Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1/[CH:11]=[CH:12]/[C:13]([O:15]C)=[O:14].O.[OH-].[Na+]>CO>[N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1/[CH:11]=[CH:12]/[C:13]([OH:15])=[O:14]
Reactant: COC(=O)/C=C/c1ccc2ccccc2n1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: O=C(O)/C=C/c1ccc2ccccc2n1
Temperature: 25 °C
Reaction time: 3.5 h
Yield: 49 %

Procedure:
To a solution of methyl (E)-3-(2-quinolinyl)-2-propenoate (2) (1.07 g, 5.02 mmol) in methanol (24 ml), a water solution of 1N NaOH (16 ml, 16.0 mmol) was added and the reaction mixture was stirred at room temperature for 3.5 hours. The mixture was supplemented with water (40 ml) and washed with ethyl acetate (40 ml). The aqueous layer was separated and the pH of the medium was brought to 5. The mixture was extracted with ethyl acetate (3×40 ml) and the combined extracts were dried (Na2SO4). The solvent was evaporated and the residue was dried in vacuum to give the title compound (0.49 g, 49%) as viscous oil. 1H NMR (DMSO-d6, HMDSO), δ: 7.02 (1H, d, J=15.7 Hz); 7.52-8.15 (5H, m); 7.75 (1H, d, J=15.7 Hz); 8.42 (1H, d, J=9.0 Hz); 12.69 (1H, br s).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([C:11]([O:13][CH3:14])=[O:12])[CH:10]=1)[C:5](O)=[O:6].O=S(Cl)Cl.[NH3:19]>C1COCC1>[Br:1][C:2]1[CH:10]=[C:9]([CH:8]=[C:4]([C:5](=[O:6])[NH2:19])[CH:3]=1)[C:11]([O:13][CH3:14])=[O:12]
Reactant: N
Reactant: COC(=O)c1cc(Br)cc(C(=O)O)c1
Solvent: C1CCOC1
Solvent: O=S(Cl)Cl
Product: COC(=O)c1cc(Br)cc(C(N)=O)c1
Yield: 94 %

Procedure:
To 3-bromo-5-methoxycarbonyl-benzoic acid (3 g, 11.6 mmol, 1 eq) was added SOCl2 (20 mL) and the reaction heated at reflux overnight. The excess SOCl2 was removed in vacuo and the residue obtained was dissolved in THF (15 mL) and added dropwise to a solution of NH3 (38% aqueous, 30 mL). The precipitate that formed was collected by filtration, washed with water and dried to give the title compound as a white solid (2.8 g, 94%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][C:11]=1[O:12][CH2:13][CH2:14][CH3:15])[C:5]([O:7]C)=[O:6].Cl.CCOC(C)=O>C(O)C.[OH-].[Na+]>[Cl:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][C:11]=1[O:12][CH2:13][CH2:14][CH3:15])[C:5]([OH:7])=[O:6]
Reactant: CCCOc1ccc(C(=O)OC)cc1Cl
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: CCOC(C)=O
Product: CCCOc1ccc(C(=O)O)cc1Cl
Yield: 67.7 %

Procedure:
A solution of methyl 3-chloro-4-(propyloxy)benzoate (D37) (RD108825-58-B1) (12.22 g, 0.053 mol) in ethanol (40 ml) and 2M NaOH aq. (40 ml) was heated at 60° C. for 3 hours. The reaction was allowed to cool and then left at room temperature over the weekend. The reaction mixture was poured into a mixture of dilute aq. HCl and EtOAc. The organic layer was separated, dried and evaporated to give a solid which was triturated with ether to give the title compound as a white solid (7.7 g). MS (ES) C10H1135ClO3 requires 214; found 213 (M−H+).
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([CH3:23])[N:5]([CH2:9][C:10]2[CH:15]=[CH:14][C:13]([O:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])=[CH:12][C:11]=2[Cl:22])[C:6]=1[CH:7]=[O:8].CC(=CC)C.P([O-])(O)(O)=[O:30].[Na+].Cl([O-])=O.[Na+].Cl>C(O)(C)(C)C.O>[Cl:1][C:2]1[N:3]=[C:4]([CH3:23])[N:5]([CH2:9][C:10]2[CH:15]=[CH:14][C:13]([O:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])=[CH:12][C:11]=2[Cl:22])[C:6]=1[C:7]([OH:30])=[O:8]
Reactant: O=P([O-])(O)O
Reactant: CCCCCOc1ccc(Cn2c(C)nc(Cl)c2C=O)c(Cl)c1
Agent: CC=C(C)C
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CC(C)(C)O
Product: CCCCCOc1ccc(Cn2c(C)nc(Cl)c2C(=O)O)c(Cl)c1
Temperature: 25 °C
Reaction time: 24 h
Yield: 92.6 %

