Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[CH2:2][CH2:3][N:4]([CH3:54])[S:5]([C:8]1[S:9][C:10]([C:13]2[C:22]3[C:17](=[CH:18][CH:19]=[C:20]([C:23]4[C:24]([C:47]5[CH:52]=[CH:51][C:50]([F:53])=[CH:49][CH:48]=5)=[N:25][N:26]([C:28]([C:41]5[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=5)([C:35]5[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=5)[C:29]5[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=5)[CH:27]=4)[CH:21]=3)[N:16]=[CH:15][N:14]=2)=[CH:11][CH:12]=1)(=[O:7])=[O:6].[CH3:55][N:56]1[CH2:61][CH2:60][NH:59][CH2:58][CH2:57]1.C(N(CC)CC)C.CN(C)C=O>O.C(OCC)(=O)C>[CH3:54][N:4]([CH2:3][CH2:2][N:59]1[CH2:60][CH2:61][N:56]([CH3:55])[CH2:57][CH2:58]1)[S:5]([C:8]1[S:9][C:10]([C:13]2[C:22]3[C:17](=[CH:18][CH:19]=[C:20]([C:23]4[C:24]([C:47]5[CH:52]=[CH:51][C:50]([F:53])=[CH:49][CH:48]=5)=[N:25][N:26]([C:28]([C:41]5[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=5)([C:35]5[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=5)[C:29]5[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=5)[CH:27]=4)[CH:21]=3)[N:16]=[CH:15][N:14]=2)=[CH:11][CH:12]=1)(=[O:7])=[O:6]
Reactant: CN(CCCl)S(=O)(=O)c1ccc(-c2ncnc3ccc(-c4cn(C(c5ccccc5)(c5ccccc5)c5ccccc5)nc4-c4ccc(F)cc4)cc23)s1
Reactant: CN1CCNCC1
Solvent: O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CN1CCN(CCN(C)S(=O)(=O)c2ccc(-c3ncnc4ccc(-c5cn(C(c6ccccc6)(c6ccccc6)c6ccccc6)nc5-c5ccc(F)cc5)cc34)s2)CC1
Temperature: 110 °C
Reaction time: 24 h

Procedure:
A mixture of 100 mg 5-{6-[3-(4-fluorophenyl)-1-trityl-1H-pyrazol-4-yl]quinazolin-4-yl}thiophen-2-sulfonic acid (2-chloroethyl)methylamide (compound in Example 746), 29 μL 1-methyl piperazine, 72 μl triethylamine and 3 mL N,N-dimethylformamide was stirred at 110° C. for 24 hours. Ethyl acetate and water were added to the reaction solution, and the organic layer was separated. The organic layer was washed with water and brine and dried over sodium sulfate, and the solvent was evaporated. The residue was purified by NH silica gel column chromatography (hexane/ethylacetate)to give 41 mg 5-{6-[3-(4-fluorophenyl)-1-trityl-1H-pyrazol-4-yl]quinazolin-4-yl}thio phen-2-sulfonic acid methyl-[2-(4-methylpiperazin-1-yl)ethyl]amide. This product was reacted in the same manner as in Example 68, to give 28 mg of the title compound as yellow crystals.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:13][CH2:14][C:15]1[N:16]=[N:17][NH:18][N:19]=1)[C:10]([OH:12])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[CH2:53]([O:55][C:56]([N:58]1[CH2:63][CH2:62][NH:61][CH2:60][CH2:59]1)=[O:57])[CH3:54]>CN(C=O)C>[CH2:53]([O:55][C:56]([N:58]1[CH2:59][CH2:60][N:61]([C:10](=[O:12])[C@@H:9]([NH:8][C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])[CH2:13][CH2:14][C:15]2[N:16]=[N:17][NH:18][N:19]=2)[CH2:62][CH2:63]1)=[O:57])[CH3:54]
Reactant: CC(C)(C)OC(=O)N[C@@H](CCc1nn[nH]n1)C(=O)O
Reactant: CCOC(=O)N1CCNCC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)N1CCN(C(=O)[C@H](CCc2nn[nH]n2)NC(=O)OC(C)(C)C)CC1

