Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]1[C:6]([CH3:7])=[C:5]([C:8]([NH:10][C:11]2[CH:26]=[CH:25][C:14]([O:15][C:16]3[CH:21]=[CH:20][N:19]=[C:18](C(N)=O)[CH:17]=3)=[CH:13][C:12]=2[F:27])=[O:9])[C:4](=[O:28])[N:3]1[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1.CC#[N:37].O.C(OI(C1C=CC=CC=1)OC(=O)C)(=O)C>CCOC(C)=O>[NH2:37][C:18]1[CH:17]=[C:16]([O:15][C:14]2[CH:25]=[CH:26][C:11]([NH:10][C:8]([C:5]3[C:4](=[O:28])[N:3]([C:29]4[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=4)[N:2]([CH3:1])[C:6]=3[CH3:7])=[O:9])=[C:12]([F:27])[CH:13]=2)[CH:21]=[CH:20][N:19]=1
Reactant: Cc1c(C(=O)Nc2ccc(Oc3ccnc(C(N)=O)c3)cc2F)c(=O)n(-c2ccccc2)n1C
Reactant: CC#N
Agent: CC(=O)OI(OC(C)=O)c1ccccc1
Solvent: O
Solvent: CCOC(C)=O
Product: Cc1c(C(=O)Nc2ccc(Oc3ccnc(N)c3)cc2F)c(=O)n(-c2ccccc2)n1C
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 17.3 %

Procedure:
A solution of 4-(4-(1,5-dimethyl-3-oxo-2-phenyl-2,3-dihydro-1H-pyrazole-4-carboxamido)-3-fluorophenoxy)picolinamide (370 mg (a little wet), 0.746 mmol) in EtOAc (4.5 mL), CH3CN (4.5 mL) and H2O (2.5 mL) was cooled and stirred at 0° C. for 30 minutes and then PhI(OAc)2 (288 mg, 0.895 mmol) was added. The resulted mixture was stirred at 0° C. for another 30 minutes, then warmed up to rt and stirred for 7 hours. The mixture was filtered and the filter cake was washed with EtOAc (5 mL). The filtrate was concentrated in vacuo and the residue was purified by a silica column gel chromatography (CH2Cl2/MeOH (v/v)=250/9), followed by purifying again by silica gel column chromatography (CH2Cl2/MeOH (v/v)=50/1) to give the title compound as a beige white solid (46 mg, 17.3%).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([Cl:8])[N:5]=[C:4]([NH2:9])[N:3]=1.[CH3:10][C:11]([NH2:14])([CH3:13])[CH3:12].C(N(CC)CC)C>CC#N>[Cl:8][C:6]1[N:5]=[C:4]([NH2:9])[N:3]=[C:2]([NH:14][C:11]([CH3:13])([CH3:12])[CH3:10])[CH:7]=1
Reactant: Nc1nc(Cl)cc(Cl)n1
Reactant: CC(C)(C)N
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CC(C)(C)Nc1cc(Cl)nc(N)n1
Temperature: 170 °C
Yield: 89.9 %

Procedure:
To 4,6-dichloro-2-pyrimidinamine (400 mg, 2.44 mmol) in CH3CN (5 mL) were added (1,1-dimethylethyl)amine (0.34 mL, 3.17 mmol) and triethylamine (1.36 mL, 9.76 mmol), and the reaction mixture was heated in a microwave at 170° C. for a total of 2.25 hours, checking the progression of the reaction at regular intervals. The mixture was cooled down and evaporated. The resulting residue was partitioned between EtOAc and water, and extracted with EtOAc (2×) and CH2Cl2 (2×). The organics were washed with water and brine, dried (MgSO4), filtered and evaporated. The resulting solid was triturated with Et2O and dried in vacuo to afford the title compound (440 mg). LC-MS (ES) m/z=201, 203 [M+H]+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[CH2:9][CH2:10][C:11]([C:13]1[NH:17][C:16]([CH3:18])=[C:15]([CH3:19])[CH:14]=1)=[O:12].Br[CH2:21][CH:22]=[CH2:23]>>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[CH2:9][CH2:10][C:11]([C:13]1[N:17]([CH2:23][CH:22]=[CH2:21])[C:16]([CH3:18])=[C:15]([CH3:19])[CH:14]=1)=[O:12]
Reactant: C=CCBr
Reactant: Cc1cc(C(=O)CCc2ccc(F)cc2F)[nH]c1C
Product: C=CCn1c(C(=O)CCc2ccc(F)cc2F)cc(C)c1C
Yield: 81.7 %

