g, 31%).
Reaction SMILES: [Br:1][C:2]1[S:15][C:5]2[S:6][CH2:7][CH:8]([CH2:11][C:12]([OH:14])=O)[C:9](=O)[C:4]=2[CH:3]=1.[Cl:16][C:17]1[CH:22]=[CH:21][C:20]([NH:23][NH2:24])=[CH:19][CH:18]=1>C(O)C>[Br:1][C:2]1[S:15][C:5]2[S:6][CH2:7][CH:8]3[CH2:11][C:12](=[O:14])[N:23]([C:20]4[CH:21]=[CH:22][C:17]([Cl:16])=[CH:18][CH:19]=4)[N:24]=[C:9]3[C:4]=2[CH:3]=1
Reactant: O=C(O)CC1CSc2sc(Br)cc2C1=O
Reactant: NNc1ccc(Cl)cc1
Solvent: CCO
Product: O=C1CC2CSc3sc(Br)cc3C2=NN1c1ccc(Cl)cc1
Yield: 40.2 %

Procedure:
A mixture of 2.4 g of 2-bromo-4-oxo-5,6-dihydro-4H-thieno[2,3-b]thiopyran-5-acetic acid and 1.3 g of 4-chlorophenylhydrazine in 40 ml of ethanol is refluxed under heating for 14 hours. After cooling, the precipitated crystals are collected by filtration, washed with ethanol and then recrystallized from a mixed solvent of chloroform and ethanol to give 1.3 g of 8-bromo-2-(4-chlorophenyl)-4a,5-dihydro-2H-thieno[2',3':2,3]thiopyrano[4,5-c]pyridazin-3(4H)-one as pale brown crystals, melting at 169°-170° C.
Reaction SMILES: [CH3:1][C:2]1[C:10]2[C:5](=[CH:6][C:7](/[CH:26]=[CH:27]/[C:28]([O:30][CH2:31][CH3:32])=[O:29])=[CH:8][C:9]=2[C:11]([NH:13][CH2:14][C:15]2[C:16](=[O:25])[NH:17][C:18]([CH3:24])=[CH:19][C:20]=2[CH2:21][CH2:22][CH3:23])=[O:12])[N:4]([CH:33]([CH3:35])[CH3:34])[CH:3]=1>C(O)C>[CH3:1][C:2]1[C:10]2[C:5](=[CH:6][C:7]([CH2:26][CH2:27][C:28]([O:30][CH2:31][CH3:32])=[O:29])=[CH:8][C:9]=2[C:11]([NH:13][CH2:14][C:15]2[C:16](=[O:25])[NH:17][C:18]([CH3:24])=[CH:19][C:20]=2[CH2:21][CH2:22][CH3:23])=[O:12])[N:4]([CH:33]([CH3:35])[CH3:34])[CH:3]=1
Reactant: CCCc1cc(C)[nH]c(=O)c1CNC(=O)c1cc(/C=C/C(=O)OCC)cc2c1c(C)cn2C(C)C
Solvent: CCO
Product: CCCc1cc(C)[nH]c(=O)c1CNC(=O)c1cc(CCC(=O)OCC)cc2c1c(C)cn2C(C)C
Reaction time: 12 h
Yield: 58.2 %

