Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[NH:9][C:8]([CH3:13])=[C:7]2[C:14](=[O:23])[C:15]1[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=1[Cl:22])(O)=[O:2].[CH2:24]([S:28]([NH2:31])(=[O:30])=[O:29])[CH2:25][CH2:26][CH3:27].C1(C2CCCCCCCCCC=2)CCCCCCCCNN=1>CN(C)C=O>[CH2:24]([S:28]([NH:31][C:1]([C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[NH:9][C:8]([CH3:13])=[C:7]2[C:14](=[O:23])[C:15]1[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=1[Cl:22])=[O:2])(=[O:30])=[O:29])[CH2:25][CH2:26][CH3:27]
Reactant: CCCCS(N)(=O)=O
Reactant: Cc1[nH]c2ccc(C(=O)O)cc2c1C(=O)c1ccc(Cl)cc1Cl
Agent: C1=C(C2=NNCCCCCCCC2)CCCCCCCCC1
Solvent: CN(C)C=O
Product: CCCCS(=O)(=O)NC(=O)c1ccc2[nH]c(C)c(C(=O)c3ccc(Cl)cc3Cl)c2c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 62.6 %

Procedure:
According to the method of Example 59, 5-carboxy-3-(2,4-dichlorobenzoyl)-2-methylindole (0.500 g) is suspended in N,N-dimethylformamide (10 ml), to which is added N,N′-carbonyldiimidazole (0.350 g), and stirred at room temperature for 2 hours. Next, 1-butanesulfonamide (0.296 g) and diazabicycloundecene (0.328 g) are added thereto, and stirred under heat at 100° C. for 6 hours. The reaction mixture is concentrated under reduced pressure, and the residue is made acidic with water and 3 M HCl added thereto, and then extracted with ethyl acetate. The organic layer is washed with a saturated saline solution, and dried with anhydrous sodium sulfate. The drying agent is removed through filtration, and the filtrate is concentrated under reduced pressure. The resulting oily residue is purified through silica gel column chromatography (eluent: chloroform methanol=10/), and recrystallized from ethanol-hexane to obtain a colorless crystal of 5-(1-butanesulfonylcarbamoyl)-3-(2,4-dichlorobenzoyl)-2-methylindole (97) (0.420 g).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([C:12]([CH:14]1[CH2:16][CH2:15]1)=[O:13])=[C:5]2[NH:17][C:18]1[CH:23]=[CH:22][C:21]([CH2:24][CH2:25][N:26]([CH3:28])[CH3:27])=[CH:20][CH:19]=1.[Cl:29][C:30]1[CH:35]=[C:34](B2OC(C)(C)C(C)(C)O2)[CH:33]=[C:32]([F:45])[C:31]=1[OH:46]>>[Cl:29][C:30]1[CH:35]=[C:34]([C:2]2[CH:3]=[C:4]3[C:9](=[CH:10][CH:11]=2)[N:8]=[CH:7][C:6]([C:12]([CH:14]2[CH2:15][CH2:16]2)=[O:13])=[C:5]3[NH:17][C:18]2[CH:23]=[CH:22][C:21]([CH2:24][CH2:25][N:26]([CH3:27])[CH3:28])=[CH:20][CH:19]=2)[CH:33]=[C:32]([F:45])[C:31]=1[OH:46]
Reactant: CN(C)CCc1ccc(Nc2c(C(=O)C3CC3)cnc3ccc(Br)cc23)cc1
Reactant: CC1(C)OB(c2cc(F)c(O)c(Cl)c2)OC1(C)C
Product: CN(C)CCc1ccc(Nc2c(C(=O)C3CC3)cnc3ccc(-c4cc(F)c(O)c(Cl)c4)cc23)cc1
Yield: 71.6 %

