Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([CH:10]=1)[C:7](Cl)=[O:8].Cl[C:12]1[CH:31]=[CH:30][C:15]([C:16]([NH:18][C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([CH:25]3[O:29]CC[O:26]3)[CH:20]=2)=O)=[CH:14][CH:13]=1.CC1CC(C(OC)=O)CC[NH:34]1.C(OC(C1CCN(CC2C=CC=C(NC(=O)C3C=CC(Cl)=CC=3)C=2)CC1)=O)C>>[CH3:24][CH:23]1[CH2:22][CH:21]([C:25]([OH:29])=[O:26])[CH2:20][CH2:19][N:18]1[CH2:16][C:15]1[CH:30]=[CH:31][CH:12]=[C:13]([NH:34][C:7]([C:6]2[CH:5]=[N:4][CH:3]=[C:2]([CH3:1])[CH:10]=2)=[O:8])[CH:14]=1
Reactant: Cc1cncc(C(=O)Cl)c1
Reactant: COC(=O)C1CCNC(C)C1
Reactant: O=C(Nc1cccc(C2OCCO2)c1)c1ccc(Cl)cc1
Agent: CCOC(=O)C1CCN(Cc2cccc(NC(=O)c3ccc(Cl)cc3)c2)CC1
Product: Cc1cncc(C(=O)Nc2cccc(CN3CCC(C(=O)O)CC3C)c2)c1

Procedure:
The title compound is prepared according to the reaction sequence 2.001a-2.001d described above using 5-methylnicotinoyl chloride instead of 4-chlorobenzoyl chloride as in 2.001a and rac-(2S*,4S*)-methyl 2-methylpiperidine-4-carboxylate instead of ethyl isonipecotate as in 2.001c: LC-MS A: tR=0.67 min; [M+H]+=422.08.
Reaction SMILES: CN(C)C(N1[CH2:10][CH:9]=[C:8]([C:11]2[NH:28][C:14]3[N:15]=[CH:16][N:17]=[C:18]([C:19]4[CH:24]=[C:23]([F:25])[CH:22]=[C:21]([NH2:26])[C:20]=4[CH3:27])[C:13]=3[CH:12]=2)[CH2:7][CH2:6]1)=O.ClC1C2C=C(C3CC[C:43]4([O:47][CH2:46][CH2:45][O:44]4)CC=3)NC=2N=CN=1>>[O:44]1[C:43]2([CH2:6][CH2:7][C:8]([C:11]3[NH:28][C:14]4[N:15]=[CH:16][N:17]=[C:18]([C:19]5[C:20]([CH3:27])=[C:21]([NH2:26])[CH:22]=[C:23]([F:25])[CH:24]=5)[C:13]=4[CH:12]=3)=[CH:9][CH2:10]2)[O:47][CH2:46][CH2:45]1
Reactant: Cc1c(N)cc(F)cc1-c1ncnc2[nH]c(C3=CCN(C(=O)N(C)C)CC3)cc12
Reactant: Clc1ncnc2[nH]c(C3=CCC4(CC3)OCCO4)cc12
Product: Cc1c(N)cc(F)cc1-c1ncnc2[nH]c(C3=CCC4(CC3)OCCO4)cc12

Procedure:
Intermediate 18 was prepared analogue to Intermediate 6 by replacing Intermediate 3 with Intermediate 17.
Reaction SMILES: [F:1][C:2]([F:31])([F:30])[C:3]1[CH:4]=[CH:5][C:6]([C:9]#[C:10][C:11]2[CH:12]=[CH:13][C:14]([N:17]3[CH2:22][CH2:21][N:20](C(OC(C)(C)C)=O)[CH2:19][CH2:18]3)=[N:15][CH:16]=2)=[N:7][CH:8]=1.FC(F)(F)C(O)=O.C(N(CC)CC)C.[CH3:46][S:47](Cl)(=[O:49])=[O:48]>C(Cl)Cl>[CH3:46][S:47]([N:20]1[CH2:21][CH2:22][N:17]([C:14]2[CH:13]=[CH:12][C:11]([C:10]#[C:9][C:6]3[CH:5]=[CH:4][C:3]([C:2]([F:31])([F:30])[F:1])=[CH:8][N:7]=3)=[CH:16][N:15]=2)[CH2:18][CH2:19]1)(=[O:49])=[O:48]
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc(C#Cc3ccc(C(F)(F)F)cn3)cn2)CC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: O=C(O)C(F)(F)F
Product: CS(=O)(=O)N1CCN(c2ccc(C#Cc3ccc(C(F)(F)F)cn3)cn2)CC1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 64.7 %