Procedure:
The title compound was prepared as a pale yellow oil in 81.7% yield in a similar procedure to that described in Referential Example 97 by using 5-[3-(2,4-difluorophenyl)propionyl]-2,3-dimethylpyrrole and 3-bromo-1-propene.
Reaction SMILES: N([N:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH2:6][CH2:5][CH2:4]1)=O.[NH:13]1[CH2:18][CH2:17][CH2:16][CH2:15][C:14]1=O>C(O)(=O)C.[Zn]>[CH:10]1[C:11]2[C:15]3[CH2:14][NH:13][CH2:18][CH2:17][C:16]=3[N:3]3[C:12]=2[C:7]([CH2:6][CH2:5][CH2:4]3)=[CH:8][CH:9]=1
Reactant: O=C1CCCCN1
Reactant: O=NN1CCCc2ccccc21
Agent: [Zn]
Solvent: CC(=O)O
Product: c1cc2c3c(c1)c1c(n3CCC2)CCNC1
Temperature: 0 °C
Yield: 81.8 %

Procedure:
1-Nitroso-1,2,3,4-tetrahydroquinoline (5.8 g, 0.0357 mol) was dissolved in acetic acid (50 mL). NH-piperidone (7.97 g, 0.0464 mol) was added and cooled to 0° C. Zinc dust was added (11.67 g, 0.1785 mol) in small portions. After addition, the reaction mixture was heated at 85° C. for 1 h. The reaction was monitored by TLC & LCMS. After completion of reaction, the mixture was filtered and the filtrate neutralized by aq. NaHCO3. The mixture was extracted with EtOAc (3×200 mL). The organic layer was dried over sodium sulfate and concentrated under reduced pressure to obtain 6.2 g product that was purified by column chromatography using 100-200 mesh silica and 5-7% MeOH in DCM+2 drops NH4OH to give pure product.
Reaction SMILES: [CH3:1][C:2]1[N:6]([C:7]2[N:8]=[C:9]([N:18]3[CH2:23][CH2:22][O:21][CH2:20][CH2:19]3)[C:10]3[N:15]=[C:14]([CH:16]=O)[S:13][C:11]=3[N:12]=2)[C:5]2[CH:24]=[CH:25][CH:26]=[CH:27][C:4]=2[N:3]=1.[NH:28]1[CH2:33][CH2:32][CH2:31][CH:30]([C:34]([OH:37])([CH3:36])[CH3:35])[CH2:29]1.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[CH3:1][C:2]1[N:6]([C:7]2[N:8]=[C:9]([N:18]3[CH2:19][CH2:20][O:21][CH2:22][CH2:23]3)[C:10]3[N:15]=[C:14]([CH2:16][N:28]4[CH2:33][CH2:32][CH2:31][CH:30]([C:34]([OH:37])([CH3:36])[CH3:35])[CH2:29]4)[S:13][C:11]=3[N:12]=2)[C:5]2[CH:24]=[CH:25][CH:26]=[CH:27][C:4]=2[N:3]=1
Reactant: CC(C)(O)C1CCCNC1
Reactant: Cc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(C=O)sc2n1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Solvent: CC(=O)O
Product: Cc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(CN3CCCC(C(C)(C)O)C3)sc2n1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A mixture of 5-(2-methylbenzoimidazol-1-yl)-7-morpholin-4-yl-thiazolo[5,4-d]pyrimidine-2-carbaldehyde (78 mg, 0.2 mmol), 2-piperidin-3-yl-propan-2-ol (43 mg, 0.3 mmol) trimethyl orthoformate (0.109 mL, 1.0 mmol) and glacial acetic acid (0.017 mL, 0.3 mmol) in 1,2-dichloroethane (2 mL) was stirred at RT under nitrogen atmosphere for 1 h. Sodium triacetoxyborohydride (85 mg, 0.4 mmol) was added and the resulting reaction mixture was stirred at RT for 16 h. The solvent was reduced in vacuo and the residue was loaded onto an Isolute® SCX-2 cartridge (10 g). The cartridge was washed with DCM/MeOH, the desired product was subsequently eluted using a mixture of 2M NH3 in MeOH and DCM. The residue was purified by column chromatography (Si—PCC, acetone:cyclohexane: 10:90 to 35:65 by volume). Solvents were reduced in vacuo to afford the title compound as a white solid. The resulting solid was further purified by reverse phase HPLC (MeOH: H2O+0.1% HCCOH, gradient 10:90 to 90:10 over 25 min). The solvent was reduced in vacuo and the aqueous residue freeze dried to afford 362 as a white solid (23 mg, 23%). LCMS (Method G): RT 6.73 min, [M+H]+ 508. 1H NMR (400 MHz, CDCl3): δ 8.18 (1 H, s), 8.04-8.03 (1 H, m), 7.70-7.69 (1 H, m), 7.27-7.26 (2 H, m), 4.38 (4 H, br s), 3.90 (2 H, s), 3.85 (4 H, t, J=4.74 Hz), 3.18 (2 H, m), 2.91 (5 H, m), 2.28-2.15 (2 H, m), 1.81 (2 H, m), 1.75-1.60 (2 H, m), 1.20 (3 H, s), 1.15 (3 H, s)
Reaction SMILES: [CH2:1]=[C:2]1[O:6][C:4](=[O:5])[CH2:3]1.Cl.[CH3:8][O:9][C:10](=[O:15])[C@H:11]([CH2:13][OH:14])[NH2:12].C([O-])(O)=O.[Na+]>C1COCC1>[O:6]=[C:2]([CH3:1])[CH2:3][C:4]([NH:12][C@H:11]([C:10]([O:9][CH3:8])=[O:15])[CH2:13][OH:14])=[O:5]
Reactant: C=C1CC(=O)O1
Reactant: COC(=O)[C@@H](N)CO
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Product: COC(=O)[C@H](CO)NC(=O)CC(C)=O
Temperature: 25 °C
Yield: 81 %