Procedure:
In a 50 ml flask was added ethyl (2E)-3-[3-methyl-1-(1-methylethyl)-4-({[(6-methyl-2-oxo-4-propyl-1,2-dihydro-3-pyridinyl)methyl]amino}carbonyl)-1H-indol-6-yl]-2-propenoate (120 mg, 0.251 mmol), and Ethanol (10 mL). PdOH2 (70.6 mg, 0.503 mmol) was added and the reaction was degassed with N2 for 15 min then H2 was bubbled in (via balloon) and the reaction stirred for 12 hr. The reaction was purged with N2 for 30 min and then filtered through an acro disc and evaporated. The residue was suspended in MeOH/Water (2 mL/4 mL) and filtered and washed with water to give a white solid. ethyl 3-[3-methyl-1-(1-methylethyl)-4-({[(6-methyl-2-oxo-4-propyl-1,2-dihydro-3-pyridinyl)methyl]amino}carbonyl)-1H-indol-6-yl]propanoate (70 mg, 0.146 mmol, 58.1% yield). 1H NMR (400 MHz, DMSO-d6) δ ppm 11.49 (br. s., 1 H) 7.90 (br. s., 1 H) 7.34 (s, 1 H) 7.21 (s, 1 H) 6.82 (s, 1 H) 5.90 (s, 1 H) 4.63-4.73 (m, 1 H) 4.34 (d, J=4.55 Hz, 2 H) 4.04 (q, J=7.07 Hz, 2 H) 2.92 (t, J=7.33 Hz, 2 H) 2.64 (t, J=7.45 Hz, 2 H) 2.55-2.62 (m, 2 H) 2.12 (s, 6 H) 1.52-1.62 (m, 2 H) 1.40 (d, J=6.32 Hz, 6 H) 1.16 (t, J=7.07 Hz, 3 H) 0.94 (t, J=7.20 Hz, 3 H). MS(ES) [M+H]+ 479.8.
Reaction SMILES: [C:1](Cl)(=O)[C:2]([Cl:4])=[O:3].[Cl:7][CH2:8][C:9]1[N:10]=[C:11]([C:14]2[CH:22]=[CH:21]C(C(O)=O)=[CH:16][CH:15]=2)[S:12][CH:13]=1.CN(C=O)C>C(Cl)Cl>[Cl:7][CH2:8][C:9]1[N:10]=[C:11]([C:14]2[CH:22]=[CH:21][C:1]([C:2]([Cl:4])=[O:3])=[CH:16][CH:15]=2)[S:12][CH:13]=1
Reactant: O=C(O)c1ccc(-c2nc(CCl)cs2)cc1
Reactant: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: O=C(Cl)c1ccc(-c2nc(CCl)cs2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Oxalyl chloride (3.2 mL, 36.6 mmol, 5 eq.) was added dropwise to a suspension of 4-[4-(chloromethyl)-1,3-thiazol-2-yl]benzoic acid (1.86 g, 7.32 mmol, 1 eq.) in DCM (10 mL) followed by a catalytic amount of DMF at RT. The reaction mixture was allowed to stir at RT overnight and then evaporated to give the title compound as the crude product.
Reaction SMILES: [Mg].Br[C:3]1[CH:8]=[CH:7][C:6]([O:9][CH2:10][CH3:11])=[C:5]([Cl:12])[C:4]=1[F:13].[B:14](OC)([O:17]C)[O:15]C.Cl>C1COCC1.C(O)(=O)C>[Cl:12][C:5]1[C:4]([F:13])=[C:3]([B:14]([OH:17])[OH:15])[CH:8]=[CH:7][C:6]=1[O:9][CH2:10][CH3:11]
Reactant: COB(OC)OC
Reactant: CCOc1ccc(Br)c(F)c1Cl
Agent: Cl
Agent: [Mg]
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: CCOc1ccc(B(O)O)c(F)c1Cl
Temperature: 50 °C
Reaction time: 1 h
Yield: 83.3 %