Procedure:
To a stirred solution of tert-butyl 4-(5-{[5-(trifluoromethyl)pyridin-2-yl]ethynyl}pyridin-2-yl)piperazine-1-carboxylate (724 mg, 1.67 mmol) in CH2Cl2 (8 mL) at 0° C. was added trifluoroacetic acid (4 mL). The reaction was brought to room temperature and stirred for 30 minutes. Volatiles were removed in vacuo. The residue was then dissolved in CH2Cl2 (20 mL) and washed with aqueous sodium hydroxide solution (2M, 2×20 mL). The layers were then separated and the aqueous phase extracted with CH2Cl2 (3×10 mL). The combined organic extracts were then dried, (MgSO4), filtered and concentrated in vacuo. The residue was dissolved in CH2Cl2 (50 mL), and cooled to 0° C. and treated sequentially with triethylamine (0.25 mL, 1.75 mmol) and methanesulfonyl chloride (0.14 mL, 13.5 mmol). The reaction was brought to RT and stirred for 1 hour. The reaction was then quenched with water (50 mL). The layers were separated and the aqueous phase extracted with CH2Cl2 (3×20 mL). The combined organic extracts were then dried, (MgSO4), filtered and concentrated in vacuo to give 1-(methylsulfonyl)-4-(5-{[5-(trifluoromethyl)pyridin-2-yl]ethynyl}pyridin-2-yl)piperazine as an orange solid (445 mg, 1.08 mmol, 65%).
Reaction SMILES: [Cl:1][C:2]1[C:3]([N:27]([CH:29]([CH3:31])[CH3:30])[CH3:28])=[CH:4][C:5]2[N:11]=[C:10]([C:12]3[CH:17]=[CH:16][CH:15]=[C:14]([N:18]4[C:22]([CH2:23]O)=[CH:21][N:20]=[N:19]4)[CH:13]=3)[CH2:9][C:8](=[O:25])[NH:7][C:6]=2[CH:26]=1.S(Cl)(Cl)=O.[Cl-].[CH:37]([NH2:40])([CH3:39])[CH3:38]>ClCCl.CN(C=O)C>[Cl:1][C:2]1[C:3]([N:27]([CH:29]([CH3:31])[CH3:30])[CH3:28])=[CH:4][C:5]2[N:11]=[C:10]([C:12]3[CH:17]=[CH:16][CH:15]=[C:14]([N:18]4[C:22]([CH2:23][NH:40][CH:37]([CH3:39])[CH3:38])=[CH:21][N:20]=[N:19]4)[CH:13]=3)[CH2:9][C:8](=[O:25])[NH:7][C:6]=2[CH:26]=1
Reactant: CC(C)N(C)c1cc2c(cc1Cl)NC(=O)CC(c1cccc(-n3nncc3CO)c1)=N2
Reactant: CC(C)N
Agent: [Cl-]
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: O=S(Cl)Cl
Product: CC(C)NCc1cnnn1-c1cccc(C2=Nc3cc(N(C)C(C)C)c(Cl)cc3NC(=O)C2)c1

Procedure:
The title compound was prepared from 8-chloro-4-[3-(5-hydroxymethyl-[1,2,3]triazol-1-yl)-phenyl]-7-(isopropyl-methyl-amino)-1,3-dihydro-benzo[b][1,4]diazepin-2-one (Example 96) (220 mg, 0.50 mmol) by reaction with thionylchloride in dichloromethane and subsequent treatment of the corresponding chloride with isopropylamine in DMF according to the method described in Example 45. Obtained as a light yellow solid (160 mg, 67%).
Reaction SMILES: [C:1](=[O:4])([O-])[O-].[K+].[K+].[C:7]1([CH:14]=[CH:13][C:11]([OH:12])=[CH:10][CH:9]=1)[OH:8].F[C:16]1[CH:23]=[CH:22][C:19]([CH:20]=[O:21])=[CH:18][CH:17]=1>CC(N(C)C)=O>[C:11]1([O:12][C:7]2[CH:14]=[CH:13][C:11]([CH:1]=[O:4])=[CH:10][CH:9]=2)[CH:13]=[CH:14][C:7]([O:8][C:16]2[CH:23]=[CH:22][C:19]([CH:20]=[O:21])=[CH:18][CH:17]=2)=[CH:9][CH:10]=1
Reactant: O=C([O-])[O-]
Reactant: O=Cc1ccc(F)cc1
Reactant: Oc1ccc(O)cc1
Agent: [K+]
Solvent: CC(=O)N(C)C
Product: O=Cc1ccc(Oc2ccc(Oc3ccc(C=O)cc3)cc2)cc1
Yield: 131.9 %