Procedure:
4-Chloro-1-(2-chloro-4-(1-pentyloxy)benzyl)-2-methyl-1H-imidazole-5-carbaldehyde (400 mg) was dissolved in t-butanol (8 ml), and 2-methyl-2-butene (355 mg) and aqueous sodium dihydrogenphosphate (135 mg) solution (2 ml) were added. To this reaction mixture was added sodium chlorite (356 mg) over 2 min and the mixture was stirred at room temperature for 24 hr. 1N Hydrochloric acid was added under ice-cooling to adjust to pH 4. Water (20 ml) was added and the precipitated crystals were collected by filtration. The crystals were dried by heating under reduced pressure to give 4-chloro-1-(2-chloro-4-(1-pentyloxy)benzyl)-2-methyl-1H-imidazole-5-carboxylic acid (387 mg) as colorless crystals.
Reaction SMILES: S(Cl)(Cl)=O.[OH:5][C:6]1[N:7]=[CH:8][C:9]([C:12]([OH:14])=[O:13])=[N:10][CH:11]=1.[CH3:15]O>>[CH3:15][O:13][C:12]([C:9]1[CH:8]=[N:7][C:6]([OH:5])=[CH:11][N:10]=1)=[O:14]
Reactant: O=C(O)c1cnc(O)cn1
Reactant: CO
Solvent: O=S(Cl)Cl
Product: COC(=O)c1cnc(O)cn1
Reaction time: 0.5 h
Yield: 65 %

Procedure:
Thionyl chloride (152 mL, 2.08 mol) was added dropwise at 20° C. to methanol (5 L). After the addition was completed, the mixture was stirred at this temperature for 30 minutes. Then 5-hydroxy-pyrazine-2-carboxylic acid (100 g, 714 mmol) was added, and the mixture was heated at reflux for 2 hours. The reaction mixture was concentrated in vacuo, and the residue was recrystallised from methanol (400 mL) to give 71 g (464 mmol) of the title compound in 65% yield.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([O:7][C:8]2[N:15]=[CH:14][CH:13]=[CH:12][C:9]=2[C:10]#[N:11])[CH:2]=1>[Ni]>[N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([O:7][C:8]2[C:9]([CH2:10][NH2:11])=[CH:12][CH:13]=[CH:14][N:15]=2)[CH:2]=1
Reactant: N#Cc1cccnc1Oc1cccnc1
Agent: [Ni]
Product: NCc1cccnc1Oc1cccnc1

Procedure:
The product of Example 139A and Raney/nickel were processed according to the method of Example 131C to provide the product. MS (ESI+) m/z 202 (M+H)+;
Reaction SMILES: COC1C=CC(C[N:8]2[C:12]3=[N:13][CH:14]=[CH:15][C:16]([O:17][C:18]4[CH:23]=[CH:22][C:21]([NH:24][C:25]([CH:27]5[CH2:31][CH2:30][N:29]([CH3:32])[C:28]5=[O:33])=[O:26])=[CH:20][C:19]=4[F:34])=[C:11]3[C:10]([C:35]3[CH:40]=[CH:39][C:38]([C:41](=[O:44])[NH:42][CH3:43])=[CH:37][CH:36]=3)=[N:9]2)=CC=1.C(O)(C(F)(F)F)=O>>[F:34][C:19]1[CH:20]=[C:21]([NH:24][C:25]([CH:27]2[CH2:31][CH2:30][N:29]([CH3:32])[C:28]2=[O:33])=[O:26])[CH:22]=[CH:23][C:18]=1[O:17][C:16]1[CH:15]=[CH:14][N:13]=[C:12]2[NH:8][N:9]=[C:10]([C:35]3[CH:36]=[CH:37][C:38]([C:41](=[O:44])[NH:42][CH3:43])=[CH:39][CH:40]=3)[C:11]=12
Reactant: CNC(=O)c1ccc(-c2nn(Cc3ccc(OC)cc3)c3nccc(Oc4ccc(NC(=O)C5CCN(C)C5=O)cc4F)c23)cc1
Solvent: O=C(O)C(F)(F)F
Product: CNC(=O)c1ccc(-c2n[nH]c3nccc(Oc4ccc(NC(=O)C5CCN(C)C5=O)cc4F)c23)cc1
Temperature: 80 °C
Reaction time: 4 h
Yield: 44.9 %