Procedure:
To a solution of 82 mg (S)-2-tert-butoxycarbonylamino-4-(2H-tetrazol-5-yl)-butyric acid in 2 ml DMF were added 115 mg HATU, 100 μl DIPEA and 44 μl 1-ethoxycarbonyl-piperazine. After 1 h the solution was concentrated and the residue directly used in the next reaction step. Yield: 120 mg.
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]([CH2:7][NH:8][C:9]2[CH:18]=[CH:17][C:16]3[C:15]([CH:19]=[O:20])=[CH:14][CH:13]=[CH:12][C:11]=3[N:10]=2)=[CH:4][CH:3]=1.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(Cl)CCl>[CH3:1][C:2]1[O:6][C:5]([CH2:7][NH:8][C:9]2[CH:18]=[CH:17][C:16]3[C:11](=[CH:12][CH:13]=[CH:14][C:15]=3[CH2:19][OH:20])[N:10]=2)=[CH:4][CH:3]=1
Reactant: Cc1ccc(CNc2ccc3c(C=O)cccc3n2)o1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCCl
Product: Cc1ccc(CNc2ccc3c(CO)cccc3n2)o1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
2-[(5-Methyl-furan-2-ylmethyl)-amino]-quinoline-5-carbaldehyde (example 21, step A+B, 150 mg, 0.564 mmol) was dissolved in 5 mL ethylendichloride and acetic acid (136 mg, 2.27 mmol) was added. The reaction mixture was stirred at room temperature for 1 h. Sodium triacetoxy borohydride (258 mg, 1.22 mmol) was added and stirring was continued overnight. The reaction mixture was quenched by addition of 50 mL water. The mixture was extracted three times with dichloromethane (50 mL each). The organic phases ware pooled, dried with sodium sulfate, filtered and evaporated. The residue was purified by flash chromatography on silica gel (cyclohexane/ethyl acetate 100:0->50:50 gradient). {2-[(5-Methyl-furan-2-ylmethyl)-amino]-quinolin-5-yl}-methanol was obtained as a light brown solid (105 mg, 69%), MS: m/e=269.5 (M+H+).
Reaction SMILES: [OH-].[Li+].[C:3]([C:5]1[CH:10]=[CH:9][C:8]([CH:11]2[C:20]3[C:19](=[O:21])[CH2:18][CH2:17][CH2:16][C:15]=3[N:14]([C:22]3[CH:27]=[CH:26][CH:25]=[C:24]([C:28]([F:31])([F:30])[F:29])[CH:23]=3)[C:13](=[O:32])[N:12]2[S:33]([CH2:36][CH2:37][CH2:38][C:39]([O:41]C)=[O:40])(=[O:35])=[O:34])=[CH:7][CH:6]=1)#[N:4]>O.O1CCOCC1>[C:3]([C:5]1[CH:10]=[CH:9][C:8]([CH:11]2[C:20]3[C:19](=[O:21])[CH2:18][CH2:17][CH2:16][C:15]=3[N:14]([C:22]3[CH:27]=[CH:26][CH:25]=[C:24]([C:28]([F:30])([F:29])[F:31])[CH:23]=3)[C:13](=[O:32])[N:12]2[S:33]([CH2:36][CH2:37][CH2:38][C:39]([OH:41])=[O:40])(=[O:34])=[O:35])=[CH:7][CH:6]=1)#[N:4]
Reactant: COC(=O)CCCS(=O)(=O)N1C(=O)N(c2cccc(C(F)(F)F)c2)C2=C(C(=O)CCC2)C1c1ccc(C#N)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: N#Cc1ccc(C2C3=C(CCCC3=O)N(c3cccc(C(F)(F)F)c3)C(=O)N2S(=O)(=O)CCCC(=O)O)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of lithium hydroxide (2 mg, 84 μmol) in water (200 mL) is added to a solution of methyl 4-(4-(4-cyanophenyl)-2,5-dioxo-1-(3-(trifluoromethyl)phenyl)-1,2,5,6,7,8-hexahydroquinazolin-3(4H)-ylsulfonyl)butanoate (example 44.10, 19 mg, 33 μmol) in 1,4-dioxane (1 mL). The mixture is stirred at room temperature for 2 h and purified by it) preparative HPLC (Waters SunFire™-C18, gradient of acetonitrile in water, 0.1% TFA). Yield: 6 mg; ESI mass spectrum [M+H]+=562; Retention time HPLC: 0.91 min (Z018_S04).
Reaction SMILES: C([O:3][C:4](=[O:32])[C:5]([S:8][C:9]1[S:13][C:12]([NH:14][C:15]([N:17]([CH2:26][CH:27]2[CH2:31][CH2:30][CH2:29][CH2:28]2)[C:18]2[CH:23]=[CH:22][C:21]([F:24])=[C:20]([F:25])[CH:19]=2)=[O:16])=[N:11][CH:10]=1)([CH3:7])[CH3:6])C.C1(CN(C2C=CC(F)=C(F)C=2)C(=O)NC2SC=C(CC(O)=O)N=2)CCCC1.FC1C=C(C=CC=1F)N.C1(C=O)CCCC1.C(OC(=O)C(SC1SC(N)=NC=1)(C)C)C>>[CH:27]1([CH2:26][N:17]([C:18]2[CH:23]=[CH:22][C:21]([F:24])=[C:20]([F:25])[CH:19]=2)[C:15](=[O:16])[NH:14][C:12]2[S:13][C:9]([S:8][C:5]([CH3:6])([CH3:7])[C:4]([OH:32])=[O:3])=[CH:10][N:11]=2)[CH2:31][CH2:30][CH2:29][CH2:28]1
Reactant: CCOC(=O)C(C)(C)Sc1cnc(NC(=O)N(CC2CCCC2)c2ccc(F)c(F)c2)s1
Agent: CCOC(=O)C(C)(C)Sc1cnc(N)s1
Agent: Nc1ccc(F)c(F)c1
Agent: O=C(O)Cc1csc(NC(=O)N(CC2CCCC2)c2ccc(F)c(F)c2)n1
Product: CC(C)(Sc1cnc(NC(=O)N(CC2CCCC2)c2ccc(F)c(F)c2)s1)C(=O)O