Procedure:
There was added 41.5 grams (0.30 mole) of anhydrous potassium carbonate to a solution of 11 grams (0.10 mole) of hydroquinone, 24.8 grams (0.20 mole) of 4-fluorobenzaldehyde and 200 ml of dimethylacetamide. The resulting solution was heated at reflux for 12 hours. The reaction mixture was then decanted from the insoluble potassium salts and allowed to cool. The cooled solution was added to water to effect precipitation of product which was isolated by filtration. The product was recrystallized from isopropanol/water to yield 21 grams (66%) of 4,4'[1,4-phenylenebis(oxy)]bisbenzaldehyde having a melting point of 157°-158° C. The identity of the product was further confirmed by proton NMR.
Reaction SMILES: N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O.[ClH:19].[F:20][C:21]1[CH:40]=[C:39](C)[C:38]([O:42][C:43]([O:45][CH3:46])=[O:44])=[CH:37][C:22]=1[NH:23][C:24]1[C:33]2[C:28](=[CH:29][C:30]([OH:36])=[C:31]([O:34][CH3:35])[CH:32]=2)[N:27]=[CH:26][N:25]=1.C(P(CCCC)CCCC)CCC.O[CH2:61][CH2:62][CH2:63][C:64]1[CH:69]=[CH:68][N:67]=[CH:66][CH:65]=1>C(Cl)Cl>[Cl:19][C:39]1[C:38]([O:42][C:43]([O:45][CH3:46])=[O:44])=[CH:37][C:22]([NH:23][C:24]2[C:33]3[C:28](=[CH:29][C:30]([O:36][CH2:61][CH2:62][CH2:63][C:64]4[CH:69]=[CH:68][N:67]=[CH:66][CH:65]=4)=[C:31]([O:34][CH3:35])[CH:32]=3)[N:27]=[CH:26][N:25]=2)=[C:21]([F:20])[CH:40]=1
Reactant: Cl
Reactant: OCCCc1ccncc1
Reactant: COC(=O)Oc1cc(Nc2ncnc3cc(O)c(OC)cc23)c(F)cc1C
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: ClCCl
Product: COC(=O)Oc1cc(Nc2ncnc3cc(OCCCc4ccncc4)c(OC)cc23)c(F)cc1Cl
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 66.8 %

Procedure:
1,1'-(Azodicarbonyl)dipiperidine (2.52 g, 10 mmol) in methylene chloride (10 ml) was added dropwise to a solution of 4-(2-fluoro-5-methoxycarbonyloxy-4-methylanilino)-7-hydroxy-6-methoxyquinazoline hydrochloride (1.38 g, 3.5 mmol), (prepared as described for the starting material in Example 22), tributylphosphine (2 g, 10.5 mmol) and 4-(3-hydroxypropyl)pyridine (720 mg, 5.25 mmol) in methylene chloride (25 ml) and the mixture stirred for 2.5 hours at ambient temperature. The solvent was removed by evaporation and the residue was triturated with petroleum ether. The solid product was collected by filtration and purified by column chromatography eluting with methylene chloride/methanol (95/5) to give 4-(4-chloro-2-fluoro-5-methoxycarbonyloxyanilino)-6-methoxy-7-(3-(4-pyridyl)propoxy)quinazoline (1.2 g, 67%).
Reaction SMILES: [C:1]1([PH:7][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:20]([I:22])[CH3:21].[CH2:23](O)[CH3:24]>>[I-:22].[C:8]1([P+:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)([CH2:20][CH3:21])[CH2:23][CH3:24])[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: CCI
Reactant: c1ccc(Pc2ccccc2)cc1
Reactant: CCO
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CC[P+](CC)(c1ccccc1)c1ccccc1
Product: [I-]
Reaction time: 48 h