Procedure:
4.79 g of well dried magnesium and 50 mL of THF were added to a reactor in a nitrogen atmosphere and heated to 50° C. 50.0 g of the compound (C2) dissolved in 200 mL of THF was added dropwise thereto over 60 minutes in a temperature range of 43 to 48° C., followed by stirring for 60 minutes. The resulting reaction mixture was cooled to 25° C. Thereafter, the reaction mixture was added dropwise to a solution of 24.6 g of trimethyl borate and 100 mL of THF cooled to −50° C. over 60 minutes in a nitrogen atmosphere in a temperature range of −60 to −40° C. The reaction mixture was warmed to 0° C. and then poured into 400 mL of 3N hydrochloric acid at 0° C. 700 mL of acetic acid was added to the solution, followed by mixing, and the mixture was then left to rest to separate into an organic layer and an aqueous layer, followed by extracting. The resulting organic layer was collected and washed with a saturated sodium hydrogen carbonate aqueous solution and water, followed by drying over anhydrous magnesium sulfate. Thereafter, the solvent was distilled off under reduced pressure to obtain a residue. The residue was recrystallized from heptane. The recrystallization operation was repeated to obtain 35.9 g of 3-chloro-4-ethoxy-2-fluorophenylboronic acid (b58). The resulting compound (b58) was a yellowish solid.
Reaction SMILES: C([O:4][CH2:5][CH2:6][N:7]1[C:11]([O:12][CH3:13])=[C:10]([C:14]2[CH:22]=[CH:21][C:17]3[O:18][CH2:19][O:20][C:16]=3[CH:15]=2)[C:9]([N:23](COC)[S:24]([CH2:27][CH2:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)(=[O:26])=[O:25])=[N:8]1)(=O)C.C(O)(=O)C(O)=O>O.CO>[O:18]1[C:17]2[CH:21]=[CH:22][C:14]([C:10]3[C:9]([NH:23][S:24]([CH2:27][CH2:28][C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=4)(=[O:26])=[O:25])=[N:8][N:7]([CH2:6][CH2:5][OH:4])[C:11]=3[O:12][CH3:13])=[CH:15][C:16]=2[O:20][CH2:19]1
Reactant: COCN(c1nn(CCOC(C)=O)c(OC)c1-c1ccc2c(c1)OCO2)S(=O)(=O)CCc1ccccc1
Agent: O=C(O)C(=O)O
Solvent: O
Solvent: CO
Product: COc1c(-c2ccc3c(c2)OCO3)c(NS(=O)(=O)CCc2ccccc2)nn1CCO
Yield: 54.5 %

Procedure:
2-{4-(1,3-Benzodioxol-5-yl)-5-methoxy-3-[(methoxymethyl)(phenethylsulfonyl)amino]-1H-pyrazol-1-yl}ethyl acetate (Preparation 54) (70 mg), oxalic acid (200 mg) were dissolved in a mixture of water (2 ml) and methanol (2 ml) and refluxed for two days. The reaction was diluted with water (10 ml) and the mixture was then extracted with dichloromethane (3×8 ml). The combined organic fractions were dried over sodium sulfate, concentrated under reduced pressure to yield a pale yellow oil which was purified by column chromatography (Sep-Pak™, 10 g) eluted with dichloromethane:methanol (97:3) to yield the title compound as a colourless oil (32 mg).
Reaction SMILES: C(OC([N:8]([CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][Si:36]([CH3:39])([CH3:38])[CH3:37])[C:9]1[CH:21]=[CH:20][C:12]([C:13](C2N=CNC=2)=[O:14])=[CH:11][CH:10]=1)=O)(C)(C)C.[OH-].[Na+].[NH2:42][CH2:43][CH:44]([OH:47])[CH2:45][OH:46]>C(Cl)(Cl)Cl>[OH:47][CH:44]([CH2:45][OH:46])[CH2:43][NH:42][C:13](=[O:14])[C:12]1[CH:11]=[CH:10][C:9]([NH:8][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][Si:36]([CH3:37])([CH3:38])[CH3:39])=[CH:21][CH:20]=1
Reactant: CC(C)(C)OC(=O)N(CCCCCCCCCCCCCC[Si](C)(C)C)c1ccc(C(=O)c2c[nH]cn2)cc1
Reactant: NCC(O)CO
Agent: [Na+]
Agent: [OH-]
Solvent: ClC(Cl)Cl
Product: C[Si](C)(C)CCCCCCCCCCCCCCNc1ccc(C(=O)NCC(O)CO)cc1
Temperature: 40 °C
Reaction time: 24 h