Procedure:
A 50 mL round-bottomed flask was charged with N-(4-(1-(4-methoxybenzyl)-3-(4-(methylcarbamoyl)phenyl)-1H-pyrazolo[3,4-b]pyridin-4-yloxy)-3-fluorophenyl)-1-methyl-2-oxopyrrolidine-3-carboxamide (10.8 mg, 0.0173 mmol) and CF3COOH (2 mL). The reaction mixture was stirred at 80° C. for 4 hours. Then the CF3COOH was removed under reduced pressure. The residue was purified by silica gel chromatography (DCM/7 M NH3 in MeOH from 50/1 to 10/1, v/v) to afford product (3.9 mg, 44.7%). LRMS (APCI pos): >99% purity, 254 nm, m/e 503 (M+1). 1H NMR (400 MHz, CD3OD) δ 8.35 (d, 1H), 8.10 (d, 2H), 7.83-7.90 (m, 3H), 7.40 (d, 1H), 7.32 (t, 1H), 6.40 (d, 1H), 3.44-3.60 (m, 3H), 2.92 (s, 3H), 2.90 (s, 3H), 2.28-2.51 (m, 2H).
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([NH2:8])=[O:7])=[CH:4][C:3]=1[C:11]1[CH2:16][CH2:15][C:14]([CH3:18])([CH3:17])[CH2:13][CH:12]=1.[K+].[C:20]([C:22]1[N:23]=[C:24]([C:35]([O-])=[O:36])[N:25]([CH2:27][O:28][CH2:29][CH2:30][Si:31]([CH3:34])([CH3:33])[CH3:32])[CH:26]=1)#[N:21]>CO.C(Cl)Cl>[C:6]([C:5]1[CH:9]=[CH:10][C:2]([NH:1][C:35]([C:24]2[N:25]([CH2:27][O:28][CH2:29][CH2:30][Si:31]([CH3:34])([CH3:33])[CH3:32])[CH:26]=[C:22]([C:20]#[N:21])[N:23]=2)=[O:36])=[C:3]([C:11]2[CH2:16][CH2:15][C:14]([CH3:18])([CH3:17])[CH2:13][CH:12]=2)[CH:4]=1)(=[O:7])[NH2:8]
Reactant: CC1(C)CC=C(c2cc(C(N)=O)ccc2N)CC1
Reactant: C[Si](C)(C)CCOCn1cc(C#N)nc1C(=O)[O-]
Agent: [K+]
Solvent: CO
Solvent: ClCCl
Product: CC1(C)CC=C(c2cc(C(N)=O)ccc2NC(=O)c2nc(C#N)cn2COCC[Si](C)(C)C)CC1
Yield: 94 %

Procedure:
The title compound was prepared by the procedure of Example 11, step (f) using 4-amino-3-(4,4-dimethyl-cyclohex-1-enyl)-benzamide (as prepared in the previous step, 51.0 mg, 0.209 mmol) and potassium 4-cyano-1-(2-trimethylsilanyl-ethoxymethyl)-1H-imidazole-2-carboxylate (as prepared in Example 11, step (d), 70.2 mg, 0.230 mmol). Silica gel chromatography (0-2% MeOH/DCM) afforded the title compound (91 mg, 94%) as a white solid. Mass spectrum (ESI, m/z): Calcd. for C26H35N5O3Si, 494.3 (M+H), found 494.1.
Reaction SMILES: [CH:1]1[C:14]2[C:5](=[CH:6][C:7]3[C:12]([CH:13]=2)=[CH:11][CH:10]=[CH:9][CH:8]=3)[CH:4]=[CH:3][CH:2]=1.[CH2:15]([OH:18])[CH:16]=[CH2:17]>C1C=CC=CC=1>[CH:4]1[C:5]2[CH:6]3[CH2:17][CH:16]([CH2:15][OH:18])[CH:13]([C:12]4[C:7]3=[CH:8][CH:9]=[CH:10][CH:11]=4)[C:14]=2[CH:1]=[CH:2][CH:3]=1
Reactant: c1ccc2cc3ccccc3cc2c1
Reactant: C=CCO
Solvent: c1ccccc1
Product: OCC1CC2c3ccccc3C1c1ccccc12
Temperature: 210 °C