Procedure:
50 g of diphenylphosphine were mixed with 150 ml of ethanol under nitrogen atmosphere. 37.12 g of potassium carbonate were then added to the mixture and the mixture was stirred. Finally, 125.73 g of ethyl iodide were added dropwise. After 48 hours at 50° C., the ethanol was removed. The product was then dissolved in chloroform. The chloroform was evaporated and the solid washed with diethyl ether and dried under vacuum. 98.45 g of diphenyl-diethyl-phosphonium iodide were obtained (98.5% wt. yield)
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].CCOCC.[C:12]1([C:18]2([CH:24]([CH3:29])[C:25](OC)=[O:26])[CH:23]=[CH:22][CH2:21][CH:20]=[CH:19]2)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C(OCC)(=O)C>O>[CH3:29][CH:24]([C:18]1([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:23]=[CH:22][CH2:21][CH:20]=[CH:19]1)[CH2:25][OH:26]
Reactant: COC(=O)C(C)C1(c2ccccc2)C=CCC=C1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Solvent: O
Solvent: CCOC(C)=O
Product: CC(CO)C1(c2ccccc2)C=CCC=C1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
0.76 g. of lithium aluminum hydride is placed in 20 ml. of absolute ether. 2.42 g. of methyl 2-(1-phenyl-2,5-cyclohexadien-1-yl)-propionate in 20 ml. of absolute ether are added dropwise thereto. After stirring at room temperature for 5 hours, the mixture is worked-up as follows: The mixture is treated with ethyl acetate and water, filtered under suction and the organic phase is separated from the aqueous phase. The organic phase is dried with sodium sulfate, filtered and evaporated. The crude product obtained is chromatographed on 80 g. of silica gel with ether/petroleum ether (1:2), oily β-methyl-1-phenyl-2,5-cyclohexadien-1ethanol being obtained.
Reaction SMILES: N12CCCN=C1CCCCC2.[F:12][C:13]([F:27])([F:26])[C:14]1[CH:19]=[CH:18][N:17]=[C:16]([C:20]2[NH:21][O:22][C:23](=[O:25])[N:24]=2)[CH:15]=1.[N:28]1([C:33](Cl)=[O:34])[CH2:32][CH2:31][CH2:30][CH2:29]1>N1C=CC=CC=1>[N:28]1([C:33]([N:24]2[C:23](=[O:25])[O:22][N:21]=[C:20]2[C:16]2[CH:15]=[C:14]([C:13]([F:12])([F:26])[F:27])[CH:19]=[CH:18][N:17]=2)=[O:34])[CH2:32][CH2:31][CH2:30][CH2:29]1
Reactant: O=C(Cl)N1CCCC1
Reactant: O=c1nc(-c2cc(C(F)(F)F)ccn2)[nH]o1
Solvent: C1CCC2=NCCCN2CC1
Solvent: c1ccncc1
Product: O=C(N1CCCC1)n1c(-c2cc(C(F)(F)F)ccn2)noc1=O
Reaction time: 15 h
Yield: 63.4 %