Procedure:
To a mixture containing 4.2 g. of 1-[4-[N-(tert-butyloxycarbonyl)-4-[14-(trimethylsilyl)tetradecylamino]benzoyl)imidazole, 50 ml. of chloroform, and 50 ml. of 5N sodium hydroxide is added 1.1 g. of 3-amino-1,2-propanediol. The solution is vigorously stirred for 24 hours, the layers are separated, and the chloroform solution is washed once with 50 ml. of 1N sodium hydroxide. The solvent is evaporated and the residue is heated for 30 minutes at 40° C. in 50 ml. of anhydrous trifluoroacetic acid. The solvent is again evaporated and the oil is crystallized to yield the product as a light yellow solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([CH2:28][CH2:29][CH2:30]CS([O-])(=O)=O)[CH2:13][CH2:12][N:11]([C:14](=[O:27])[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)[CH2:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8].Cl.[C:37]1([C:43]2([C:49]([NH2:51])=[O:50])[CH2:48][CH2:47][NH:46][CH2:45][CH2:44]2)[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1>>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([CH2:28][CH2:29][CH2:30][N:46]3[CH2:45][CH2:44][C:43]([C:37]4[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=4)([C:49]([NH2:51])=[O:50])[CH2:48][CH2:47]3)[CH2:13][CH2:12][N:11]([C:14](=[O:27])[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)[CH2:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: NC(=O)C1(c2ccccc2)CCNCC1
Reactant: COc1cc(C(=O)N2CCC(CCCCS(=O)(=O)[O-])(c3ccc(Cl)c(Cl)c3)C2)cc(OC)c1OC
Agent: Cl
Product: COc1cc(C(=O)N2CCC(CCCN3CCC(C(N)=O)(c4ccccc4)CC3)(c3ccc(Cl)c(Cl)c3)C2)cc(OC)c1OC

Procedure:
Prepare according to the method of example 3.3 using 3-[3-(3,4-dichloro-phenyl)-1(3,4,5-trimethoxy-benzoyl)-pyrrolidin-3-yl]-propyl-methanesulfonate (5 mmol) and 4-phenyl-piperidine-4-carboxylic acid amide hydrochloride (7.5 mmol, 1.5 eq.). Chromatograph on silica gel to give the title compound.
Reaction SMILES: [NH2:1][N:2]1[CH:6]=[CH:5][CH:4]=[C:3]1[C:7]#[N:8].[OH-:9].[K+].OO>O>[NH2:1][N:2]1[CH:6]=[CH:5][CH:4]=[C:3]1[C:7]([NH2:8])=[O:9]
Reactant: [OH-]
Reactant: N#Cc1cccn1N
Agent: OO
Agent: [K+]
Solvent: O
Product: NC(=O)c1cccn1N
Temperature: 25 °C
Reaction time: 8 h
Yield: 86.7 %

Procedure:
1-Amino-1H-pyrrole-2-carbonitrile (2.52 g, 23.5 mmole) was suspended in 75 ml water, treated with potassium hydroxide (32 g, 0.57 mole), 30% hydrogen peroxide (2 ml) and stirred overnight at room temperature. Cooled reaction mixture to 0° C. for 30 min and isolated product by filtration, washed with cold water and dried under vacuum to give 2.55 g product (yield: 87%)
Reaction SMILES: [C:1]([C:3]1[CH:31]=[CH:30][C:6]2[NH:7][C:8]([CH2:10][C:11]3[C:19]([O:20][CH3:21])=[CH:18][C:17]([CH3:22])=[C:16]4[C:12]=3[CH:13]=[CH:14][N:15]4C(OC(C)(C)C)=O)=[N:9][C:5]=2[CH:4]=1)#[N:2].C([O-])([O-])=O.[Cs+].[Cs+]>C1COCC1.CO>[CH3:21][O:20][C:19]1[C:11]([CH2:10][C:8]2[NH:7][C:6]3[CH:30]=[CH:31][C:3]([C:1]#[N:2])=[CH:4][C:5]=3[N:9]=2)=[C:12]2[C:16](=[C:17]([CH3:22])[CH:18]=1)[NH:15][CH:14]=[CH:13]2
Reactant: COc1cc(C)c2c(ccn2C(=O)OC(C)(C)C)c1Cc1nc2cc(C#N)ccc2[nH]1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1CCOC1
Solvent: CO
Product: COc1cc(C)c2[nH]ccc2c1Cc1nc2cc(C#N)ccc2[nH]1
Temperature: 58 °C
Reaction time: 1 h