Procedure:
10.8 g (0.13 mol) of diketene, 20 g L-serine methyl ester hydrochloride (0.13 mol) and 21.6 g (0.26 mol, 2 eq) of NaHCO3 were mixed in 1000 ml of THF at 0° C. Then the ice bath was removed and it was stirred further at room temperature. After 24 h stirring at room temperature, the reaction mixture was filtered and the residue was recrystallized from 100 ml of ethyl acetate. This gave 21.14 g (0.10 mol, 81% yield) as a white solid.
Reaction SMILES: [C-:1]#[N:2].[K+].CS(O[CH2:9][CH2:10][CH:11]([C:24]1[CH:29]=[CH:28][C:27]([Cl:30])=[CH:26][C:25]=1[Cl:31])[C:12]1[C:20]2[C:15](=[C:16]([CH2:21][S:22][CH3:23])[CH:17]=[CH:18][CH:19]=2)[NH:14][CH:13]=1)(=O)=O>CN(C=O)C>[Cl:31][C:25]1[CH:26]=[C:27]([Cl:30])[CH:28]=[CH:29][C:24]=1[CH:11]([C:12]1[C:20]2[C:15](=[C:16]([CH2:21][S:22][CH3:23])[CH:17]=[CH:18][CH:19]=2)[NH:14][CH:13]=1)[CH2:10][CH2:9][C:1]#[N:2]
Reactant: [C-]#N
Reactant: CSCc1cccc2c(C(CCOS(C)(=O)=O)c3ccc(Cl)cc3Cl)c[nH]c12
Agent: [K+]
Solvent: CN(C)C=O
Product: CSCc1cccc2c(C(CCC#N)c3ccc(Cl)cc3Cl)c[nH]c12
Temperature: 80 °C
Reaction time: 2 h