Procedure:
Following general procedure D, (6-bromo-4-(4-(2-(dimethylamino)ethyl)phenylamino)quinolin-3-yl)(cyclopropyl)methanone (100 mg, 0.23 mmol) was reacted with 2-chloro-6-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol (93 mg, 0.34 mmol) to afford the desired product (83 mg, 72%) as a yellow-brown solid: 1H NMR (500 MHz, CD3OD+TFA-d) δ 9.46 (s, 1H), 8.21 (dd, J=8.8, 1.9 Hz, 1H), 8.01 (d, J=8.8 Hz, 1H), 7.89 (s, 1H), 7.57 (d, J=8.4 Hz, 2H), 7.47 (d, J=8.4 Hz, 2H), 7.04 (m, 2H), 3.41 (m, 2H), 3.21 (m, 2H), 2.99 (s, 7H), 2.90 (m, 1H), 1.23 (m, 4H); ESI MS m/z 504 [C29H27ClFN3O2+H]+; HPLC 97.0% (AUC), tR=10.95 min.
Reaction SMILES: [CH:1]1([CH2:6][CH:7]([C:21]2[CH:26]=[CH:25][C:24]([S:27]([CH3:30])(=[O:29])=[O:28])=[CH:23][CH:22]=2)[C:8]([NH:10][C:11]2[S:12][C:13]([S:16][CH2:17][C:18](O)=[O:19])=[CH:14][N:15]=2)=[O:9])[CH2:5][CH2:4][CH2:3][CH2:2]1.ON1C(=O)C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC.[CH2:55]([NH:57][CH2:58][CH3:59])[CH3:56].CCN(C(C)C)C(C)C>CN(C=O)C>[CH:1]1([CH2:6][CH:7]([C:21]2[CH:26]=[CH:25][C:24]([S:27]([CH3:30])(=[O:29])=[O:28])=[CH:23][CH:22]=2)[C:8]([NH:10][C:11]2[S:12][C:13]([S:16][CH2:17][C:18](=[O:19])[N:57]([CH2:58][CH3:59])[CH2:55][CH3:56])=[CH:14][N:15]=2)=[O:9])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CS(=O)(=O)c1ccc(C(CC2CCCC2)C(=O)Nc2ncc(SCC(=O)O)s2)cc1
Reactant: CCNCC
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: O=c1c2ccccc2nnn1O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCN(CC)C(=O)CSc1cnc(NC(=O)C(CC2CCCC2)c2ccc(S(C)(=O)=O)cc2)s1
Reaction time: 20 h