Procedure:
To a solution of tert-butyl 4-((5-cyano-1H-benzo[d]imidazol-2-yl)methyl)-5-methoxy-7-methyl-1H-indole-1-carboxylate (878 mg, 2.108 mmol) in THF (12 mL) and MeOH (12 mL) was added Cs2CO3 (3.4 g, 10.54 mmol). The mixture was stirred at 58° C. for 1 hour. The reaction mixture was cooled to room temperature, concentrated and purified by flash chromatography (DCM:EtOAc) to provide the title compound. 1H NMR (400 MHz, DICHLOROMETHANE-d2) δ ppm 8.24 (br. s., 1H) 7.86 (s, 1H) 7.59 (d, J=8.34 Hz, 1H) 7.46-7.54 (m, 1H) 7.30 (t, J=2.91 Hz, 1H) 6.87 (s, 1H) 6.71 (m, 1H) 4.60 (s, 2H) 4.03 (s, 3H) 2.53 (s, 3H). HRMS calcd. for C13H16N4O (M+H)+ 317.1397. found 317.1400.
Reaction SMILES: CO.[F:3][C:4]([F:23])([F:22])[C:5]([C:8]1[CH:17]=[CH:16][C:15]2[C:10](=[CH:11][CH:12]=[C:13]([C:18]([O:20]C)=[O:19])[CH:14]=2)[N:9]=1)([CH3:7])[CH3:6].[OH-].[Na+]>C1COCC1>[F:23][C:4]([F:3])([F:22])[C:5]([C:8]1[CH:17]=[CH:16][C:15]2[C:10](=[CH:11][CH:12]=[C:13]([C:18]([OH:20])=[O:19])[CH:14]=2)[N:9]=1)([CH3:7])[CH3:6]
Reactant: COC(=O)c1ccc2nc(C(C)(C)C(F)(F)F)ccc2c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: CC(C)(c1ccc2cc(C(=O)O)ccc2n1)C(F)(F)F
Yield: 99.8 %

Procedure:
A methanol (6 ml) and THF (6 ml) solution of methyl 2-(2,2,2-trifluoro-1,1-dimethylethyl)quinoline-6-carboxylate (777 mg, 2.6 mmol) and 2M sodium hydroxide aqueous solution (2.6 ml, 5.2 mmol) was treated in the procedure described in Step C-2C to furnish the title compound (735 mg, 99% yield) as a white solid. 1H NMR (300 MHz, CDCl3) δ 1.75 (6H, s), 7.74 (1H, d, J=8.8 Hz), 8.19 (1H, d, J=8.8 Hz), 8.29 (1H, d, J=8.8 Hz), 8.35-8.40 (1H, m), 8.69-8.70 (1H, m). MS (ESI): m/z 284 (M+H)+.
Reaction SMILES: FC(F)(F)C(O)=O.[F:8][C:9]1[C:14]([F:15])=[CH:13][CH:12]=[CH:11][C:10]=1[C@H:16]1[CH2:22][N:21]([C:23]2[CH:28]=[CH:27][N:26]=[CH:25][CH:24]=2)[C:20](=[O:29])[C@H:19]([NH:30]C(=O)OC(C)(C)C)[CH2:18][CH2:17]1>ClCCl>[NH2:30][C@@H:19]1[CH2:18][CH2:17][C@@H:16]([C:10]2[CH:11]=[CH:12][CH:13]=[C:14]([F:15])[C:9]=2[F:8])[CH2:22][N:21]([C:23]2[CH:24]=[CH:25][N:26]=[CH:27][CH:28]=2)[C:20]1=[O:29]
Reactant: CC(C)(C)OC(=O)N[C@@H]1CC[C@@H](c2cccc(F)c2F)CN(c2ccncc2)C1=O
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: N[C@@H]1CC[C@@H](c2cccc(F)c2F)CN(c2ccncc2)C1=O
Reaction time: 1 h

Procedure:
Trifluoroacetic acid (2 mL) was added to a solution of tert-butyl (3R,6S)-6-(2,3-difluorophenyl)-2-oxo-1-pyridin-4-ylazepan-3-ylcarbamate (55 mg, 0.132 mmol) in dichloromethane (2 mL). After 1 h, the solution was concentrated. Saturated aqueous sodium bicarbonate solution was added and the mixture was extracted with dichloromethane (3×). The combined organic extracts were washed with saturated brine, dried over magnesium sulfate, filtered and concentrated. MS 318.2 (M+1).
Reaction SMILES: [Br:1][C:2]1[C:3]([O:9][CH3:10])=[N:4][C:5](Cl)=[N:6][CH:7]=1.[CH:11]([NH2:14])([CH3:13])[CH3:12].O>C1COCC1>[Br:1][C:2]1[C:3]([O:9][CH3:10])=[N:4][C:5]([NH:14][CH:11]([CH3:13])[CH3:12])=[N:6][CH:7]=1
Reactant: CC(C)N
Reactant: COc1nc(Cl)ncc1Br
Solvent: O
Solvent: C1CCOC1
Product: COc1nc(NC(C)C)ncc1Br
Temperature: 60 °C
Yield: 63.6 %