Procedure:
The title compound was prepared via 2-{2-[3-cyclopentylmethyl-3-(3,4-difluoro-phenyl)-ureido]-thiazol-5-ylsulfanyl}-2-methyl-propionic acid ethyl ester in a similar manner as described for the synthesis of {2-[3-cyclopentylmethyl-3-(3,4-difluoro-phenyl)-ureido]-thiazol-4-yl}-acetic acid, using 3,4-difluoroaniline, cyclopentanecarbaldehyde and 2-(2-amino-thiazol-5-ylsulfanyl)-2-methyl-propionic acid ethyl ester.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([CH:12]([C:14]3[CH:21]=[C:20]([Cl:22])[C:17]([C:18]#[N:19])=[C:16]([CH:23]4[CH2:26][NH:25][CH2:24]4)[C:15]=3[O:27][CH2:28][CH3:29])[CH3:13])[N:9]=[C:10]([CH3:11])[C:3]=12.[CH3:30][C@H:31]1[CH2:33][O:32]1>C(O)C.CO>[NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([CH:12]([C:14]3[CH:21]=[C:20]([Cl:22])[C:17]([C:18]#[N:19])=[C:16]([CH:23]4[CH2:24][N:25]([CH2:30][C@@H:31]([OH:32])[CH3:33])[CH2:26]4)[C:15]=3[O:27][CH2:28][CH3:29])[CH3:13])[N:9]=[C:10]([CH3:11])[C:3]=12
Reactant: C[C@H]1CO1
Reactant: CCOc1c(C(C)n2nc(C)c3c(N)ncnc32)cc(Cl)c(C#N)c1C1CNC1
Solvent: CCO
Solvent: CO
Product: CCOc1c(C(C)n2nc(C)c3c(N)ncnc32)cc(Cl)c(C#N)c1C1CN(C[C@H](C)O)C1
Temperature: 125 °C
Yield: 47.9 %

Procedure:
A solution of 4-[1-(4-amino-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl]-2-azetidin-3-yl-6-chloro-3-ethoxybenzonitrile (50 mg, 0.12 mmol, chiral intermediate from example 212) in ethanol (1.7 mL) was treated with (S)-(−)-methyloxirane (21 μL, 0.30 mmol) and heated in the microwave at 125° C. for 15 min. The reaction mixture was diluted with methanol and purified by preparative LCMS (XBridge C18 column, eluting with a gradient of acetonitrile/water containing 0.1% ammonium hydroxide, at flow rate of 60 mL/min) to give the desired product (27 mg, 47%). The product was isolated as a single diastereomer. 1H NMR (300 MHz, DMSO-d6) δ 8.11 (s, 1H), 7.48 (s, 1H), 6.23 (q, J=6.9 Hz, 1H), 4.35 (d, J=4.5 Hz, 1H), 4.13-3.99 (m, 1H), 3.97-3.88 (m, 2H), 3.85-3.63 (m, 2H), 3.61-3.51 (m, 1H), 3.15-2.99 (m, 2H), 2.55 (s, 3H), 2.28 (d, J=5.9 Hz, 2H), 1.71 (d, J=7.0 Hz, 3H), 1.32 (t, J=6.9 Hz, 3H), 1.00 (d, J=6.2 Hz, 3H). LCMS for C23H29ClN7O2 (M+H)+: m/z=470.2; Found: 470.2.
Reaction SMILES: [C:1]([OH:8])(=O)[CH2:2][CH2:3][C:4]([CH3:6])=[O:5].C(N(CC)CC)C.ClC(OCC(C)C)=O.[CH3:24][NH:25][CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>CC(C)=O>[CH2:26]([N:25]([CH3:24])[C:1](=[O:8])[CH2:2][CH2:3][C:4](=[O:5])[CH3:6])[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: CC(=O)CCC(=O)O
Reactant: CNCc1ccccc1
Agent: CC(C)COC(=O)Cl
Solvent: CCN(CC)CC
Solvent: CC(C)=O
Product: CC(=O)CCC(=O)N(C)Cc1ccccc1
Yield: 88.6 %

Procedure:
A! Starting from 10 g (0.086 mole) of levulinic acid, 11.8 ml (0.086 mole) of triethylamine, 11.2 ml (0.086 mole) of isobutyl chloroformate and 13.3 ml (0.103 mole) of N-methyl-benzylamine in 200 ml of acetone, and following the procedure of Example 6,B!, there were obtained 16.7 g (yield: 88%) of N-benzyl-N-methyl-4-oxo-pentanamide.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[CH2:5]2.N1CCC([CH2:17][CH2:18][NH:19][C:20]([C:22]2[C:26]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)=[C:25]([CH:33]=O)[NH:24][C:23]=2[CH3:35])=[O:21])C1>>[N:7]1([CH2:17][CH2:18][NH:19][C:20]([C:22]2[C:26]([C:27]3[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=3)=[C:25]([CH:33]=[C:5]3[C:4]4[C:8](=[CH:9][CH:10]=[C:2]([Br:1])[CH:3]=4)[NH:7][C:6]3=[O:11])[NH:24][C:23]=2[CH3:35])=[O:21])[CH2:8][CH2:4][CH2:5][CH2:6]1
Reactant: Cc1[nH]c(C=O)c(-c2ccccc2)c1C(=O)NCCC1CCNC1
Reactant: O=C1Cc2cc(Br)ccc2N1
Product: Cc1[nH]c(C=C2C(=O)Nc3ccc(Br)cc32)c(-c2ccccc2)c1C(=O)NCCN1CCCC1
Yield: 27 %

Procedure:
5-Bromo-1,3-dihydroindol-2-one (44 mg, 0.21 mmol) was condensed with 5-formyl-2-methyl-4-phenyl-1H-pyrrole-3-carboxylic acid (2-pyrrolidin-3-ylethyl)amide (70 mg, prepared in the same manner as the isopropyl analog, above) to give 0.03 g (27%) of the title compound as a yellow solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:7]=[CH:8][C:9]=1[O:10][CH3:11])[NH2:6].[CH:12]1[C:21]2[CH:20]=[CH:19][CH:18]=[C:17]([S:22](Cl)(=[O:24])=[O:23])[C:16]=2[CH:15]=[CH:14][N:13]=1.Cl>N1C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH:6][S:22]([C:17]2[C:16]3[CH:15]=[CH:14][N:13]=[CH:12][C:21]=3[CH:20]=[CH:19][CH:18]=2)(=[O:23])=[O:24])[CH:7]=[CH:8][C:9]=1[O:10][CH3:11]
Reactant: COc1ccc(N)cc1OC
Reactant: O=S(=O)(Cl)c1cccc2cnccc12
Agent: Cl
Solvent: c1ccncc1
Product: COc1ccc(NS(=O)(=O)c2cccc3cnccc23)cc1OC
Reaction time: 0.5 h
Yield: 82 %

Procedure:
3.06 g of 3,4-dimethoxyaniline was dissolved in 30 ml of pyridine, to the solution was added in small portions 5.28 g of 5-isoquinolinesulfonyl chloride.HCl with stirring under ice cooling, and the mixture was stirred for 30 minutes, and further stirred at a room temperature overnight. After evaporating off the pyridine under a reduced pressure and additing 20 ml of water, the mixture was extracted twice with 50 ml of chloroform/isopropanol (10:1). The extract was dried over magnesium sulfate and evaporated under a reduced pressure to remove the solvent. To the resulting residue was added 20 ml of benzene/chloroform (3:1), and the mixture was slightly warmed and collected to obtain 5.64 g of the title compound as colorless crystals.
Reaction SMILES: [F:1][C:2]1[C:10]2[O:9][CH:8]([CH:11]3[CH2:16][CH2:15][N:14]([C:17]4[N:22]=[CH:21][C:20]([CH2:23][CH2:24][CH3:25])=[CH:19][N:18]=4)[CH2:13][CH2:12]3)[CH2:7][C:6]=2[CH:5]=[C:4]([C:26]2[CH2:31][CH2:30][N:29](C(OC(C)(C)C)=O)[CH2:28][CH:27]=2)[CH:3]=1.C(O)(C(F)(F)F)=O.FC1C2OC(C3(O)CCN(C4N=CC(CCC)=CN=4)CC3)CC=2C=C(C2CCNCC=2)C=1>>[F:1][C:2]1[C:10]2[O:9][CH:8]([CH:11]3[CH2:12][CH2:13][N:14]([C:17]4[N:22]=[CH:21][C:20]([CH2:23][CH2:24][CH3:25])=[CH:19][N:18]=4)[CH2:15][CH2:16]3)[CH2:7][C:6]=2[CH:5]=[C:4]([C:26]2[CH2:31][CH2:30][NH:29][CH2:28][CH:27]=2)[CH:3]=1
Reactant: CCCc1cnc(N2CCC(C3Cc4cc(C5=CCN(C(=O)OC(C)(C)C)CC5)cc(F)c4O3)CC2)nc1
Agent: CCCc1cnc(N2CCC(O)(C3Cc4cc(C5=CCNCC5)cc(F)c4O3)CC2)nc1
Solvent: O=C(O)C(F)(F)F
Product: CCCc1cnc(N2CCC(C3Cc4cc(C5=CCNCC5)cc(F)c4O3)CC2)nc1

Procedure:
Compound 3H was prepared from Compound 3G and TFA in a similar manner to the procedure described for Compound 1J in Example 1. LC/MS (m/z)=423 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=1[OH:11].C(=O)([O-])[O-].[K+].[K+].Br[CH2:19][CH2:20][F:21]>CN(C=O)C.O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=1[O:11][CH2:19][CH2:20][F:21]
Reactant: FCCBr
Reactant: O=[N+]([O-])c1ccc(Br)c(O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1ccc(Br)c(OCCF)c1
Temperature: 100 °C
Reaction time: 3 h

Procedure:
Intermediate 16A (475 mg, 2.179 mmol) was dissolved in DMF (1 mL) and to this solution was added potassium carbonate (903 mg, 6.54 mmol) and 1-bromo-2-fluoroethane (415 mg, 3.27 mmol). The reaction mixture was stirred at 100° C. for 3 hours, cooled, diluted with water (20 mL) and then extracted with EtOAc (2×20 mL). The combined organics were washed with brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. Intermediate 16B was obtained as a pale yellow semi-solid (570 mg, 2.159 mmol, 99% yield). MS (ES): m/z=199.0 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ ppm 4.47-4.51 (m, 1 H) 4.55-4.59 (m, 1 H) 4.73-4.78 (m, 1 H) 4.85-4.91 (m, 1 H) 7.77-7.83 (m, 1 H) 7.91 (d, J=2.51 Hz, 1 H) 7.94 (d, J=8.53 Hz, 1 H).
Reaction SMILES: C1N2CN3CN(C2)CN1C3.Br[CH2:12][C:13]1[CH:18]=[CH:17][C:16]([O:19][C:20]([F:23])([F:22])[F:21])=[CH:15][CH:14]=1.BrC(Br)C1C=CC([O:32]C(F)(F)F)=CC=1>C(O)C.O>[F:21][C:20]([F:23])([F:22])[O:19][C:16]1[CH:17]=[CH:18][C:13]([CH:12]=[O:32])=[CH:14][CH:15]=1
Reactant: FC(F)(F)Oc1ccc(C(Br)Br)cc1
Reactant: FC(F)(F)Oc1ccc(CBr)cc1
Agent: C1N2CN3CN1CN(C2)C3
Solvent: CCO
Solvent: O
Product: O=Cc1ccc(OC(F)(F)F)cc1

Procedure:
To a solution of hexamethylenetetramine (300 g; 2.14 mole) in ethanol (900 ml) and water (600 ml) a mixture of α-bromo-4-trifluoromethoxytoluene and α,α-dibromo-4-trifluoromethoxytoluene (300 g; 1.11 mole; 76:24 mixture) is added. The reaction mixture is stirred and heated at reflux for 3 hours under a nitrogen atmosphere, and then stirred overnight at room temperature.
Reaction SMILES: [CH3:1][C:2]1[N:6]([C:7]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:5]=[N:4][C:3]=1[CH2:26][NH:27]C.[CH3:29][CH:30]1[CH2:39][CH2:38][C:37]2[C:32]3=[C:33]([C:40]([C:42]([OH:44])=O)=[CH:41][N:31]13)[CH:34]=[CH:35][CH:36]=2>C(#N)C>[CH3:1][C:2]1[N:6]([C:7]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)([C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)[C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH:5]=[N:4][C:3]=1[CH2:26][NH:27][C:42]([C:40]1[C:33]2=[C:32]3[C:37](=[CH:36][CH:35]=[CH:34]2)[CH2:38][CH2:39][CH:30]([CH3:29])[N:31]3[CH:41]=1)=[O:44]
Reactant: CC1CCc2cccc3c(C(=O)O)cn1c23
Reactant: CNCc1ncn(C(c2ccccc2)(c2ccccc2)c2ccccc2)c1C
Solvent: CC#N
Product: Cc1c(CNC(=O)c2cn3c4c(cccc24)CCC3C)ncn1C(c1ccccc1)(c1ccccc1)c1ccccc1
Reaction time: 12 h

Procedure:
A mixture of 3.4 g (9.3 mmol) of 5-methyl-4-(methylamino) methyl-1-triphenylmethyl-1H-imidazole, 2.0 g (9.3 mmol) of 4-methyl-5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinoline-1-carboxylic acid, and 2.06 g (10 mmol) of N,N-dicyclohexylcarbodiimide in 100 ml of acetonitrile was stirred for 12 hours under nitrogen. The precipitate was sucked off and the filtrate was evaporated in vacuo. The residue was dissolved in ethylacetate and washed with 2 N sodium hydroxide and saturated saline respectively, and then evaporated in vacuo. The residue was chromatographed on silicagel using methylene chloride/methanol (95/5) as an eluent. After evaporating the desired fractions 3.6 g of N-methyl, N-[(5-methyl-1-triphenylmethyl-1H-imidazol-4-yl)methyl]-4-methyl-5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinoline-1-carboxamide were obtained.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12](Br)=[CH:11][C:10]=1[O:16][CH3:17])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Li]CCCC.[N:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[CH2:29][CH2:30][N:31]1[C:39](=[O:40])[C:38]2[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=2)[C:32]1=[O:41]>C1COCC1>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:39]2([OH:40])[C:38]3[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=3)[C:32](=[O:41])[N:31]2[CH2:30][CH2:29][C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][N:23]=2)=[CH:11][C:10]=1[O:16][CH3:17])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C1c2ccccc2C(=O)N1CCc1ccccn1
Reactant: COc1cc(Br)ccc1OCc1ccccc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: COc1cc(C2(O)c3ccccc3C(=O)N2CCc2ccccn2)ccc1OCc1ccccc1
Reaction time: 1 h
Yield: 45.7 %

Procedure:
A solution of 2 (4.0 g, 13.7 mmol) in dry THF (40 mL) at −78° C. was treated with n-BuLi (2.5 M, 6.0 mL, 15.0 mmol) for 15 min to produce 3. To this solution, 5 (3.1 g, 12.2 mmol) in dry THF (40 mL) was added slowly over a 10 min period. The reaction mixture turned light brown in color and stirring was continued for 1 h. The reaction was quenched by the addition of saturated aqueous NH4Cl (10 mL) and the organic layer was separated. The aqueous layer was extracted with EtOAc (3×25 mL) and the combined organic layer was washed with brine (15 mL). Volatiles were evaporated under reduced pressure and the crude residue was purified by column chromatography using 20% acetone/hexane as the eluent to afford the title compound 6 as a white solid (2.6 g, 46%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[C:11](=[O:26])[NH:12][C:13]1[CH:18]=[CH:17][C:16]([Cl:19])=[C:15]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=2)[CH:14]=1)[C:5]([OH:7])=O.[CH3:27][S:28]([CH2:31][CH2:32][NH2:33])(=[O:30])=[O:29]>>[Cl:1][C:2]1[CH:3]=[C:4]([C:5]([NH:33][CH2:32][CH2:31][S:28]([CH3:27])(=[O:30])=[O:29])=[O:7])[CH:8]=[CH:9][C:10]=1[C:11]([NH:12][C:13]1[CH:18]=[CH:17][C:16]([Cl:19])=[C:15]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=2)[CH:14]=1)=[O:26]
Reactant: CS(=O)(=O)CCN
Reactant: O=C(O)c1ccc(C(=O)Nc2ccc(Cl)c(-c3ccccn3)c2)c(Cl)c1
Product: CS(=O)(=O)CCNC(=O)c1ccc(C(=O)Nc2ccc(Cl)c(-c3ccccn3)c2)c(Cl)c1

Procedure:
50 mg of 3-chloro-4-(4-chloro-3-(pyridin-2-yl)phenylcarbamoyl)benzoic acid was coupled to 2-(methylsulfonyl)ethanamine via Procedure G. The crude product was purified on reverse phase HPLC to yield 2-chloro-N1-(4-chloro-3-(pyridin-2-yl)phenyl)-N4-(2-(methylsulfonyl)ethyl)terephthalamide. MS (Q1) 492 (M)+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([O:18][CH3:19])[CH2:9][NH:10]C(=O)OC(C)(C)C)=[CH:4][CH:3]=1.FC(F)(F)C(O)=O>ClCCl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]([O:18][CH3:19])[CH2:9][NH2:10])=[CH:6][CH:7]=1
Reactant: COC(CNC(=O)OC(C)(C)C)c1ccc(Cl)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COC(CN)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 84.8 %

Procedure:
To a solution of tert-butyl 2-(4-chlorophenyl)-2-methoxyethylcarbamate (0.129 g, 0.451 mmol) in dichloromethane (5 ml) was added trifluoroacetic acid (5 ml), and the reaction was stirred at ambient temperature for 16 hours. The reaction was concentrated and taken up in water. Sodium hydroxide (1M) was added until the pH was >13. The mixture was extracted twice with dichloromethane, and the combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated to yield 71 mg of the title compound (84.7% yield).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH:15]([OH:22])[C:16]#[C:17][C:18]([CH3:21])([OH:20])[CH3:19])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1C=C[NH+]=CC=1.[O-][Cr](Cl)(=O)=O>C(Cl)Cl>[CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([C:15](=[O:22])[C:16]#[C:17][C:18]([OH:20])([CH3:19])[CH3:21])=[CH:13][CH:14]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(O)C#CC(O)c1ccc(OCc2ccccc2)cc1
Agent: O=[Cr](=O)([O-])Cl
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Product: CC(C)(O)C#CC(=O)c1ccc(OCc2ccccc2)cc1
Reaction time: 1 h
Yield: 51 %

Procedure:
To a solution of 1-(4-(benzyloxy)phenyl)-4-methylpent-2-yne-1,4-diol (3.0 g, 0.01 mol) in DCM (30 mL) were added Celite® (1.0 g) followed by PCC (2.61 g, 0.01 mol) at RT. The reaction mixture was stirred for 1 h, filtered through a pad of Celite® and the filtrate was concentrated in vacuo to obtain the crude product. The crude material was purified via silica gel column chromatography to afford 1-(4-(benzyloxy)phenyl)-4-hydroxy-4-methylpent-2-yn-1-one (1.5 g, 51%) as a solid.
Reaction SMILES: [C:1]1([CH3:21])[CH:6]=[CH:5][C:4]([S:7]([N:10]2[CH:14]=[C:13]([CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17])[N:12]=[CH:11]2)(=[O:9])=[O:8])=[CH:3][CH:2]=1.C[Si]([N-][Si](C)(C)C)(C)C.[Li+].C([C:34]([O:36][CH2:37][CH3:38])=[O:35])#N>C1COCC1>[C:1]1([CH3:21])[CH:2]=[CH:3][C:4]([S:7]([N:10]2[CH:14]=[C:13]([CH:15]([C:34]([O:36][CH2:37][CH3:38])=[O:35])[C:16]([O:18][CH2:19][CH3:20])=[O:17])[N:12]=[CH:11]2)(=[O:9])=[O:8])=[CH:5][CH:6]=1
Reactant: CCOC(=O)Cc1cn(S(=O)(=O)c2ccc(C)cc2)cn1
Reactant: CCOC(=O)C#N
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: CCOC(=O)C(C(=O)OCC)c1cn(S(=O)(=O)c2ccc(C)cc2)cn1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 31.6 %

Procedure:
A solution of 1.000 g (3.243 mmol) of ethyl [1-(toluene-4-sulfonyl)-1H-imidazol-4-yl]-acetate was dissolved in 20 ml of THF and cooled to 0° C. Over a period of 10 min, 3.567 ml of lithium bis(trimethylsilyl)amide (3.567 mmol, 1M in THF) were added dropwise. This mixture was stirred at 0° C. for 30 min, 350 μl (3.567 mmol) of ethyl cyanoformate were then added and the mixture was stirred at RT for another 2 h. The reaction mixture was quenched with saturated ammonium chloride solution and extracted with ethyl acetate. The organic phase was washed with water and saturated NaCl solution, dried over Na2SO4, filtered and concentrated. Chromatography on silica gel (heptane/ethyl acetate 1:1) gave the title compound (0.390 g, 32%).
Reaction SMILES: C(OC([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([Cl:17])[CH:15]=2)/[C:10](=[CH:18]/[C:19]2[CH:24]=[C:23]([Cl:25])[CH:22]=[CH:21][C:20]=2[O:26][CH2:27][C:28]#[N:29])/[C:9]1=[O:30])=O)(C)(C)C.[F:31][C:32]1[CH:33]=[CH:34][C:35]([CH3:47])=[C:36]([CH:38]=[N:39][C:40]([O:42][Si](C)(C)C)=[CH2:41])[CH:37]=1>C1(C)C=CC=CC=1>[Cl:17][C:14]1[CH:15]=[C:16]2[NH:8][C:9](=[O:30])[C:10]3([CH:18]([C:19]4[CH:24]=[C:23]([Cl:25])[CH:22]=[CH:21][C:20]=4[O:26][CH2:27][C:28]#[N:29])[CH2:41][C:40](=[O:42])[NH:39][CH:38]3[C:36]3[CH:37]=[C:32]([F:31])[CH:33]=[CH:34][C:35]=3[CH3:47])[C:11]2=[CH:12][CH:13]=1
Reactant: CC(C)(C)OC(=O)N1C(=O)/C(=C\c2cc(Cl)ccc2OCC#N)c2ccc(Cl)cc21
Reactant: C=C(N=Cc1cc(F)ccc1C)O[Si](C)(C)C
Solvent: Cc1ccccc1
Product: Cc1ccc(F)cc1C1NC(=O)CC(c2cc(Cl)ccc2OCC#N)C12C(=O)Nc1cc(Cl)ccc12
Yield: 1.7 %

Procedure:
In a manner similar to the method described in Example 10d, E/Z-6-chloro-3-(5-chloro-2-cyanomethoxy-benzylidene)-2-oxo-2,3-dihydro-indole-1-carboxylic acid tert-butyl ester (5 g, 11 mmol) was reacted with 1-(5-fluoro-2-methyl-phenyl)-3-trimethylsilyoxy-2-aza-1,3-butadiene (44 mmol) in toluene to give the title compound as a white solid (100 mg).