Procedure:
To a solution of {2-[3-cyclopentyl-2-(4-methanesulfonyl-phenyl)propionylamino]-thiazol-5-ylsulfanyl}-acetic acid (33 mg, 70.4 mmol) in DMF (0.5 mL) was added 3-hydroxy-1,2,3-benzotriazin-4-(3H)-one (12 mg, 73.5 mmol) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (14 mg, 73 mmol). The reaction mixture was stirred at room temperature for 2 hours after which diethyl amine (10 μL, 96.3 mmol) and DIPEA (12 μL, 70.3 mmol) were added. Stirring was continued for 20 hours. The reaction mixture was purified by HPLC (C18, gradient 25%-100% acetonitrile) to give 3-cyclopentyl-N-(5-diethylcarbamoylmethylsulfanyl-thiazol-2-yl)-2-(4-methanesulfonyl-phenyl)propionamide as an oil. Yield: 15 mg (42%). 1H-NMR (CDCl3): δ 7.91 (d, 2H), 7.62 (d, 2H), 7.45 (s, 1H), 3.93 (t, 1H), 3.63 (s, 3H), 3.38 (q, 2H), 3.31 (q, 2H), 3.05 (s, 3H), 2.28-2.21 (m, 1H), 1.97-1.90 (m, 1H), 1.75-1.47 (m, 7H), 1.23-1.11 (m, 8H); HPLC-MS: m/z: 525 (M+1).
Reaction SMILES: C([O:5][C:6]([CH:8]1[NH:12][CH:11]([CH2:13][C:14]([CH3:17])([CH3:16])[CH3:15])[C:10]2([C:25]3[C:20](=[CH:21][C:22]([Cl:26])=[CH:23][CH:24]=3)[NH:19][C:18]2=[O:27])[CH:9]1[C:28]1[CH:33]=[CH:32][CH:31]=[C:30]([Cl:34])[C:29]=1[F:35])=[O:7])(C)(C)C.[F:36][C:37]([F:42])([F:41])[C:38]([OH:40])=[O:39]>ClCCl>[F:36][C:37]([F:42])([F:41])[C:38]([OH:40])=[O:39].[Cl:26][C:22]1[CH:21]=[C:20]2[NH:19][C:18](=[O:27])[C:10]3([CH:9]([C:28]4[CH:33]=[CH:32][CH:31]=[C:30]([Cl:34])[C:29]=4[F:35])[CH:8]([C:6]([OH:7])=[O:5])[NH:12][CH:11]3[CH2:13][C:14]([CH3:16])([CH3:15])[CH3:17])[C:25]2=[CH:24][CH:23]=1
Reactant: CC(C)(C)CC1NC(C(=O)OC(C)(C)C)C(c2cccc(Cl)c2F)C12C(=O)Nc1cc(Cl)ccc12
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(C)(C)CC1NC(C(=O)O)C(c2cccc(Cl)c2F)C12C(=O)Nc1cc(Cl)ccc12
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A solution of rac-(2′R,3′S,4′S,5′R)-6-chloro-4′-(3-chloro-2-fluoro-phenyl)-2′-(2,2-dimethyl-propyl)-2-oxo-1,2-dihydro-spiro[indole-3,3′-pyrrolidine]-5′-carboxylic acid tert-butyl ester (1 g, 1.9 mmol) in dichloromethane (20 mL) was added trifluoroacetic acid (10 g). The reaction mixture was stirred at room temperature for 18 h, then concentrated. The residue was then triturated with ethyl ether hexanes, concentrated, dried in vacuo to give rac-(2′R,3′S,4′S,5′R)-6-chloro-4′-(3-chloro-2-fluoro-phenyl)-2′-(2,2-dimethyl-propyl)-2-oxo-1,2-dihydro-spiro[indole-3,3′-pyrrolidine]-5′-carboxylic acid trifluoroacetic acid as a off white solid (1.1 g, 99%).
Reaction SMILES: [C:1]([O:5][C:6](=[O:22])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=2)=[CH:10][C:9]=1[NH2:21])([CH3:4])([CH3:3])[CH3:2].CC1(C)[O:29][C:28]([C:30]2[CH:31]=[C:32]([CH:35]=[CH:36][CH:37]=2)[C:33]#[N:34])=[CH:27][C:26](=O)[O:25]1>>[C:1]([O:5][C:6](=[O:22])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:15]=[CH:16][C:17]([F:20])=[CH:18][CH:19]=2)=[CH:10][C:9]=1[NH:21][C:26](=[O:25])[CH2:27][C:28]([C:30]1[CH:37]=[CH:36][CH:35]=[C:32]([C:33]#[N:34])[CH:31]=1)=[O:29])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)Nc1ccc(-c2ccc(F)cc2)cc1N
Reactant: CC1(C)OC(=O)C=C(c2cccc(C#N)c2)O1
Product: CC(C)(C)OC(=O)Nc1ccc(-c2ccc(F)cc2)cc1NC(=O)CC(=O)c1cccc(C#N)c1