Procedure:
563 mg (8.64 mmol) of potassium cyanide were added to 1.98 g (4.32 mmol) of the compound from Example 57A in 26 ml of DMF. The mixture was stirred at 80° C. for 2 h and then concentrated, and the crude product was purified by preparative HPLC (RP18 column; mobile phase: acetonitrile/water gradient with addition of 0.1% formic acid) to result in 1.42 g (84% of theory) of the title compound.
Reaction SMILES: [F:1][C:2]1[C:3]([F:12])=[C:4](Br)[C:5]2[O:9][CH:8]=[CH:7][C:6]=2[CH:10]=1.C([Li])(C)(C)C.[C:18]([O:22][C:23]([N:25]1[CH2:30][CH2:29][C:28](=[O:31])[CH2:27][CH:26]1[CH3:32])=[O:24])([CH3:21])([CH3:20])[CH3:19]>O1CCCC1>[C:18]([O:22][C:23]([N:25]1[CH2:30][CH2:29][C:28]([OH:31])([C:4]2[C:5]3[O:9][CH:8]=[CH:7][C:6]=3[CH:10]=[C:2]([F:1])[C:3]=2[F:12])[CH2:27][CH:26]1[CH3:32])=[O:24])([CH3:21])([CH3:19])[CH3:20]
Reactant: Fc1cc2ccoc2c(Br)c1F
Reactant: CC1CC(=O)CCN1C(=O)OC(C)(C)C
Agent: [Li]C(C)(C)C
Solvent: C1CCOC1
Product: CC1CC(O)(c2c(F)c(F)cc3ccoc23)CCN1C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A solution of 2.28 gm (9.8 mMol) 5,6-difluoro-7-bromobenzofuran in 30 mL tetrahydrofuran was cooled to −78° C. and then 9.8 mL (19.6 mMol) tert-butyllithium (1.7M in tetrahydrofuran) were added. After stirring for 30 minutes, a solution of 1.9 gm (8.9 mMol) 1-(tert-butoxycarbonyl)-2-methyl-4-oxo-piperidine in 20 mL tetrahydrofuran was added dropwise over 30 minutes. The reaction mixture was allowed to warm to room temperature over 16 hours and was then concentrated under reduced pressure. The residue was dissolved in 200 mL ethyl acetate and extracted sequentially with 50 mL 1N hydrochloric acid, saturated aqueous sodium bicarbonate, and saturated aqueous sodium chloride. The remaining organic phase was dried over magnesium sulfate and concentrated under reduced pressure to provide 1-(tert-butoxycarbonyl)-2-methyl-4-hydroxy-4-(5,6-difluorobenzofur-7-yl)piperidine. This alcohol was converted to a mixture of the title compounds essentially as described in EXAMPLE 1.
Reaction SMILES: C([SiH2][O:6][C:7](C)(C)[C@@H:8]1[CH2:12][NH:11][CH2:10][C@H:9]1[CH2:13][N:14]([CH2:24][CH:25]([CH3:27])[CH3:26])[S:15]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)(=[O:17])=[O:16])(C)(C)C.CC#N.O.CC#N>O>[OH:6][CH2:7][C@@H:8]1[CH2:12][NH:11][CH2:10][C@H:9]1[CH2:13][N:14]([CH2:24][CH:25]([CH3:27])[CH3:26])[S:15]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)(=[O:17])=[O:16]
Reactant: CC(C)CN(C[C@@H]1CNC[C@H]1C(C)(C)O[SiH2]C(C)(C)C)S(=O)(=O)c1ccccc1
Solvent: CC#N
Solvent: O
Product: CC(C)CN(C[C@@H]1CNC[C@H]1CO)S(=O)(=O)c1ccccc1

Procedure:
The title compound is prepared as described above for Example 9/step H (Scheme 5) from N-[(3S*,4S*)-4-(tert-butyl-dimethyl-silanyloxymethyl)-pyrrolidin-3-ylmethyl]-N-isobutyl-benzenesulfonamide. MS (LC-MS): 327.1 [M-Boc+H]+; tR (HPLC, Waters Symmetry C18 column, 20-95% CH3CN/H2O/3.5 min, 95% CH3CN/H2O, 2 min, CH3CN and H2O containing 0.1% TFA, flow: 0.6 mL/min): 4.17 min.
Reaction SMILES: Cl[CH2:2][CH2:3][NH:4][C@:5]12[CH2:40][CH2:39][C@@H:38]([C:41]([CH3:43])=[CH2:42])[C@@H:6]1[C@@H:7]1[C@@:20]([CH3:23])([CH2:21][CH2:22]2)[C@@:19]2([CH3:24])[C@@H:10]([C@:11]3([CH3:37])[C@@H:16]([CH2:17][CH2:18]2)[C:15]([CH3:26])([CH3:25])[C:14]([C:27]2[CH:36]=[CH:35][C:30]([C:31]([O:33][CH3:34])=[O:32])=[CH:29][CH:28]=2)=[CH:13][CH2:12]3)[CH2:9][CH2:8]1.CCN(C(C)C)C(C)C.[N:53]1([C:59]([O:61][C:62]([CH3:65])([CH3:64])[CH3:63])=[O:60])[CH2:58][CH2:57][NH:56][CH2:55][CH2:54]1>CS(C)=O>[CH3:34][O:33][C:31]([C:30]1[CH:29]=[CH:28][C:27]([C:14]2[C:15]([CH3:25])([CH3:26])[C@H:16]3[C@:11]([CH3:37])([CH2:12][CH:13]=2)[C@@H:10]2[C@:19]([CH3:24])([C@@:20]4([CH3:23])[C@H:7]([CH2:8][CH2:9]2)[C@H:6]2[C@H:38]([C:41]([CH3:43])=[CH2:42])[CH2:39][CH2:40][C@:5]2([NH:4][CH2:3][CH2:2][N:56]2[CH2:57][CH2:58][N:53]([C:59]([O:61][C:62]([CH3:65])([CH3:64])[CH3:63])=[O:60])[CH2:54][CH2:55]2)[CH2:22][CH2:21]4)[CH2:18][CH2:17]3)=[CH:36][CH:35]=1)=[O:32]
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: C=C(C)[C@@H]1CC[C@]2(NCCCl)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(c6ccc(C(=O)OC)cc6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Solvent: CCN(C(C)C)C(C)C
Solvent: CS(C)=O
Product: C=C(C)[C@@H]1CC[C@]2(NCCN3CCN(C(=O)OC(C)(C)C)CC3)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(c6ccc(C(=O)OC)cc6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Temperature: 120 °C
Yield: 52.3 %