Procedure:
Anthracene (45.4 gm) was combined with allyl alcohol (90.8 gm) and benzene (260 ml) in a Parr bomb and heated to 210° C. for 12 hours. The benzene was removed on a rotary evaporator and the residue was recrystallized from n-heptane to provide the product as a white solid (mp=104-105° C.).
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5]([C:7](=[O:9])[CH3:8])[N:6]=1.[Li+].[BH4-].CO>C1COCC1>[NH2:1][C:2]1[S:3][CH:4]=[C:5]([CH:7]([OH:9])[CH3:8])[N:6]=1
Reactant: CC(=O)c1csc(N)n1
Agent: [BH4-]
Agent: [Li+]
Solvent: CO
Solvent: C1CCOC1
Product: CC(O)c1csc(N)n1
Temperature: 25 °C
Reaction time: 18 h
Yield: 19.7 %

Procedure:
To a stirred solution of 1-(2-amino-1,3-thiazol-4-yl)ethanone (10 g, 70.33 mmol, 1 eq.) in 100 ml dry THF cooled to 5° C., was added LiBH4 (2M in THF, 38.7 ml, 77.36 mmol, 1.1 eq.) followed by MeOH (3.2 ml, 78 mmol, 1.11 eq.). The reaction was allowed to warm to r.t. and was stirred for further 18 hrs. The solvent was evaporated and the residue was partitioned between 250 ml EtOAc/250 ml water. Stirring was allowed for 10 mins. And the brown solid was filtered. The organic layer was separated, washed with brine, dried with MgSO4 and evaporated to give viscous orange oil. The residue was purified by chromatography on silica gel to give 1-(2-amino-1,3-thiazol-4-yl)ethanol (2 g, 19% yield) as a white solid.
Reaction SMILES: C[O:2][C:3](=[O:41])[C@H:4]([C@H:37]([CH2:39][CH3:40])[CH3:38])[NH:5][CH2:6][C@@H:7]([NH:29][C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[CH2:8][S:9][C:10]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.[OH-].[Na+]>CO>[C:33]([O:32][C:30]([NH:29][C@@H:7]([CH2:8][S:9][C:10]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)([C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1)[C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1)[CH2:6][NH:5][C@H:4]([C:3]([OH:41])=[O:2])[C@H:37]([CH2:39][CH3:40])[CH3:38])=[O:31])([CH3:35])([CH3:36])[CH3:34]
Reactant: CC[C@H](C)[C@H](NC[C@H](CSC(c1ccccc1)(c1ccccc1)c1ccccc1)NC(=O)OC(C)(C)C)C(=O)OC
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CC[C@H](C)[C@H](NC[C@H](CSC(c1ccccc1)(c1ccccc1)c1ccccc1)NC(=O)OC(C)(C)C)C(=O)O
Temperature: 25 °C
Reaction time: 4 h
Yield: 101.5 %

Procedure:
N-[2(R)-(t-butoxycarbonyl)amino-3-triphenylmethylmercaptopropyl]-L-isoleucine methyl ester (1.63 g, 0.0028 mol) was dissolved in MeOH (50 mL) and 1N NaOH solution (11.23 mL, 0.0112 mol) was added with stirring at ambient temperature. After 4 h,.solid NaOH (2.0 g) was added and stirring was continued for 16 h. The reaction mixture was concentrated to remove MeOH and extracted with EtOAc (2×100 mL). The extract was washed with brine and dried (Na2SO4). Filtration and concentration to dryness gave 1.6 g of the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[CH:9]1[C:14]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[C:13]([CH3:20])[NH:12][C:11]([C:21]2[S:22][CH:23]=[N:24][N:25]=2)=[N:10]1.C1C(=O)N([Br:33])C(=O)C1>>[Br:33][CH2:20][C:13]1[NH:12][C:11]([C:21]2[S:22][CH:23]=[N:24][N:25]=2)=[N:10][CH:9]([C:3]2[CH:4]=[CH:5][C:6]([Cl:8])=[CH:7][C:2]=2[Cl:1])[C:14]=1[C:15]([O:17][CH2:18][CH3:19])=[O:16]
Reactant: O=C1CCC(=O)N1Br
Reactant: CCOC(=O)C1=C(C)NC(c2nncs2)=NC1c1ccc(Cl)cc1Cl
Product: CCOC(=O)C1=C(CBr)NC(c2nncs2)=NC1c1ccc(Cl)cc1Cl
Yield: 59.6 %