Procedure:
Prepared from (3-amino-4′-fluoro-biphenyl-4-yl)-carbamic acid tert.-butyl ester (Example G39) and 3-(2,2-dimethyl-6-oxo-6H-[1,3]dioxin-4-yl)-benzonitrile (Example J4) according to the general procedure K. Obtained as a yellow solid (257 mg).
Reaction SMILES: [CH:1]([O:4][C:5]1[N:10]=[CH:9][C:8]([C@@H:11]([NH:13][S@@](C(C)(C)C)=O)[CH3:12])=[CH:7][CH:6]=1)([CH3:3])[CH3:2].Cl>CO.O>[CH:1]([O:4][C:5]1[N:10]=[CH:9][C:8]([C@@H:11]([NH2:13])[CH3:12])=[CH:7][CH:6]=1)([CH3:3])[CH3:2]
Reactant: CC(C)Oc1ccc([C@H](C)N[S@](=O)C(C)(C)C)cn1
Agent: Cl
Solvent: CO
Solvent: O
Product: CC(C)Oc1ccc([C@H](C)N)cn1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
(R)-2-Methyl-propane-2-sulfinic acid [(S)-1-(6-isopropoxy-pyridin-3-yl)ethyl]-amide (2.90 g, 10.2 mmol) was dissolved in methanol (48 mL). A mixture of 12.0 M HCl in water (4.25 mL) and water (4.25 mL) was added drop wise over 3 minutes. The mixture was stirred at room temperature overnight. The mixture was evaporated to dryness. The oily residue was subjected to flash chromatography (silica, EtOAc/EtOH/triethylamine 90:5:5) on a short column to give (S)-1-(6-isopropoxy-pyridin-3-yl)-ethylamine IM24 (1.71 g, 93%) as a pale-yellow oil sufficiently pure for the next step. The overall yield from 1-(6-isopropoxy-pyridin-3-yl)-ethanone IM16 was 54%.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[Cl:7][C:8]1[N:13]=[C:12]([NH:14][C:15]2[CH:19]=[C:18]([CH3:20])[NH:17][N:16]=2)[C:11]([F:21])=[C:10](Cl)[N:9]=1.CCN(C(C)C)C(C)C>C(O)C>[Cl:7][C:8]1[N:13]=[C:12]([NH:14][C:15]2[CH:19]=[C:18]([CH3:20])[NH:17][N:16]=2)[C:11]([F:21])=[C:10]([N:1]2[CH2:6][CH2:5][O:4][CH2:3][CH2:2]2)[N:9]=1
Reactant: Cc1cc(Nc2nc(Cl)nc(Cl)c2F)n[nH]1
Reactant: C1COCCN1
Solvent: CCO
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cc(Nc2nc(Cl)nc(N3CCOCC3)c2F)n[nH]1
Temperature: 80 °C

Procedure:
To a solution of 2,4,6-trichloro-5-fluoropyrimidine (4.03 g) in absolute ethanol (100 mL) was added DIEPA (5.3 mL) and 5-methyl-1H-pyrazol-3-amine (2.03 g). The resulting solution was stirred at room temperature for 6 hours. The precipitation was filtered and washed with cold ethanol. The compound was dried by vacuum oven give 2,6-dichloro-5-fluoro-N-(5-methyl-1H-pyrazol-3-yl)pyrimidin-4-amine as solid (3.7 g). m/z 262. A mixture of morpholine (0.181 mL), 2,6-dichloro-5-fluoro-N-(5-methyl-1H-pyrazol-3-yl)pyrimidin-4-amine (500 mg) and DIPEA (0.505 ml) in absolute ethanol (10.0 ml) was heated at 80° C. for 5 hours. The solvent was removed under reduced pressure and the residue was purified by Gilson (10-50% MeCN/H2O, 15 minutes) to give the titled compound as solid (236 mg). 1H NMR δ 12.05 (bs, 1H) 9.57 (s, 1H) 6.21 (s, 1H) 3.67 (t, 4H) 3.57 (t, 4H) 2.22 (s, 3H); m/z 313.
Reaction SMILES: [CH:1]1([CH2:16][OH:17])[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C1C=C[NH+]=CC=1.[O-][Cr](Cl)(=O)=O>C(Cl)Cl.CCOCC>[CH:1]1([CH:16]=[O:17])[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: OCC1CCCCCCCCCCCCCC1
Agent: O=[Cr](=O)([O-])Cl
Agent: c1cc[nH+]cc1
Solvent: CCOCC
Solvent: ClCCl
Product: O=CC1CCCCCCCCCCCCCC1

Procedure:
To a solution of alcohol 52 (300 mg, 1.25 mmol) in CH2Cl2 (20 mL) was added PCC (404 mg, 1.87 mmol) at room temperature. The reaction was monitored by TLC (50% hexanes/50% CH2Cl2) until complete (60 min) Upon reaching completion, the mixture was then diluted with Et2O, filtered through Celite and concentrated in vacuo to give aldehyde 53 as a yellow oil that was used without further purification (250 mg crude). 1H NMR (CDCl3) δ 9.61 (s, 1H), 2.43 (m, 2H), 2.29 (m, 1H), 1.62 (m, 4H), 1.49 (m, 4H), 1.44-1.31 (m, 20H). This aldehyde was found to be unstable and was best used immediately in subsequent steps.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[CH2:14][N:15]2[CH2:20][CH2:19][N:18]([C:21]3[CH:31]=[CH:30][C:24]([C:25]([O:27]CC)=[O:26])=[CH:23][CH:22]=3)[CH2:17][CH2:16]2)=[CH:4][CH:3]=1.O.[OH-].[Li+]>O1CCOCC1.O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[CH2:14][N:15]2[CH2:20][CH2:19][N:18]([C:21]3[CH:22]=[CH:23][C:24]([C:25]([OH:27])=[O:26])=[CH:30][CH:31]=3)[CH2:17][CH2:16]2)=[CH:6][CH:7]=1
Reactant: CCOC(=O)c1ccc(N2CCN(Cc3ccccc3-c3ccc(Cl)cc3)CC2)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: O=C(O)c1ccc(N2CCN(Cc3ccccc3-c3ccc(Cl)cc3)CC2)cc1
Temperature: 80 °C