Procedure:
A solution of 5-bromo-2-chloro-4-methoxypyrimidine (1.2 g, 5.37 mmol) in THF (20 mL) was treated with TEA (1.57 mL, 10.74 mmol) and isopropylamine (0.7 mL, 8.1 mmol) and heated at 60° C. for 5 h. The mixture was cooled to RT, treated with water, extracted with EtOAc (2×) and the combined organics were washed with brine, dried over Na2SO4, concentrated to dryness and purified by silica gel chromatography (EtOAc/Hex) to afford 5-bromo-N-isopropyl-4-methoxypyrimidin-2-amine (0.84 g, 634%). 1H NMR (400 MHz, DMSO-d6): δ 8.10 (s, 1H), 7.17 (br s, 1H), 3.96-3.94 (m, 1H), 3.87 (s, 3H), 1.12 (d, J=6.5 Hz, 6H); MS (ESI) m/z: 246.0 (M+H+).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[NH:12][C:11]([C:13]([O:15]CC)=[O:14])=[CH:10][C:9]=2[S:18][CH:19]([F:21])[F:20])=[CH:4][CH:3]=1.[OH-].[Na+].Cl>C(O)C.O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[NH:12][C:11]([C:13]([OH:15])=[O:14])=[CH:10][C:9]=2[S:18][CH:19]([F:21])[F:20])=[CH:6][CH:7]=1
Reactant: CCOC(=O)c1cc(SC(F)F)c(-c2ccc(Cl)cc2)[nH]1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: O=C(O)c1cc(SC(F)F)c(-c2ccc(Cl)cc2)[nH]1
Temperature: 0 °C
Yield: 104 %

Procedure:
A solution of ethyl 5-(p-chlorophenyl)-4-[(difluoromethyl)thio]pyrrole-2-carboxylate (166 mg, 0.5 mmol) in ethanol is treated under nitrogen with a solution of sodium hydroxide (100 mg, 2.5 mmol) in water. The reaction mixture is refluxed for three hours, poured into ice-water, treated with hydrochloric acid and extracted with ethyl acetate. The combined organic extracts are washed with water and brine, dried over anhydrous sodium sulfate and concentrated in vacuo to obtain the title product as an orange solid (158 mg, mp 165° C. (dec)) which is identified by 1HNMR and 13CNMR spectral analyses.
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]([OH:18])([C:14]([F:17])([F:16])[F:15])[C:10]([F:13])([F:12])[F:11])=[CH:5][CH:4]=1.[N:19]1([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[F:11][C:10]([F:13])([F:12])[C:9]([C:6]1[CH:7]=[CH:8][C:3]([CH2:2][N:22]2[CH2:21][CH2:20][N:19]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:24][CH2:23]2)=[CH:4][CH:5]=1)([OH:18])[C:14]([F:17])([F:16])[F:15]
Reactant: OC(c1ccc(CBr)cc1)(C(F)(F)F)C(F)(F)F
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CC(C)(C)OC(=O)N1CCN(Cc2ccc(C(O)(C(F)(F)F)C(F)(F)F)cc2)CC1
Yield: 108.5 %

Procedure:
2-(4-(Bromomethyl)phenyl)-1,1,1,3,3,3-hexafluoropropan-2-ol (14.83 mmol, 5 g), tert-butyl piperazine-1-carboxylate (14.83 mmol, 2.76 g) and potassium carbonate (44.5 mmol, 6.15 g) were combined and stirred at room temperature overnight in acetonitrile (50 mL). The reaction mixture was filtered and the solvent removed at reduced pressure. The residue was taken up in ethyl acetate and washed with saturated sodium bicarbonate solution. The organic layer was dried over magnesium sulphate and concentrated under vacuum to afford the title compound (7.12 g).