Procedure:
A mixture of methyl 4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-((2-chloroethyl)amino)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoate (230 mg, 0.379 mmol), Hunig's Base (0.331 mL, 1.895 mmol) and tert-butyl piperazine-1-carboxylate (141 mg, 0.759 mmol) in DMSO (3 mL) was heated up at 120° C. for 1 hour. The reaction mixture was quenched with water (10 mL), extracted with ethyl acetate (3×8 mL), the extracts were combined, dried over sodium sulfate, filtered and concentrated under reduced pressure to provide the crude, the crude was purified by silica gel chromatography with 0-30% ethyl acetate/hexanes to provide the desired product as a white solid (150 mg, 52%). LCMS: m/e 756.66 (M+H)+, 2.50 min (method 11).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][CH:5]=[C:4](Cl)[C:3]=1[NH:9][C:10]([N:12]1[C:20]2[C:15](=[CH:16][C:17]([NH:21][C:22]([C:24]3[O:28][C:27]([N:29]4[CH2:34][CH2:33][CH2:32][CH:31]([CH3:35])[CH2:30]4)=[N:26][C:25]=3[C:36]([F:39])([F:38])[F:37])=[O:23])=[CH:18][CH:19]=2)[CH:14]=[CH:13]1)=[O:11].N1C2C(=CC(NC(C3OC(N4CCCC(C)C4)=NC=3C(F)(F)F)=O)=CC=2)C=C1.[N+:68](C1C=CC=CC=1N=C=O)([O-:70])=[O:69]>>[CH3:35][CH:31]1[CH2:32][CH2:33][CH2:34][N:29]([C:27]2[O:28][C:24]([C:22]([NH:21][C:17]3[CH:16]=[C:15]4[C:20](=[CH:19][CH:18]=3)[N:12]([C:10]([NH:9][C:3]3[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=3[N+:68]([O-:70])=[O:69])=[O:11])[CH:13]=[CH:14]4)=[O:23])=[C:25]([C:36]([F:39])([F:38])[F:37])[N:26]=2)[CH2:30]1
Reactant: CC1CCCN(c2nc(C(F)(F)F)c(C(=O)Nc3ccc4c(ccn4C(=O)Nc4c(Cl)cccc4Cl)c3)o2)C1
Reactant: O=C=Nc1ccccc1[N+](=O)[O-]
Agent: CC1CCCN(c2nc(C(F)(F)F)c(C(=O)Nc3ccc4[nH]ccc4c3)o2)C1
Product: CC1CCCN(c2nc(C(F)(F)F)c(C(=O)Nc3ccc4c(ccn4C(=O)Nc4ccccc4[N+](=O)[O-])c3)o2)C1