Procedure:
A mixture of EXAMPLE 2B (13 g) and lithium hydroxide hydrate (3.78 g) in dioxane (250 mL) and water (100 mL) at 95° C. was stirred for 16 hours and concentrated. The concentrate in water was heated at 80° C. and filtered. The filtrate was treated with 1M HCl (90 mL) and filtered.
Reaction SMILES: [C:1]([C:11]1[CH:16]=[CH:15][C:14]([CH2:17][CH2:18][CH2:19][C:20]([OH:22])=[O:21])=[CH:13][CH:12]=1)(=[O:10])[CH:2]=[CH:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[CH3:23]O>S(=O)(=O)(O)O>[C:1]([C:11]1[CH:12]=[CH:13][C:14]([CH2:17][CH2:18][CH2:19][C:20]([O:22][CH3:23])=[O:21])=[CH:15][CH:16]=1)(=[O:10])[CH:2]=[CH:3][C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: CO
Reactant: O=C(O)CCCc1ccc(C(=O)C=Cc2ccccc2)cc1
Agent: O=S(=O)(O)O
Product: COC(=O)CCCc1ccc(C(=O)C=Cc2ccccc2)cc1

Procedure:
To a solution of 10.00 g of 4-(4-cinnamoylphenyl)butyric acid in 50 ml of methanol, 0.25 ml of sulfuric acid was added, and the mixture was refluxed for 1 hour. The solvent was removed under reduced pressure, and then the residue was added with water and extracted with ether. The ether layer was washed with water and dried, and then the solvent was removed under reduced pressure. The residue was purified by column chromatography on silica gel (methylene chloride:n-hexane=3:2) to yield 8.94 g of pale yellow crystals. Recrystallization from n-hexane gave pale yellow needles, mp 43°~44° C.
Reaction SMILES: Br[CH2:2][C:3]1[CH:4]=[C:5]([C:10]2[CH:15]=[CH:14][C:13]([C:16]#[N:17])=[CH:12][CH:11]=2)[CH:6]=[C:7]([Cl:9])[CH:8]=1.[OH:18][CH2:19][C:20]1([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[CH2:25][CH2:24][N:23]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH2:22][CH2:21]1.[H-].[Na+]>CN(C)C=O.O>[Cl:9][C:7]1[CH:8]=[C:3]([CH2:2][O:18][CH2:19][C:20]2([C:33]3[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=3)[CH2:25][CH2:24][N:23]([C:26]([O:28][C:29]([CH3:31])([CH3:32])[CH3:30])=[O:27])[CH2:22][CH2:21]2)[CH:4]=[C:5]([C:10]2[CH:15]=[CH:14][C:13]([C:16]#[N:17])=[CH:12][CH:11]=2)[CH:6]=1
Reactant: CC(C)(C)OC(=O)N1CCC(CO)(c2ccccc2)CC1
Reactant: N#Cc1ccc(-c2cc(Cl)cc(CBr)c2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC(COCc2cc(Cl)cc(-c3ccc(C#N)cc3)c2)(c2ccccc2)CC1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
3′-(Bromomethyl)-5′-chlorobiphenyl-4-carbonitrile (38.3 mg, 0.12 mmol) and tert-butyl 4-(hydroxymethyl)-4-phenylpiperidine-1-carboxylate (30.3 mg, 0.1 mmol) were combined in dimethylformamide (2 mL) and cooled to 0° C. The reaction was treated with sodium hydride (5 mg, 0.2 mmol), stirred at 0° C. for 1 h, and at room temperature for 30 min. The reaction mixture was diluted with water and extracted with ethyl acetate (2×). The organic layers were pooled together, washed with brine (2×), dried over sodium sulfate, and concentrated. Column chromatography on silica gel (25% ethyl acetate/hexanes) gave 35 mg (56%). 1H-NMR (CDCl3, 300 MHz) δ 7.71 (s, 1H), 7.68 (s, 1H), 7.55 (s, 1H), 7.52 (s, 1H), 7.39 (s, 1H), 7.28-7.35 (m, 4H), 7.19-7.21 (m, 1H), 7.10-7.13 (m, 2H), 4.36 (s, 2H), 3.69-3.76 (m, 2H), 3.41 (s, 2H), 2.97-3.06 (m, 2H), 2.15-2.19 (m, 2H), 1.80-1.90 (m, 2H), 1.40 (s, 9H). Mass spec.: 517.21 (MH)+.
Reaction SMILES: Cl.[F:2][C:3]1[CH:4]=[C:5]([CH:26]=[CH:27][CH:28]=1)[CH2:6][O:7][C:8]1[CH:13]=[CH:12][C:11]([NH:14][C:15]2[C:24]3[C:19](=[CH:20][CH:21]=[C:22](I)[CH:23]=3)[N:18]=[CH:17][N:16]=2)=[CH:10][CH:9]=1.[CH:29]([O-])=[O:30].[Na+].C(N(CC)CC)C>CN(C)C=O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[F:2][C:3]1[CH:4]=[C:5]([CH:26]=[CH:27][CH:28]=1)[CH2:6][O:7][C:8]1[CH:13]=[CH:12][C:11]([NH:14][C:15]2[C:24]3[C:19](=[CH:20][CH:21]=[C:22]([CH:29]=[O:30])[CH:23]=3)[N:18]=[CH:17][N:16]=2)=[CH:10][CH:9]=1
Reactant: O=C[O-]
Reactant: Fc1cccc(COc2ccc(Nc3ncnc4ccc(I)cc34)cc2)c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: Cl
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: O=Cc1ccc2ncnc(Nc3ccc(OCc4cccc(F)c4)cc3)c2c1
Temperature: 80 °C
Yield: 77.8 %

Procedure:
In 100 ml of dimethylformamide was dissolved 4-(4-(3-fluorobenzyloxy)phenylamino)-6-iodoquinazoline hydrochloride (III-1, 5.0 g), and 1.25 g of sodium formate, dichlorobis(triphenylphosphine)palladium (324 mg), and triethylamine (3.2 ml) were added. The reaction mixture was degassed, and stirred under heating at 80° C. for 3 hours under the carbon monoxide atmosphere. Thereafter, the reaction mixture was poured into ice water, and extracted with ethyl acetate. The extract was washed with water and sodium chloride solution, and dried with magnesium sulfate. The dried solution was filtered with Celite, concentrated, and powdered with an ethyl acetate-hexane (1:2) to obtain 4-(4-(3-fluorobenzyloxy)phenylamino)-6-formylquinazoline (IV-1, 2.86 g) as a yellow solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[C:5]#[N:6].[CH2:10]([OH:12])[CH3:11].Cl>>[ClH:1].[Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[C:5](=[NH:6])[O:12][CH2:10][CH3:11]
Reactant: CCO
Reactant: N#Cc1cccc(Cl)c1
Agent: Cl
Product: CCOC(=N)c1cccc(Cl)c1
Temperature: 25 °C
Reaction time: 54 h
Yield: 84 %

Procedure:
A 500-mL round bottomed flask was charged with 3-chlorobenzonitrile (23.3 g, 169 mmol, 1 eq.), ethanol (8.48 g, 184 mmol, 1.09 eq.), and HCl (4 N in dioxane, 169 mL, 676 mmol, 4 eq.). The resulting mixture was stirred at room temperature for 54 hr. The volatile material was removed under reduced pressure and the residue was treated with ether. The resulting solid was collected by filtration and washed with ether. The product was used in the next step without further purification (26.9 g, 84% yield). 1H NMR (DMSO-d6, 500 MHz) δ 12.0 (br s, 2H), 8.25-8.20 (m, 1H), 8.12-8.08 (m, 1H), 7.90-7.85 (m, 1H), 7.67 (t, J=8.0 Hz, 1H), 4.63 (q, J=7.0 Hz, 2H), 1.48 (t, J=7.0 Hz, 3H).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:17])[C:5]([O:8][C:9]1[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][C:10]=1[CH3:16])([CH3:7])[CH3:6])[CH3:2].[F:18][C:19]([F:33])([F:32])[C:20]1[CH:21]=[C:22]([C:26]#[C:27][CH2:28][CH2:29][CH2:30]O)[CH:23]=[CH:24][CH:25]=1.CN(C)C(N=NC(N(C)C)=O)=O.C(P(CCCC)CCCC)CCC>>[CH2:1]([O:3][C:4](=[O:17])[C:5]([CH3:6])([O:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH2:30][CH2:29][CH2:28][C:27]#[C:26][C:22]2[CH:23]=[CH:24][CH:25]=[C:20]([C:19]([F:18])([F:32])[F:33])[CH:21]=2)=[CH:11][C:10]=1[CH3:16])[CH3:7])[CH3:2]
Reactant: CCOC(=O)C(C)(C)Oc1ccc(O)cc1C
Reactant: OCCCC#Cc1cccc(C(F)(F)F)c1
Agent: CCCCP(CCCC)CCCC
Agent: CN(C)C(=O)N=NC(=O)N(C)C
Product: CCOC(=O)C(C)(C)Oc1ccc(OCCCC#Cc2cccc(C(F)(F)F)c2)cc1C

Procedure:
In analogy to the procedure described for example 21A], 2-(4-hydroxy-2-methyl-phenoxy)-2-methyl-propionic acid ethyl ester (described in WO 02/092590) was reacted with 5-(3-trifluoromethyl-phenyl)-pent-4-yn-1-ol in the presence of N,N,N′,N′-tetramethyl azodicarboxamide and tributylphosphine to give the title compound as colorless oil.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([CH2:14][C:15]1[CH:24]=[CH:23][C:22]2[C:17](=[CH:18][CH:19]=[C:20]([O:25][C@H:26]3[CH2:31][CH2:30][C@H:29]([C:32]([CH3:35])([CH3:34])[CH3:33])[CH2:28][CH2:27]3)[CH:21]=2)[CH:16]=1)[CH2:9][CH2:10][C:11](O)=[O:12])=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH4+:36].[Cl-].CCN(CC)CC.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>C1COCC1>[NH2:36][C:11](=[O:12])[CH2:10][CH2:9][N:8]([CH2:14][C:15]1[CH:24]=[CH:23][C:22]2[C:17](=[CH:18][CH:19]=[C:20]([O:25][C@H:26]3[CH2:27][CH2:28][C@H:29]([C:32]([CH3:35])([CH3:34])[CH3:33])[CH2:30][CH2:31]3)[CH:21]=2)[CH:16]=1)[C:6](=[O:7])[O:5][C:1]([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N(CCC(=O)O)Cc1ccc2cc(O[C@H]3CC[C@H](C(C)(C)C)CC3)ccc2c1
Reactant: [NH4+]
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: [Cl-]
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N(CCC(N)=O)Cc1ccc2cc(O[C@H]3CC[C@H](C(C)(C)C)CC3)ccc2c1
Temperature: 45 °C
Reaction time: 0.25 h

Procedure:
The mixture of 3-(tert-butoxycarbonyl((6-((trans)-4-tert-butylcyclohexyloxy)naphthalen-2-yl)methyl)amino)propanoic acid (483 mg, 1.0 mmol), NH4Cl (215 mg, 5.0 mmol, 5.0 equiv), Et3N (510 mg, 5.0 mmol, 5.0 equiv) and HATU (760 mg, 2.0 mmol, 2.0 equiv) in anhydrous THF (20 mL) was stirred at 45° C. for 15 min. The reaction mixture was concentrated in vacuum and the residue was purified by chromatography with silica gel (DCM/MeOH=20/1) to give compound the title compound as a white solid (337 mg, yield: 70%). ESI-MS (M+H+): 483.3. 1H NMR (400 MHz, DMSO-d6) δ: 7.76 (d, 2H), 7.60 (s, 1H), 7.34 (s, 1H), 7.30 (d, 1H), 7.12 (dd, 1H), 4.49 (s, 2H), 4.38-4.31 (m, 1H), 3.30 (t, 2H), 2.30 (t, 2H), 2.19 (d, 2H), 1.81 (d, 2H), 1.45-1.33 (m, 11H), 1.23-1.16 (m, 3H), 0.88 (s, 9H).
Reaction SMILES: [CH2:1]([C:7]1[N:8]([CH2:20][CH2:21][CH2:22][CH2:23][NH2:24])[C:9]2[C:18]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[N:12]=[CH:11][C:10]=2[N:19]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].[C:25]1([S:31](Cl)(=[O:33])=[O:32])[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>>[CH2:1]([C:7]1[N:8]([CH2:20][CH2:21][CH2:22][CH2:23][NH:24][S:31]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)(=[O:33])=[O:32])[C:9]2[C:18]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[N:12]=[CH:11][C:10]=2[N:19]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: CCCCCCc1nc2cnc3ccccc3c2n1CCCCN
Product: CCCCCCc1nc2cnc3ccccc3c2n1CCCCNS(=O)(=O)c1ccccc1
Yield: 43.6 %

Procedure:
Using the general method of Example 233 Part B except that the reaction was run at ambient temperature, 4-(2-hexyl-1H-imidazo[4,5-c]quinolin-1-yl)butan-1-amine (1.20 g, 3.7 mmol) was reacted with benzenesulfonyl chloride (429 μL, 3.7 mmol) to provide 0.75 g of N-[4-(2-hexyl-1H-imidazo[4,5-c]quinolin-1-yl)butyl]benzenesulfonamide as a light yellow solid, m.p. 137.0-138.1° C.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7]([O:9][CH2:10][CH3:11])=[O:8])[C:2]=1[C:12]([O:14][CH2:15][CH3:16])=[O:13].S(=O)(=O)(O)[OH:18].OO>C(O)(=O)C>[N+:1]1([O-:18])[CH:6]=[CH:5][CH:4]=[C:3]([C:7]([O:9][CH2:10][CH3:11])=[O:8])[C:2]=1[C:12]([O:14][CH2:15][CH3:16])=[O:13]
Reactant: O=S(=O)(O)O
Reactant: CCOC(=O)c1cccnc1C(=O)OCC
Agent: OO
Solvent: CC(=O)O
Product: CCOC(=O)c1ccc[n+]([O-])c1C(=O)OCC

Procedure:
A mixture of 99 g of diethyl pyridine-2,3-dicarboxylate, 7.2 mL of concentrated sulfuric acid, 85 mL of 30% hydrogen peroxide and 256 mL acetic acid is stirred and heated at 85° for 4 hours. The reaction is concentrated in vacuo, and the residue is dissolved in methylene chloride, and washed with water, then saturated sodium bicarbonate. After drying, the organic phase is concentrated in vacuo to afford 79 g of the desired product, mp 80°-85°. A portion recrystallized from carbon tetrachloride-pentane has mp 87°-88°.
Reaction SMILES: CO[C:3]1[CH:4]=[C:5]([CH2:9][CH2:10][NH:11][CH:12]=[O:13])[CH:6]=[CH:7][CH:8]=1.[CH3:14][S:15]C1C=C(CCN)C=CC=1.C(OC=O)C>>[CH3:14][S:15][C:3]1[CH:4]=[C:5]([CH2:9][CH2:10][NH:11][CH:12]=[O:13])[CH:6]=[CH:7][CH:8]=1
Reactant: COc1cccc(CCNC=O)c1
Reactant: CSc1cccc(CCN)c1
Solvent: CCOC=O
Product: CSc1cccc(CCNC=O)c1
Yield: 78 %

Procedure:
A procedure identical to that described for the preparation of N-[2-(3-methoxy-phenyl)-ethyl]-formamide in Example 1 was followed using 2-(3-methylsulfanyl-phenyl)-ethylamine (7.4 g, 44 mmol) and formic acid ethyl ester (3.6 g, 48 mmol) to give the desired product (6.7 g, 78%). MS: 168.9 (M+1+).