Procedure:
To 1 ml of pyridine were added 0.3 g of 1,8-diazabicyclo[5,4,0]undec-7-ene, and 0.3 g of 3-(4-trifluoromethylpyridin-2-yl)-1,2,4-oxadiazol-5-one, and 0.26 g of 1-pyrrolidinecarbonyl chloride was added at room temperature. After stirring for 15 hours, the resultant solution was concentrated, and the residue was subjected to silica gel column chromatography to obtain 0.27 g of 4-(1-pyrrolidinecarbonyl)-3-(4-trifluoromethylpyridin-2-yl)-1,2,4-oxadiazol-5-one (present compound (15)).
Reaction SMILES: [Al+3].[Cl-].[Cl-].[Cl-].[CH3:5][O:6][C:7]1[N:15]=[C:14]2[C:10]([CH:11]=[CH:12][NH:13]2)=[CH:9][CH:8]=1.[C:16](Cl)(=[O:18])[CH3:17].CO>C(Cl)Cl>[CH3:5][O:6][C:7]1[N:15]=[C:14]2[NH:13][CH:12]=[C:11]([C:16](=[O:18])[CH3:17])[C:10]2=[CH:9][CH:8]=1
Reactant: COc1ccc2cc[nH]c2n1
Reactant: CC(=O)Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: CO
Solvent: ClCCl
Product: COc1ccc2c(C(C)=O)c[nH]c2n1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a suspension of AlCl3 (1.37 g, 10.3 mmol) in CH2Cl2 (40 mL) was added 6-methoxy-7-azaindole (315 mg, 2.07 mmol) and the mixture was stirred at RT for 30 min under nitrogen. Acetyl chloride (736 μL, 10.3 mmol) was added dropwise and the resulting mixture stirred at RT overnight. MeOH (8 mL) was added cautiously to quench the reaction and the solvents were removed under vacuum. The residue was purified by flash column chromatography on silica gel (CH2Cl2 to CH2Cl2/MeOH 93-7) and by preparative HPLC (Waters Sunfire C18-ODB, 5 μm, 30×100 mm, 5% to 100% CH3CN in H2O in 25 min, CH3CN and H2O containing 0.1% TFA, flow: 40 mL/min) to give after neutralization (aqueous saturated NaHCO3) and extraction (CH2Cl2) of the purified fractions the desired compound TLC, Rf (CH2Cl2/MeOH 9:1)=0.55; MS (UPLC/MS): 191.2 [M+H]+, 189.1 [M−H]−, 379.2 [2M−H]−; tR (HPLC conditions f): 1.45 min. 1H-NMR (400 MHz, DMSO): δ (ppm): 8.35 (d, 1H), 8.29 (s, 1H), 6.75 (d, 1H), 5.04 (s, 2H), 3.89 (s, 3H), 2.44 (s, 3H).
Reaction SMILES: [NH2:1][N:2]1[N:11]=[C:10]([C:12]2[CH:17]=[CH:16][N:15]=[C:14]([Cl:18])[CH:13]=2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]1=[O:19].[OH:20][C:21]1([CH2:27][C:28](O)=[O:29])[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]1>>[Cl:18][C:14]1[CH:13]=[C:12]([C:10]2[C:9]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[C:3](=[O:19])[N:2]([NH:1][C:28](=[O:29])[CH2:27][C:21]3([OH:20])[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]3)[N:11]=2)[CH:17]=[CH:16][N:15]=1
Reactant: O=C(O)CC1(O)CCCCC1
Reactant: Nn1nc(-c2ccnc(Cl)c2)c2ccccc2c1=O
Product: O=C(CC1(O)CCCCC1)Nn1nc(-c2ccnc(Cl)c2)c2ccccc2c1=O

Procedure:
The product from Example 29B and 2-(1-hydroxycyclohexyl)acetic acid were processed using a method similar to that described in Example 10C to afford the title compound. 1H NMR (500 MHz, CDCl3) δ ppm 9.29 (s, 1H), 8.58 (d, J=4.9 Hz, 1H), 8.52-8.57 (m, 1H), 7.82-7.93 (m, 2H), 7.70-7.72 (m, 1H), 7.62 (s, 1H), 7.50 (dd, J=5.0, 1.4 Hz, 1H), 2.62 (s, 2H), 1.79-1.90 (m, 3H), 1.65-1.74 (m, 2H), 1.52-1.65 (m, 5H), 1.28-1.38 (m, 1H)); MS (APCI+) M/Z 413 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[N:11]([CH2:12][C:13]2[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=2)[CH2:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([N:21]([CH3:23])[CH3:22])[CH:8]=2)[N:3]=1.C(=O)([O-])[O-].[K+].[K+].I[CH2:31][C:32](OCC)=[O:33]>CN(C)C=O>[CH3:23][N:21]([CH3:22])[C:7]1[CH:8]=[C:9]2[C:4](=[CH:5][CH:6]=1)[N:3]1[CH2:31][C:32](=[O:33])[N:1]=[C:2]1[N:11]([CH2:12][C:13]1[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=1)[CH2:10]2
Reactant: CCOC(=O)CI
Reactant: COc1ccc(CN2Cc3cc(N(C)C)ccc3N=C2N)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1ccc(CN2Cc3cc(N(C)C)ccc3N3CC(=O)N=C23)cc1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
A solution of 19.5 g of 2-amino-6-dimethylamino-3,4-dihydro-3-(p-methoxybenzyl)-quinazoline in 300 ml of dimethylformamide was treated with 90 g of potassium carbonate and 12.9 g of ethyl iodoacetate and the mixture was stirred at room temperature for 20 hours and then at 85° for 5 hours. The mixture was then cooled, poured into ice/water and the crude product was filtered. Pure 7-dimethylamino-4,5-dihydro-4-(p-methoxybenzyl)-imidazo[1,2-a]quinazolin-2(1H)-one of melting point 196°-200° was obtained by recrystallization from methanol.
Reaction SMILES: [OH:1][N:2]=[C:3]1[CH:8]=[CH:7][C:6](=[C:9]([C:12]2[S:13][CH:14]=[CH:15][CH:16]=2)[C:10]#[N:11])[CH:5]=[CH:4]1.C(N(CC)CC)C.[CH3:24][S:25](Cl)(=[O:27])=[O:26].O>C1COCC1>[CH3:24][S:25]([O:1][N:2]=[C:3]1[CH:4]=[CH:5][C:6](=[C:9]([C:12]2[S:13][CH:14]=[CH:15][CH:16]=2)[C:10]#[N:11])[CH:7]=[CH:8]1)(=[O:27])=[O:26]
Reactant: CS(=O)(=O)Cl
Reactant: N#CC(=C1C=CC(=NO)C=C1)c1cccs1
Solvent: C1CCOC1
Solvent: O
Solvent: CCN(CC)CC
Product: CS(=O)(=O)ON=C1C=CC(=C(C#N)c2cccs2)C=C1
Temperature: 0 °C
Yield: 29.4 %

Procedure:
4.5 g (20 mmol) of (4-Hydroxyimino-cyclohexa-2,5-dienylidene)-thiophen-2-yl-acetonitrile are dissolved in 50 ml of THF and cooled in an ice bath. After adding 4.2 ml (30 mmol) of triethylamine to the solution, 1.7 ml (22 mmol) of methanesulfonyl chloride are added dropwise, keeping the temperature below 5° C. The reaction mixture is stirred in the ice bath for 30 min. The reaction mixture is poured into 200 ml of water, and extracted with ethyl acetate. The organic phase is washed with hydrochloric acid solution, water, and sodium chloride solution. The organic phase is dried over MgSO4, the solvent is distilled off, and the residue is purified by recrystallization from toluene. 1.8 g (30%) of (4-Methylsulfonyloxyimino-cyclohexa-2,5-dienylidene)-thiophen-2-yl-acetonitrile are obtained in the form of orange crystals having a melting point of 123-125° C. (dec.).
Reaction SMILES: [NH2:1][C:2]1[C:3]([CH3:13])=[CH:4][C:5]([CH2:8][C:9]([O:11][CH3:12])=[O:10])=[N:6][CH:7]=1.[CH:14](OCC)(OCC)OCC.[N-:24]=[N+:25]=[N-:26].[Na+]>C(O)(=O)C.[Cl-].[Na+].O>[CH3:13][C:3]1[C:2]([N:1]2[CH:14]=[N:26][N:25]=[N:24]2)=[CH:7][N:6]=[C:5]([CH2:8][C:9]([O:11][CH3:12])=[O:10])[CH:4]=1
Reactant: [N-]=[N+]=[N-]
Reactant: CCOC(OCC)OCC
Reactant: COC(=O)Cc1cc(C)c(N)cn1
Agent: [Cl-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: COC(=O)Cc1cc(C)c(-n2cnnn2)cn1
Temperature: 80 °C
Reaction time: 3 h

Procedure:
Methyl 2-(5-amino-4-methylpyridin-2-yl)acetate (90 mg, 0.499 mmol) was stirred in acetic acid (3 ml) then added triethyl orthoformate (0.166 ml, 0.999 mmol) and sodium azide (58.4 mg, 0.899 mmol). The mixture was stirred at 80° C. for 3 hrs then diluted with brine and extracted with ethyl acetate. The organic layer was dried over Na2SO4, filtered and evaporated to dryness. The residue was chromatographed thru 40 g ISCO Redi-sep column and eluted with 5% MeOH/DCM to yield methyl 2-(4-methyl-5-(1H-tetrazol-1-yl)pyridin-2-yl)acetate: 1H-NMR (500 MHz, CDCl3) δ ppm 8.867 (s, 1H), 8.527 (s, 1H), 7.438 (s, 1H), 3.963 (s, 2H), 3.790 (s, 3H), 2.308 (s, 3H).
Reaction SMILES: [C:1]([O:4][C:5]1[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[C:8]2[O:9][CH:10]=[C:11]([C:12]3[CH:17]=[CH:16][C:15]([CH:18]([CH3:20])[CH3:19])=[CH:14][CH:13]=3)[C:7]=2[C:6]=1[CH3:27])(=[O:3])[CH3:2]>CCCCCC.C(OCC)(=O)C>[C:1]([O:4][C:5]1[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[C:8]2[O:9][CH2:10][CH:11]([C:12]3[CH:13]=[CH:14][C:15]([CH:18]([CH3:20])[CH3:19])=[CH:16][CH:17]=3)[C:7]=2[C:6]=1[CH3:27])(=[O:3])[CH3:2]
Reactant: CC(=O)Oc1c(C)c2c(-c3ccc(C(C)C)cc3)coc2c2ccccc12
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: CC(=O)Oc1c(C)c2c(c3ccccc13)OCC2c1ccc(C(C)C)cc1
Yield: 74 %

Procedure:
Using 3-(4-isopropylphenyl)-4-methylnaphtho[1,2-b]furan-5-yl acetate obtained in Reference Example 195, the title compound was synthesized in the same manner as in Reference Example 199. Yield 74%. Melting point: 109-110° C. (hexane-ethyl acetate).
Reaction SMILES: [CH:1]1([NH:7][C:8]([NH:10][C:11]2[N:12]=[C:13]3[C:19]([C:20](=[O:25])[C:21]([CH3:24])([CH3:23])[CH3:22])=[CH:18][N:17](COCC[Si](C)(C)C)[C:14]3=[N:15][CH:16]=2)=[O:9])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.O.O.O.C([O-])(=O)C.[Na+]>ClCCl.FC(F)(F)C(O)=O>[CH:1]1([NH:7][C:8]([NH:10][C:11]2[N:12]=[C:13]3[C:19]([C:20](=[O:25])[C:21]([CH3:23])([CH3:22])[CH3:24])=[CH:18][NH:17][C:14]3=[N:15][CH:16]=2)=[O:9])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: CC(C)(C)C(=O)c1cn(COCC[Si](C)(C)C)c2ncc(NC(=O)NC3CCCCC3)nc12
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: O
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(C)(C)C(=O)c1c[nH]c2ncc(NC(=O)NC3CCCCC3)nc12
Reaction time: 16 h
Yield: 67.7 %

Procedure:
A solution of 1-cyclohexyl-3-[7-(2,2-dimethyl-propionyl)-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazin-2-yl]-urea (0.102 g, 0.215 mmol) in 2 mL of dichloromethane and 2 mL of trifluoroacetic acid was stirred for 1 h, then concentrated, chasing twice with toluene. The residue was dissolved in 2 mL of ethanol and treated with sodium acetate trihydrate (0.293 g, 2.15 mmol). The mixture was stirred for 16 h, then concentrated to a residue. Column chromatography (50→80% EtOAc/hexanes) afforded 0.050 g (68%) of 1-cyclohexyl-3-[7-(2,2-dimethyl-propionyl)-5H-pyrrolo[2,3-b]pyrazin-2-yl]-urea as a white solid.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8](=[C:16]2[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]2)[C:9]2[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][CH:10]=2)=[CH:4][CH:3]=1.[O:23]1[CH:27]=[CH:26][C:25](B(O)O)=[CH:24]1.C([O-])([O-])=O.[Na+].[Na+].COCCOC>CCOCC.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:16]1(=[C:8]([C:5]2[CH:6]=[CH:7][C:2]([C:25]3[CH:26]=[CH:27][O:23][CH:24]=3)=[CH:3][CH:4]=2)[C:9]2[CH:10]=[CH:11][C:12]([OH:15])=[CH:13][CH:14]=2)[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22]1
Reactant: OB(O)c1ccoc1
Reactant: Oc1ccc(C(=C2CCCCCC2)c2ccc(Br)cc2)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOCC
Solvent: COCCOC
Product: Oc1ccc(C(=C2CCCCCC2)c2ccc(-c3ccoc3)cc2)cc1
Temperature: 25 °C
Yield: 92 %

Procedure:
A round-boftom flash was charged with 4-[(4-bromophenyl)(cycloheptylidene)methyl]phenol (200) (1.0 g, 2.8 mmol), Pd(PPh3)4, (0.323 g, 0.28 mmol), 3-furanylboronic acid (0.627 g, 5.6 mmol), aqueous 2 M Na2CO3, (1.2 g, 4.7 mL, 11.2 mmol), and DME (15 mL) under a nitrogen atmosphere. The reaction mixture was refluxed for 5 h. Reaction mixture was cooled at room temperature, diluted with Et2O (30 ml) and filtered. The filtrate was diluted with EtOAc (100 mL), washed with brine, dried (Na2SO4) and concentrated under reduced pressure to afford the crude product. The product was purified by silica gel chromatography using n-hexanes:EtOAc (19:1 to 4:1) as an eluent to give 0.887 g (92%) of the title compound 201 as a white solid. 1H NMR (300 MHz, CDCl3): δ 7.73 (s, 1H), 7.48 (t, J=1.5 Hz, 1H), 7.42 (d, J=8.1 Hz, 2H), 7.18 (d, J=8.1 Hz, 2H), 7.07 (d, J=8.4 Hz, 2H), 6.77 (d, J=8.4 Hz, 1H), 6.70 (d, J=1.2 Hz, 1H), 2.37 (br s, 4H), 1.62 (br s, 8H). LCMS (ESI): m/z 343 (M−H)−. Anal. Calcd for C24H24O2, C, 83.69; H, 7.02; Found: C, 82.69, H, 7.06.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10]([OH:12])=O)[CH:5]=[CH:6][C:7]=1[Cl:8].Cl.[CH2:14]([O:18][C:19](=[O:23])[C@H:20]([CH3:22])[NH2:21])[CH:15]([CH3:17])[CH3:16]>>[CH2:14]([O:18][C:19](=[O:23])[C@H:20]([CH3:22])[NH:21][C:10](=[O:12])[CH2:9][C:4]1[CH:5]=[CH:6][C:7]([Cl:8])=[C:2]([Cl:1])[CH:3]=1)[CH:15]([CH3:17])[CH3:16]
Reactant: CC(C)COC(=O)[C@H](C)N
Reactant: O=C(O)Cc1ccc(Cl)c(Cl)c1
Agent: Cl
Product: CC(C)COC(=O)[C@H](C)NC(=O)Cc1ccc(Cl)c(Cl)c1

Procedure:
Following General Procedure B′ and using 3,4-dichlorophenylacetic acid (Aldrich) and L-alanine iso-butyl ester hydrochloride (from Example B′ above), the title compound was prepared as a solid having a melting point of 81-83° C. The reaction was monitored by tlc on silica gel and purification was by extraction with Et2O followed by washes with aqueous K2CO3 and aqueous HCl.
Reaction SMILES: [F:1][C:2]([F:9])([CH3:8])/[CH:3]=[CH:4]/[C:5]([OH:7])=O.C(Cl)(=O)C(Cl)=O.[CH2:16]([O:18][C:19]1[CH:24]=[CH:23][N:22]=[C:21]([NH:25][CH2:26][CH2:27][NH2:28])[CH:20]=1)[CH3:17].C(N(C(C)C)CC)(C)C>ClCCl>[CH2:16]([O:18][C:19]1[CH:24]=[CH:23][N:22]=[C:21]([NH:25][CH2:26][CH2:27][NH:28][C:5](=[O:7])/[CH:4]=[CH:3]/[C:2]([F:1])([F:9])[CH3:8])[CH:20]=1)[CH3:17]
Reactant: CCOc1ccnc(NCCN)c1
Reactant: CC(F)(F)/C=C/C(=O)O
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCOc1ccnc(NCCNC(=O)/C=C/C(C)(F)F)c1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 41.7 %

Procedure:
(E)-4,4-Difluoropent-2-enoic acid (31 mg, 0.23 mmol) was dissolved in dichloromethane (0.5 ml containing one drop of dimethyl formamide), oxalyl chloride was added (20 μl, 0.23 mmol) and the solution was stirred at room temperature for 15 minutes. This solution was added to a solution of N-(4-ethoxy-2-pyridyl)ethane-1,2-diamine (27 mg, 0.15 mmol) and diisopropylethylamine (88 μl, 0.5 mmol) dissolved in DCM (2 ml) and the resulting mixture was stirred at room temperature for three hours. The volatiles were removed under reduced pressure and the residue was purified by preparative HPLC (gradient of water containing 0.1% NH3 and 10% to 100% acetonitrile) to yield 18.7 mg of a residue that was purified again by preparative HPLC (gradient of water containing 0.1% trifluoroacetic acid and 10% to 100% acetonitrile). The product obtained was converted to the free base by dissolving in DCM, washing with 1N NaOH solution, water and evaporation to dryness under reduced pressure to yield 13.2 mg of a solid (0.044 mmol, 29%).