Procedure:
Compound 47 was prepared by the general procedure for compound 45, using compound 44 and 2-nitrophenyl isocyanate as starting materials. 1H NMR (500 MHz, DMSO-d6) δ 10.55 (br s, 1H), 10.18 (br s, 1H), 8.14 (br d, 1H, J=8.5 Hz), 8.08 (br s, 1H), 8.05 (br d, 1H, J=8.5 Hz), 8.00 (br d, 1H, J=8.0 Hz), 7.79 (tm, 1H, J=7.6 Hz), 7.72 (br d, 1H, J=8.2 Hz), 7.51 (br d, 1H, J=8.2 Hz), 7.46 (m, 1H), 6.84 (m, 1H), 4.13 (m, 2H), 3.06 (br t, 1H, J=12.0 Hz), 2.76 (br t, 1H, J=11.7 Hz), 1.74 (m, 3H), 1.54 (m, 1H), 1.16 (m, 1H), 0.94 (d, 3H, J=6.3 Hz). MS (M+1): 557.
Reaction SMILES: CN1CCCCC1.[CH:8]([O:11][C:12]([NH:14][C@H:15]([C:19]([OH:21])=O)[CH:16]([CH3:18])[CH3:17])=[O:13])([CH3:10])[CH3:9].ClC(OCC(C)C)=O.[S:30]1[C:34]2[CH:35]=[CH:36][CH:37]=[CH:38][C:33]=2[N:32]=[C:31]1[CH:39]([NH2:41])[CH3:40]>C(Cl)Cl>[S:30]1[C:34]2[CH:35]=[CH:36][CH:37]=[CH:38][C:33]=2[N:32]=[C:31]1[CH:39]([NH:41][C:19](=[O:21])[C@H:15]([CH:16]([CH3:17])[CH3:18])[NH:14][C:12]([O:11][CH:8]([CH3:9])[CH3:10])=[O:13])[CH3:40]
Reactant: CC(C)OC(=O)N[C@H](C(=O)O)C(C)C
Reactant: CC(N)c1nc2ccccc2s1
Agent: CC(C)COC(=O)Cl
Solvent: CN1CCCCC1
Solvent: ClCCl
Product: CC(C)OC(=O)N[C@H](C(=O)NC(C)c1nc2ccccc2s1)C(C)C
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 58.9 %

Procedure:
0.3 g of N-methylpiperidine was added to a solution containing 0.6 g of N-isopropoxycarbonyl-L-valine dissolved in 40 mL of methylene chloride, at -20° C., and then the mixture was stirred for 10 minutes at the same temperature. 0.4 g of isobutyl chloroformate was added to the mixture at -40° C., and then stirred for 1 hour at -40° C. to -15° C. After 0.5 g of 1-(2-benzothiazolyl)ethylamine was added to this mixture at -60° C. and the refrigerant was put off, the reaction mixture was warmed naturally to room temperature while being stirred. After completion of the reaction, the reaction mixture was washed successively with water, a 5% aqueous solution of sodium bicarbonate, and water. The organic layer was dried over anhydrous magnesium sulfate and the solvent was removed under reduced pressure. The residue, which was a crude crystal, was purified by column chromatography on silica gel, thus yielding 0.6 g of the desired product in the form of a white powder (yield: 59%).
Reaction SMILES: [N:1]1([CH2:6][CH2:7][CH2:8][NH2:9])[CH:5]=[CH:4][N:3]=[CH:2]1.[C:10]([NH:13][C:14]1[CH:23]=[CH:22][C:17]([S:18](Cl)(=[O:20])=[O:19])=[CH:16][CH:15]=1)(=[O:12])[CH3:11].[OH-].[Na+].ClCCl>O>[N:1]1([CH2:6][CH2:7][CH2:8][NH:9][S:18]([C:17]2[CH:16]=[CH:15][C:14]([NH:13][C:10](=[O:12])[CH3:11])=[CH:23][CH:22]=2)(=[O:20])=[O:19])[CH:5]=[CH:4][N:3]=[CH:2]1
Reactant: NCCCn1ccnc1
Reactant: CC(=O)Nc1ccc(S(=O)(=O)Cl)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: ClCCl
Product: CC(=O)Nc1ccc(S(=O)(=O)NCCCn2ccnc2)cc1
Temperature: 25 °C
Reaction time: 20 h
Yield: 82.9 %

Procedure:
A mixture of 1.25 g of 1H-imidazol-1-propanamine in 25 ml of water was stirred at room temperature then 2.34 g of N-acetylsulfanilyl chloride was added and stirring was continued for 20 hours resulting in a clear solution. With the addition of 4 ml of 5N sodium hydroxide the solution turned milky and resulted in the separation of an oil. The addition of dichloromethane resulted in the formation of a suspended precipitate which was collected by filtration and gave 2.67 g of the desired compound as tan crystals, mp 178°-180° C.
Reaction SMILES: C([CH:3]1[CH2:5][CH:4]1[C:6]([O:8][CH2:9][CH3:10])=[O:7])=O.C(C=P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)=O.[O:33]1C[CH2:36][CH2:35][CH2:34]1>>[CH:4]1([C:6]([O:8][CH2:9][CH2:10][CH:36]=[CH:35][CH:34]=[O:33])=[O:7])[CH2:3][CH2:5]1
Reactant: C1CCOC1
Reactant: CCOC(=O)C1CC1C=O
Agent: O=CC=P(c1ccccc1)(c1ccccc1)c1ccccc1
Product: O=CC=CCCOC(=O)C1CC1
Yield: 80 %