Procedure:
Ethyl 4-(2,4-dichlorophenyl)-6-methyl-2-(1,3,4-thiadiazol-2-yl)-1,4-dihydropyrimidine-5-carboxylate (1 g, 2.5 mmol) was reacted with NBS (0.5 g, 2.8 mmol) according to the procedure as described in Example 1, Step B to give the title compound as a yellow solid (0.71 g, 60%). The compound was characterized by the following spectroscopic data:
Reaction SMILES: C1(P(C2CCCCC2)C2C=CC=CC=2C2C(C(C)C)=CC(C(C)C)=CC=2C(C)C)CCCCC1.[O:35]1[CH2:40][CH2:39][N:38]([C:41]2[C:46]([NH2:47])=[CH:45][C:44]([N:48]3[CH2:53][CH2:52][O:51][CH2:50][CH2:49]3)=[CH:43][N:42]=2)[CH2:37][CH2:36]1.Cl[C:55]1[C:64]2[C:59](=[CH:60][C:61]([F:66])=[CH:62][C:63]=2[F:65])[N:58]=[C:57]([C:67]2[CH:68]=[N:69][C:70]([N:73]3[CH2:78][CH2:77][NH:76][CH2:75][CH2:74]3)=[CH:71][CH:72]=2)[C:56]=1[CH3:79].CC(C)([O-])C.[Na+]>C1(C)C=CC=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[O:35]1[CH2:40][CH2:39][N:38]([C:41]2[C:46]([NH:47][C:55]3[C:64]4[C:59](=[CH:60][C:61]([F:66])=[CH:62][C:63]=4[F:65])[N:58]=[C:57]([C:67]4[CH:68]=[N:69][C:70]([N:73]5[CH2:74][CH2:75][NH:76][CH2:77][CH2:78]5)=[CH:71][CH:72]=4)[C:56]=3[CH3:79])=[CH:45][C:44]([N:48]3[CH2:49][CH2:50][O:51][CH2:52][CH2:53]3)=[CH:43][N:42]=2)[CH2:37][CH2:36]1
Reactant: Cc1c(-c2ccc(N3CCNCC3)nc2)nc2cc(F)cc(F)c2c1Cl
Reactant: Nc1cc(N2CCOCC2)cnc1N1CCOCC1
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Solvent: Cc1ccccc1
Product: Cc1c(-c2ccc(N3CCNCC3)nc2)nc2cc(F)cc(F)c2c1Nc1cc(N2CCOCC2)cnc1N1CCOCC1

Procedure:
The Buchwald coupled product was prepared according to Procedure S using of dicyclohexyl(2′,4′,6′-triisopropylbiphenyl-2-yl)phosphine (0.020 g, 0.043 mmol), 2,5-dimorpholinopyridin-3-amine (0.085 g, 0.32 mmol), 4-chloro-5,7-difluoro-3-methyl-2-(6-(piperazin-1-yl)pyridin-3-yl)quinoline (0.1 g, 0.27 mmol), Pd2dba3 (0.009 g, 0.011 mmol) and sodium tert-butoxide (0.064 g, 0.67 mmol) in toluene (3.3 mL) at 100° C. for 2.1 h. The crude product was further purified with HPLC (10-90% of 0.1% TFA acetonitrile solution in 0.1% TFA water solution). The desired fractions were concd then diluted with EtOAc. After washing twice with satd aqueous sodium bicarbonate solution, the solvent was removed under reduced pressure to yield desired product N-(2,5-dimorpholinopyridin-3-yl)-5,7-difluoro-3-methyl-2-(6-(piperazin-1-yl)pyridin-3-yl)quinolin-4-amine. 1H NMR (500 MHz, CD2Cl2) δ ppm 8.50 (1H, d, J=2.2 Hz), 7.89 (1H, dd, J=8.6, 2.4 Hz), 7.63 (1H, d, J=10.0 Hz), 7.61 (1H, d, J=2.7 Hz), 7.51-7.56 (1H, m), 6.99 (1H, ddd, J=13.3, 8.7, 2.4 Hz), 6.81 (1H, d, J=8.8 Hz), 6.34 (1H, d, J=2.4 Hz), 3.85 (4H, m), 3.78-3.83 (4H, m), 3.73-3.78 (4H, m), 3.12-3.21 (4H, m), 2.97-3.05 (4H, m), 2.22 (3H, s). Mass Spectrum (ESI) m/e=603.2 (M+1).
Reaction SMILES: Cl.Cl.[NH2:3][C@@H:4]1[CH:9]2[CH2:10][CH2:11][N:6]([CH2:7][CH2:8]2)[CH2:5]1.CCN(C(C)C)C(C)C.[CH3:21][N:22]1[C:26]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)=[CH:25][CH:24]=[C:23]1[C:33](O)=[O:34].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>C1COCC1.C(Cl)Cl>[N:6]12[CH2:11][CH2:10][CH:9]([CH2:8][CH2:7]1)[C@@H:4]([NH:3][C:33]([C:23]1[N:22]([CH3:21])[C:26]([C:27]3[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=3)=[CH:25][CH:24]=1)=[O:34])[CH2:5]2
Reactant: Cn1c(C(=O)O)ccc1-c1ccccc1
Reactant: N[C@H]1CN2CCC1CC2
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: Cn1c(C(=O)N[C@H]2CN3CCC2CC3)ccc1-c1ccccc1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 31.1 %

Procedure:
To a solution of (R)-(+)-3-aminoquinuclidine dihydrochloride (0.831 g, 4.17 mmol) in 55 mL of dry THF is added DIEA (2.08 mL, 11.9 mmol). After allowing the mixture to stir under nitrogen for 15 min, the product from Step 152c (0.800 g, X 3.98 mmol) is added. The mixture is allowed to stir for another 15 min, cooled in an A ice bath, and HATU (1.59 g, 4.17 mmol) is added. The reaction mixture is stirred on >an ice bath for 0.5 h, then at rt for an additional 2 h. The mixture is diluted with 60 mL CH2Cl2, washed with 50 mL of 1N NaOH and 50 mL of satd NaHCO3 solution, dried over MgSO4, filtered, and concentrated in vacuo. The crude product is purified by flash column chromatography (10% EtOAc, 1% NH4OH in CH2Cl2) to give 0.383 grams of N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-1-methyl-5-phenyl-1H-pyrrole-2-carboxamide (31%) as a white solid. MS for C19H23N3O (ESI) (M+H)+ m/z 310.3.
Reaction SMILES: C(OC(N[C@H](CCCCNC(OC(C)(C)C)=O)C(NCC[C:15]([O:17][C:18]1[CH:19]=[CH:20][C:21]2[C:27]3[C:28]([O:36][CH3:37])=[C:29]([O:34][CH3:35])[C:30]([O:32][CH3:33])=[CH:31][C:26]=3[CH2:25][CH2:24][C@H:23]([NH:38][C:39](=[O:41])[CH3:40])[C:22]=2[CH:42]=1)=[O:16])=O)=O)(C)(C)C.[CH3:55][N:56]1[CH2:61][CH2:60][NH:59][CH2:58][CH2:57]1.[I-].[Na+]>C(#N)C>[CH3:55][N:56]1[CH2:61][CH2:60][N:59]([CH2:27][C:21]2[CH:22]=[CH:42][C:18]([C:15]([O:17][C:18]3[CH:19]=[CH:20][C:21]4[C:27]5[C:28]([O:36][CH3:37])=[C:29]([O:34][CH3:35])[C:30]([O:32][CH3:33])=[CH:31][C:26]=5[CH2:25][CH2:24][C@H:23]([NH:38][C:39](=[O:41])[CH3:40])[C:22]=4[CH:42]=3)=[O:16])=[CH:19][CH:20]=2)[CH2:58][CH2:57]1
Reactant: COc1cc2c(c(OC)c1OC)-c1ccc(OC(=O)CCNC(=O)[C@@H](CCCCNC(=O)OC(C)(C)C)NC(=O)OC(C)(C)C)cc1[C@@H](NC(C)=O)CC2
Reactant: CN1CCNCC1
Agent: [I-]
Agent: [Na+]
Solvent: CC#N
Product: COc1cc2c(c(OC)c1OC)-c1ccc(OC(=O)c3ccc(CN4CCN(C)CC4)cc3)cc1[C@@H](NC(C)=O)CC2
Yield: 75 %

Procedure:
A solution of N-[(5S)-3-(4-chloromethylphenylcarbonyloxy)-9,10,11-trimethoxy-6,7-dihydro-5H-dibenzo[a,c]cyclohepten-5-yl]acetamide (1) (0.308 g; 0.604 mmol), 1-methylpiperazine (0.088 ml; 0.785 mmol) and sodium iodide (0.02 g; 0.121 mmol) in acetonitrile (10 ml) was stirred under argon atmosphere overnight. After evaporation to dryness, the residue was purified by flash chromatography eluting with a 5–12% gradient of methanol/dichloromethane. After evaporation of the appropriate fractions, the solid was triturated in ether/pentane to give N-[(5S)-3-(4-{4-methylpiperazin-1-ylmethyl}phenylcarbonyloxy)-9,10,11-trimethoxy-6,7-dihydro-5H-dibenzo[a,c]cyclohepten-5-yl]acetamide as a solid.
Reaction SMILES: [CH2:1]([CH2:3][NH2:4])[OH:2].C(N(CC)CC)C.Cl.[CH:13]1([CH2:16][N:17]2[C:21]3[CH:22]=[CH:23][C:24]([S:26]([C:29]([CH3:34])([CH3:33])[C:30](Cl)=[O:31])(=[O:28])=[O:27])=[CH:25][C:20]=3[N:19]=[C:18]2[CH2:35][C:36]([CH3:39])([CH3:38])[CH3:37])[CH2:15][CH2:14]1>ClCCl>[CH:13]1([CH2:16][N:17]2[C:21]3[CH:22]=[CH:23][C:24]([S:26]([C:29]([CH3:33])([CH3:34])[C:30]([NH:4][CH2:3][CH2:1][OH:2])=[O:31])(=[O:28])=[O:27])=[CH:25][C:20]=3[N:19]=[C:18]2[CH2:35][C:36]([CH3:39])([CH3:38])[CH3:37])[CH2:14][CH2:15]1
Reactant: CC(C)(C)Cc1nc2cc(S(=O)(=O)C(C)(C)C(=O)Cl)ccc2n1CC1CC1
Reactant: NCCO
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)Cc1nc2cc(S(=O)(=O)C(C)(C)C(=O)NCCO)ccc2n1CC1CC1
Reaction time: 1 h
Yield: 54.4 %

Procedure:
To a mixture of ethanolamine (54 mg, 0.886 mmol), triethylamine (0.184 mL, 1.32 mmol) and dichloromethane (3 mL) was added a solution of 2-{[1-(cyclopropylmethyl)-2-(2,2-dimethylpropyl)-1H-benzimidazol-5-yl]sulfonyl}-2-methylpropanoyl chloride hydrochloride (Step A of Example 7, 198 mg, 0.443 mmol) in dichloromethane (2 mL) at room temperature. After stirring at the same temperature for 1 h, the mixture was concentrated under reduced pressure. The residue was purified by HPLC (ODS, gradient elution with acetonitrile/0.01% aq. NH3=4:96 to 96:4, by volume; flow rate 40 mL/min) to afford the title compound (105 mg, 55%) as an amorphous.
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[CH2:3][N:4]=[C:5](Cl)[C:6]1[CH:11]=[CH:10][C:9]([Cl:12])=[CH:8][CH:7]=1.Cl[C:17](=[CH2:22])[C:18]([O:20][CH3:21])=[O:19].N12CCCN=C1CCCCC2>CN(C)C=O>[Cl:12][C:9]1[CH:10]=[CH:11][C:6]([C:5]2[NH:4][C:3]([C:2]([F:15])([F:14])[F:1])=[CH:22][C:17]=2[C:18]([O:20][CH3:21])=[O:19])=[CH:7][CH:8]=1
Reactant: C=C(Cl)C(=O)OC
Reactant: FC(F)(F)CN=C(Cl)c1ccc(Cl)cc1
Solvent: C1CCC2=NCCCN2CC1
Solvent: CN(C)C=O
Product: COC(=O)c1cc(C(F)(F)F)[nH]c1-c1ccc(Cl)cc1
Reaction time: 2 h
Yield: 34.6 %

Procedure:
A solution of N-(2,2,2-trifluoroethyl)-4-chloro-benzimidoyl chloride (10.2 g, 0.04 mol) and methyl 2-chloroacrylate (5.8 g, 0.048 mol) in N,N-dimethylformamide is treated with 1,8-diazabicyclo[5.4.0]undec-7-ene (DEU, 19.5 g, 0.128 mol) over 30 minutes at such a rate that the temperature is kept at 40° C., stirred for two hours, and quenched with water and ethyl acetate. The organic layer is separated, washed sequentially with aqueous HCl and water, and concentrated in vacuo to obtain an oil. Flash column chromatography of the oil using silica gel and a 20% ethyl acetate in heptane solution and crystallization from heptane gives the title product as white crystals (4.2 g, 34.6% yield, mp 120.0-122.5° C.).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:20]=[CH:21][C:22]=1[NH:23][C:24]([NH:26][C:27]1[CH:32]=[C:31]([CH3:33])[CH:30]=[CH:29][C:28]=1[F:34])=[O:25])[O:5][C:6]1[CH:11]=[CH:10][N:9]=[C:8]([C:12]2[NH:16][CH:15]=[C:14]([C:17](O)=[O:18])[CH:13]=2)[CH:7]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C.[N:68]1([C:74]([O:76][C:77]([CH3:80])([CH3:79])[CH3:78])=[O:75])[CH2:73][CH2:72][NH:71][CH2:70][CH2:69]1.Cl>CN(C=O)C.O>[F:1][C:2]1[CH:3]=[C:4]([CH:20]=[CH:21][C:22]=1[NH:23][C:24]([NH:26][C:27]1[CH:32]=[C:31]([CH3:33])[CH:30]=[CH:29][C:28]=1[F:34])=[O:25])[O:5][C:6]1[CH:11]=[CH:10][N:9]=[C:8]([C:12]2[NH:16][CH:15]=[C:14]([C:17]([N:71]3[CH2:72][CH2:73][N:68]([C:74]([O:76][C:77]([CH3:80])([CH3:79])[CH3:78])=[O:75])[CH2:69][CH2:70]3)=[O:18])[CH:13]=2)[CH:7]=1
Reactant: Cc1ccc(F)c(NC(=O)Nc2ccc(Oc3ccnc(-c4cc(C(=O)O)c[nH]4)c3)cc2F)c1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1ccc(F)c(NC(=O)Nc2ccc(Oc3ccnc(-c4cc(C(=O)N5CCN(C(=O)OC(C)(C)C)CC5)c[nH]4)c3)cc2F)c1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a stirred solution of 5-{4-[3-fluoro-4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)phenoxy]pyridin-2-yl}-1H-pyrrole-3-carboxylic acid (300 mg, 0.65 mmol) in 10 ml of anhydrous DMF were added HATU (296 mg, 0.78 mmol) and N,N-diisopropylethylamine (185 mg, 1.43 mmol). The mixture was stirred at room temperature for 10 minutes, followed by addition of tert-butyl 1-piperazinecarboxylate (182 mg, 0.98 mmol). The mixture was stirred for another 10 minutes and poured into 100 ml of water. 1M HCl was added slowly until pH=5. The precipitates were filtered, washed with water and dried in vacuo to give tert-butyl 4-[(5-{4-[3-fluoro-4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)phenoxy]pyridin-2-yl}-1H-pyrrol-3-yl)carbonyl]piperazine-1-carboxylate as white solid. Yield: 290 mg, 84%.
Reaction SMILES: [CH2:1]([NH:3][C:4]([NH:6][C:7]1[S:8][C:9]2[C:15]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=3)=[CH:14][C:13]([C:22]3[CH:23]=[N:24][C:25]([C:28]([OH:31])([CH3:30])[CH3:29])=[N:26][CH:27]=3)=[CH:12][C:10]=2[N:11]=1)=[O:5])[CH3:2].BrC1C=NC(C23OC2[CH2:43][O:42][CH2:41]C3)=NC=1.C([O-])([O-])=O.[Cs+].[Cs+]>O1CCOCC1.O>[CH:30]12[O:31][C:28]1([C:25]1[N:26]=[CH:27][C:22]([C:13]3[CH:14]=[C:15]([C:16]4[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=4)[C:9]4[S:8][C:7]([NH:6][C:4]([NH:3][CH2:1][CH3:2])=[O:5])=[N:11][C:10]=4[CH:12]=3)=[CH:23][N:24]=1)[CH2:29][CH2:43][O:42][CH2:41]2
Reactant: Brc1cnc(C23CCOCC2O3)nc1
Reactant: CCNC(=O)Nc1nc2cc(-c3cnc(C(C)(C)O)nc3)cc(-c3ccccn3)c2s1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1COCCO1
Solvent: O
Product: CCNC(=O)Nc1nc2cc(-c3cnc(C45CCOCC4O5)nc3)cc(-c3ccccn3)c2s1
Temperature: 80 °C
Yield: 57 %

Procedure:
Intermediate 1 (29 mg, 0.085 mmol), ii (20 mg, 78 mmol), Cs2CO3 (55 mg 0.17 mmol) and Pd(Ph3)2Cl2 (3 mg, 4 mmol) were dissolved in 1,4-dioxane:H2O (10:1, 10 mL). The mixture was degassed with a stream of N2 for 10 min, then heated in a microwave reactor at 80° C. for 1 h. The reaction was concentrated in vacuo, re-dissolved in a minimum quantity of DCM and purified by chromatography on silica (0-10% DCM-MeOH) yielding iii (23 mg 57%). MS: 475.0, [M+H]+.