Procedure:
A mixture of ethyl 2-formyl-1-cyclopropanecarboxylate (55 g, 0.39 moles) and formylmethylenetriphenylphosphorane (117.7 g, 0.39 moles) in tetrahydrofuran (600 ml) is refluxed for 40 hours. The solvent is removed under reduced pressure. The residue is triturated with ether/hexane (1:1) and filtered. The filtrate is evaporated, dissolved in ether/petroleum ether and filtered through a column of silica gel. The solvent is stripped from the filtrate to give a dark oil. The oil is distilled under reduced pressure to give the product as a clear colorless oil (52.1 g, 80%), b.p. 105°-113° C. (2.0 mm).
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[C:13]3[CH:20]=[CH:19][CH:18]=[CH:17][C:14]=3[S:15][CH:16]=2)=[CH:8][CH:7]=1.[N:21]1[CH:26]=[CH:25][CH:24]=[N:23][C:22]=1[N:27]1[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[S:15]1[CH:16]=[C:12]([C:9]2[CH:10]=[CH:11][C:6]([O:5][CH2:4][CH2:3][CH2:2][N:30]3[CH2:31][CH2:32][N:27]([C:22]4[N:21]=[CH:26][CH:25]=[CH:24][N:23]=4)[CH2:28][CH2:29]3)=[CH:7][CH:8]=2)[C:13]2[CH:20]=[CH:19][CH:18]=[CH:17][C:14]1=2
Reactant: BrCCCOc1ccc(-c2csc3ccccc23)cc1
Reactant: c1cnc(N2CCNCC2)nc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: c1cnc(N2CCN(CCCOc3ccc(-c4csc5ccccc45)cc3)CC2)nc1

Procedure:
The title compound is prepared from 3-[4-(3-bromo-propoxy)-phenyl]-benzo[b]thiophene, 1-(2-pyrimidyl)piperazine, potassium carbonate and acetonitrile essentially as described above in Example 118. Purity by LC/MS=99%, [M+H]+=431.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:10]=[CH:9][N:8]([CH:11]([CH3:13])[CH3:12])[C:7]=1[CH:14]([C:16]1[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=1)O)=[O:5])[CH3:2].[NH2:23][C:24]1[CH:25]=[C:26]([Cl:32])[C:27](=[O:31])[N:28]([CH3:30])[CH:29]=1.COC(C1C=C(Br)N(C(C)C)C=1C(C1C=CC(Cl)=CC=1)O)=O.ClC1C=C(C=CC=1F)N>>[CH2:1]([O:3][C:4]([C:6]1[CH:10]=[CH:9][N:8]([CH:11]([CH3:13])[CH3:12])[C:7]=1[CH:14]([NH:23][C:24]1[CH:25]=[C:26]([Cl:32])[C:27](=[O:31])[N:28]([CH3:30])[CH:29]=1)[C:16]1[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1ccn(C(C)C)c1C(O)c1ccc(Cl)cc1
Reactant: Cn1cc(N)cc(Cl)c1=O
Agent: COC(=O)c1cc(Br)n(C(C)C)c1C(O)c1ccc(Cl)cc1
Agent: Nc1ccc(F)c(Cl)c1
Product: CCOC(=O)c1ccn(C(C)C)c1C(Nc1cc(Cl)c(=O)n(C)c1)c1ccc(Cl)cc1

Procedure:
The title compound was prepared in analogy to the procedure described for Step D2, but 2-[(4-chloro-phenyl)-hydroxy-methyl]-1-isopropyl-1H-pyrrole-3-carboxylic acid ethyl ester (Step E4) and 5-amino-3-chloro-1-methyl-1H-pyridin-2-one (Step E5) were used instead of 5-bromo-2-[(4-chloro-phenyl)-hydroxy-methyl]-1-isopropyl-1H-pyrrole-3-carboxylic acid methyl ester and 3-chloro-4-fluoroaniline respectively to afford the title compound as a white solid. tR: 7.36 min (HPLC 2); ESI-MS: tR=1.25 min, [M+H]+ 462/464 (LC-MS 1); TLC: Rf=0.31 (EtOAc).
Reaction SMILES: [O:1]=[C:2]1[N:11]2[N:12]=[C:13]([C:15]([OH:17])=O)[CH:14]=[C:10]2[C:9]2[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=2[NH:3]1.[Na].C(Cl)(=O)C([Cl:22])=O>C1C=CC=CC=1>[O:1]=[C:2]1[N:11]2[N:12]=[C:13]([C:15]([Cl:22])=[O:17])[CH:14]=[C:10]2[C:9]2[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=2[NH:3]1
Reactant: O=C(O)c1cc2c3ccccc3[nH]c(=O)n2n1
Reactant: O=C(Cl)C(=O)Cl
Agent: [Na]
Solvent: c1ccccc1
Product: O=C(Cl)c1cc2c3ccccc3[nH]c(=O)n2n1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
4.8 g (0.019 mole) of 5,6-dihydro-5-oxopyrazolo[1,5-c]-quinazoline-2-carboxylic acid, sodium salt is added to a solution of 3.27 g (0.026 mole) of oxalyl chloride in 200 ml of benzene. The suspension is stirred at room temperature for 20 minutes and then refluxed under nitrogen for 2 hours. The solvent is stripped to give the product.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]=1)[CH2:5][Mg]Cl.CON(C)[C:14]([C:16]1[C:24]2[C:19](=[N:20][CH:21]=[CH:22][CH:23]=2)[N:18]([Si:25]([CH:32]([CH3:34])[CH3:33])([CH:29]([CH3:31])[CH3:30])[CH:26]([CH3:28])[CH3:27])[CH:17]=1)=[O:15]>>[Cl:1][C:2]1[CH:3]=[C:4]([CH2:5][C:14]([C:16]2[C:24]3[C:19](=[N:20][CH:21]=[CH:22][CH:23]=3)[N:18]([Si:25]([CH:29]([CH3:31])[CH3:30])([CH:32]([CH3:34])[CH3:33])[CH:26]([CH3:27])[CH3:28])[CH:17]=2)=[O:15])[CH:8]=[CH:9][CH:10]=1
Reactant: Cl[Mg]Cc1cccc(Cl)c1
Reactant: CON(C)C(=O)c1cn([Si](C(C)C)(C(C)C)C(C)C)c2ncccc12
Product: CC(C)[Si](C(C)C)(C(C)C)n1cc(C(=O)Cc2cccc(Cl)c2)c2cccnc21
Yield: 94 %

Procedure:
This compound was prepared by the reaction of 3-chlorobenzylmagnesium chloride (0.25 M solution in diethyl ether) with N-methoxy-N-methyl-1-triisopropylsilanyl-1H-pyrrolo[2,3-b]pyridine-3-carboxamide as described in General Method 1. The desired compound was obtained in 94% yield as a viscous clear oil.
Reaction SMILES: [Cl:1][C:2]1[C:3]([OH:16])=[C:4]([C:11](OCC)=[O:12])[C:5](=[O:10])[N:6]([CH3:9])[C:7]=1[CH3:8].[NH2:17][C:18]1[S:19][CH:20]=[N:21][N:22]=1.BrC1C=CC=CC=1>CCCCCC>[S:19]1[CH:20]=[N:21][N:22]=[C:18]1[NH:17][C:11]([C:4]1[C:5](=[O:10])[N:6]([CH3:9])[C:7]([CH3:8])=[C:2]([Cl:1])[C:3]=1[OH:16])=[O:12]
Reactant: Nc1nncs1
Reactant: CCOC(=O)c1c(O)c(Cl)c(C)n(C)c1=O
Solvent: CCCCCC
Solvent: Brc1ccccc1
Product: Cc1c(Cl)c(O)c(C(=O)Nc2nncs2)c(=O)n1C
Temperature: 25 °C
Reaction time: 5 h
Yield: 81 %

Procedure:
197 mg of ethyl 5-chloro-1,6-dimethyl-4-hydroxy-2-oxo-1,2-dihydropyridine-3-carboxylate and 76 mg of 2-amino-1,3,4-thiadiazole were added to 2 ml of bromobenzene, then, the mixture was stirred for 5 hours under heat refluxing condition. The reaction mixture was cooled to room temperature, then, to the reaction mixture was added n-hexane. The resulting solid was collected by filtration, and washed with a mixture of t-butyl methyl ether and n-hexane and dried to obtain 183 mg of N-(1,3,4-thiadiazol-2-yl)-5-chloro-1,6-dimethyl-4-hydroxy-2-oxo-1,2-dihydropyridine-3-carboxamide (hereinafter, referred to as present compound 14) represented by the formula: