Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][CH2:4][C:5]1[N:6]([CH2:18][C:19]2([NH:25]C(=O)OC(C)(C)C)[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]2)[C:7]2[C:16]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[N:10]=[CH:9][C:8]=2[N:17]=1)[CH3:2].Cl>C(O)C>[CH2:1]([O:3][CH2:4][C:5]1[N:6]([CH2:18][C:19]2([NH2:25])[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]2)[C:7]2[C:16]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[N:10]=[CH:9][C:8]=2[N:17]=1)[CH3:2]
Reactant: CCOCc1nc2cnc3ccccc3c2n1CC1(NC(=O)OC(C)(C)C)CCCCC1
Agent: Cl
Solvent: CCO
Product: CCOCc1nc2cnc3ccccc3c2n1CC1(N)CCCCC1
Temperature: 65 °C
Yield: 79.5 %

Procedure:
To a solution of tert-butyl 1-{[2-(ethoxymethyl)-1H-imidazo[4,5-c]quinolin-1-yl]methyl}cyclohexylcarbamate (24.6 g, 56.1 mmol) in ethanol (100 mL) was added 2.7 M HCl in ethanol (150 mL). The solution was heated at 65° C. for 4 h, the was allowed to cool to rt overnight. A light brown precipitate was isolated by filtration and washed with ethanol. The precipitate was dissolved in water (100 mL) and NaOH was added until the pH=14. The mixture was extracted with dichloromethane (3×200 mL). The organic layers were combined, dried over Na2SO4, filtered, and concentrated to an oil that was dissolved in ethanol (100 mL). To the ethanol solution was added 2.7 M HCl in ethanol (18.7 mL). A pale tan solid crashed out of solution and was isolated by filtration and dried. The solid was dissolved in water (100 mL) and NaOH was added until the pH=14. The mixture was extracted with dichloromethane (3×200 mL). The organic layers were combined, dried over Na2SO4, filtered, and concentrated to yield 1-{[2-(ethoxymethyl)-1H-imidazo[4,5-c]quinolin-1-yl]methyl}cyclohexanamine as a light yellow oil (15.1 g, 79%).
Reaction SMILES: C([O:3][CH:4](OCC)[CH2:5][N:6]([CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][O:25][CH2:26][CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[C:7](=[O:19])[CH2:8][CH2:9][O:10][CH2:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)C.Cl.ClCCl>O1CCOCC1>[O:3]=[CH:4][CH2:5][N:6]([CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][O:25][CH2:26][CH2:27][C:28]1[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=1)[C:7](=[O:19])[CH2:8][CH2:9][O:10][CH2:11][CH2:12][C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: CCOC(CN(CCCCCOCCc1ccccc1)C(=O)CCOCCc1ccccc1)OCC
Agent: Cl
Solvent: ClCCl
Solvent: C1COCCO1
Product: O=CCN(CCCCCOCCc1ccccc1)C(=O)CCOCCc1ccccc1

Procedure:
N-(2,2-Diethoxyethyl)-3-phenethyloxy-N-(5-phenethyloxypentyl)propanamide (Example 9b), 0.18 g) was dissolved in anhydrous dioxane (5 mL) and treated with concentrated hydrochloric acid (5 mL) at room temperature. The resultant solution was stirred for 1 hour and then poured into dichloromethane (10 mL), washed with water (2×10 mL) and brine (10 mL). The organic layer was isolated, dried over anhydrous magnesium sulphate, filtered and concentrated to give the sub-titled compound (0.12 g) as a viscous oil.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:26])[CH:5]([N+:23]([O-])=O)[CH:6]([C:10]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][C:17]=2[CH2:19][O:20][CH2:21][CH3:22])[NH:12][CH:11]=1)[CH2:7][O:8][CH3:9])[CH3:2]>C(O)C.[Ni]>[CH2:1]([O:3][C:4](=[O:26])[CH:5]([NH2:23])[CH:6]([C:10]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][C:17]=2[CH2:19][O:20][CH2:21][CH3:22])[NH:12][CH:11]=1)[CH2:7][O:8][CH3:9])[CH3:2]
Reactant: CCOCc1cccc2[nH]cc(C(COC)C(C(=O)OCC)[N+](=O)[O-])c12
Agent: [Ni]
Solvent: CCO
Product: CCOCc1cccc2[nH]cc(C(COC)C(N)C(=O)OCC)c12
Yield: 78.5 %

Procedure:
Ethyl-3-(4-ethoxymethylindol-3-yl)-4-methoxy-2-nitrobutyrate (11.1 g) in ethanol (350 ml) was catalytically hydrogenated with Raney-nickel at room temperature under atmospheric pressure. The product obtained after filtration of the catalyst and evaporation of the solvent, was dissolved in a mixture of diethylether and ethylacetate. The solution was treated with water and evaporated. 8 g of oily ethyl-2-amino-3-(4-ethoxymethylindol-3-yl)-4-methoxybutyrate were obtained.
Reaction SMILES: [Cl:1][C:2]1[S:3][CH:4]=[C:5]([Cl:7])[N:6]=1.[Cl:8][S:9](O)(=[O:11])=[O:10]>>[Cl:1][C:2]1([S:9]([Cl:8])(=[O:11])=[O:10])[NH:6][C:5]([Cl:7])=[CH:4][S:3]1
Reactant: O=S(=O)(O)Cl
Reactant: Clc1csc(Cl)n1
Product: O=S(=O)(Cl)C1(Cl)NC(Cl)=CS1

Procedure:
can be prepared in a process in which, in a first step, 2,4-dichloro-thiazole is reacted with chlorosulphonic acid to give 2,4-dichloro-thiazole-sulphonyl chloride, in which, in a second step, the 2,4-dichloro-thiazole-sulphonyl chloride is reacted with primary amines or with a primary and a secondary amine to give 2-amino-4-chloro-thiazole-sulphonamides, and in which, in a third step, the sulphonamides mentioned are reacted with dichlorohalogenomethylsulphenyl chlorides to give the substances of the formula (I).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([CH:8]([CH3:13])[CH2:9][C:10](O)=[O:11])[CH:5]=[CH:4][C:3]=1[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-].C(OCC)(=O)C.Cl>O1CCCC1.O>[F:1][C:2]1[CH:7]=[C:6]([CH:8]([CH3:13])[CH2:9][CH2:10][OH:11])[CH:5]=[CH:4][C:3]=1[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: CC(CC(=O)O)c1ccc(-c2ccccc2)c(F)c1
Agent: Cl
Agent: [Al+3]
Agent: [H-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: O
Product: CC(CCO)c1ccc(-c2ccccc2)c(F)c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A solution of 25.83 gm (0.10 mol) of 3-(2-fluoro-4-biphenylyl)-butyric acid in 100 ml of absolute tertrahydrofuran was added dropwise at room temperature to a stirred suspension of 2.85 gm (0.075 mol) of lithium aluminum hydride in 100 ml of absolute tetrahydrofuran, the resulting mixture was stirred for 60 minutes more at room temperature and for 30 minutes at 30°-35°C, and then ethyl acetate was added dropwise until no more exothermic reaction occurred. The reaction mixture was then stirred for 15 minutes at room temperature, and thereafter first 50 ml of water and then aqueous 5% hydrochloric acid were added dropwise, accompanied by exterior cooling with ice water, until the precipitate first formed dissolved. The solution was stirred into 2 liters of water, extracted exhaustively with ether, and the combined ether extracts were washed successively with water, saturated aqueous sodium bicarbonate solution and again with water, dried over sodium sulfate, filtered, and evaporated. 18.0 gm (74% of theory) of colorless 3-(2-fluoro-4-biphenylyl)-1-butanol of the formula ##EQU25## which had a melting point of 72°C after recrystallization from cyclohexane.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8](=O)[CH3:9].[C:11]([O:15][CH2:16][CH3:17])(=[O:14])[NH:12][NH2:13].O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[CH2:16]([O:15][C:11]([NH:12][N:13]=[C:8]([C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[CH3:1])[CH3:9])=[O:14])[CH3:17]
Reactant: CC(=O)c1ccccc1C
Reactant: CCOC(=O)NN
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: O
Product: CCOC(=O)NN=C(C)c1ccccc1C

Procedure:
A solution of 2′-methylacetophenone (0.98 ml, 7.4 mmol), ethyl carbazate (0.81 g, 7.8 mmol) and p-toluenesulfonic acid monohydrate (70 mg, 0.37 mmol) in toluene (30 ml) was heated at reflux temperature with a Dean-Stark apparatus for 2 h. Solvent evaporation and flash chromatography (silica gel, hexane-ethyl acetate, 80:20) gave N′-(1-o-tolyl-ethylidene)-hydrazinecarboxylic acid ethyl ester; 1H NMR (CDCl3, 400 MHz) δ 7.72 (bs, 1H), 7.21 (m, 4H), 4.31 (q, 2H, J=7.1 Hz), 2.37 (s, 3H), 2.17 (s, 3H), 1.34 (t, 3H, J=7.1 Hz).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]=[C:9]=[O:10].[NH2:11][C:12]1[C:13]2[C:20]([C:21]([C:23]3[CH:28]=[CH:27][N:26]=[C:25]([NH2:29])[CH:24]=3)=[O:22])=[CH:19][N:18]([CH:30]([CH3:32])[CH3:31])[C:14]=2[N:15]=[CH:16][N:17]=1>N1C=CC=CC=1>[NH2:11][C:12]1[C:13]2[C:20]([C:21]([C:23]3[CH:28]=[CH:27][N:26]=[C:25]([NH:29][C:9]([NH:8][C:3]4[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=4[F:1])=[O:10])[CH:24]=3)=[O:22])=[CH:19][N:18]([CH:30]([CH3:32])[CH3:31])[C:14]=2[N:15]=[CH:16][N:17]=1
Reactant: CC(C)n1cc(C(=O)c2ccnc(N)c2)c2c(N)ncnc21
Reactant: O=C=Nc1ccccc1F
Solvent: c1ccncc1
Product: CC(C)n1cc(C(=O)c2ccnc(NC(=O)Nc3ccccc3F)c2)c2c(N)ncnc21
Temperature: 80 °C
Yield: 55.1 %

Procedure:
1-Fluoro-2-isocyanato-benzene (0.09 mL, 0.81 mmol) was added to a solution of (4-Amino-7-isopropyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-(2-amino-pyridin-4-yl)-methanone (0.20 g, 0.67 mmol) in pyridine (2 mL). The mixture was heated to 80° C. in a sealed tube for 2 h. The reaction mixture was quenched with water (10 mL) and extracted with hot EtOAc/MeOH (95:5, 3×10 mL). The combined organic extracts were dried (Na2SO4), filtered, and concentrated in vacuo. Purification by flash column chromatography (ethyl acetate/MeOH 99:1) afforded the title compound as a yellow solid (160 mg, 55%). MS: 434.2 (MH+); HPLC Rf: 5.83 min. (HPLC method 4); HPLC purity: 98%.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([O:7][C:8]2[CH:9]=[C:10]3[C:15](=[CH:16][CH:17]=2)[C:14]([C:18](Cl)=[O:19])=[CH:13][CH:12]=[CH:11]3)=[CH:3][CH:2]=1.C([O-])(O)=O.[Na+].[Cl:26][C:27]1[CH:28]=[C:29]([CH:31]=[CH:32][CH:33]=1)[NH2:30]>C(Cl)Cl.C(Cl)(Cl)Cl.O>[Cl:26][C:27]1[CH:28]=[C:29]([NH:30][C:18]([C:14]2[C:15]3[C:10](=[CH:9][C:8]([O:7][C:4]4[CH:5]=[CH:6][N:1]=[CH:2][CH:3]=4)=[CH:17][CH:16]=3)[CH:11]=[CH:12][CH:13]=2)=[O:19])[CH:31]=[CH:32][CH:33]=1
Reactant: O=C(Cl)c1cccc2cc(Oc3ccncc3)ccc12
Reactant: Nc1cccc(Cl)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: O
Solvent: ClCCl
Product: O=C(Nc1cccc(Cl)c1)c1cccc2cc(Oc3ccncc3)ccc12
Temperature: 25 °C
Reaction time: 1 h

Procedure:
6-(Pyridin-4-yloxy)-1-naphthoyl chloride (50 mg, 0.18 mmol) was suspended in CH2Cl2 and solid NaHCO3 (excess) was added. The mixture was blanketed with nitrogen and 3-chloroaniline (18.6 μL, 0.18 mmol) was added and the reaction mixture stirred at RT for 1 h. The reaction mixture was diluted with CHCl3 and water (using heat to dissolve the solids) and the organic layer further washed with brine, dried with Na2SO4, filtered and concentrated in-vacuo. The residue was crystallized from CH2Cl2/hexanes to give the title compound as a brown solid. MS (ESI pos. ion) m/z: 375.1 (M+H). Cal'd for C22H15ClN2O2-374.82.
Reaction SMILES: Cl[C:2]1[C:7]2[C:8]([CH3:12])=[C:9]([CH3:11])[NH:10][C:6]=2[CH:5]=[CH:4][N:3]=1.[CH2:13]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH2:16][CH2:15][NH:14]1>>[CH3:11][C:9]1[NH:10][C:6]2[CH:5]=[CH:4][N:3]=[C:2]([N:14]3[CH2:15][CH2:16][C:17]4[C:22](=[CH:21][CH:20]=[CH:19][CH:18]=4)[CH2:13]3)[C:7]=2[C:8]=1[CH3:12]
Reactant: Cc1[nH]c2ccnc(Cl)c2c1C
Reactant: c1ccc2c(c1)CCNC2
Product: Cc1[nH]c2ccnc(N3CCc4ccccc4C3)c2c1C
Temperature: 160 °C
Reaction time: 12 h
Yield: 77.1 %

Procedure:
A mixture of 4-chloro-2,3-dimethyl-1H-pyrrolo[3,2-c]pyridine (1.49 g, 8.25 mmol) prepared in Preparation 1 and 1,2,3,4-tetrahydroisoquinoline (4 ml) was stirred for 12 hours at 160° C. The reaction mixture was cooled to room temperature and purified with silica gel column chromatography (ethyl acetate) to give the titled compound as a white solid. (Yield: 77.1%)
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([C:15]#[N:16])=[CH:11][CH:10]=2)[N:5]=[C:4]([O:17][C:18]2[C:25]([CH3:26])=[CH:24][C:21]([C:22]#[N:23])=[CH:20][C:19]=2[CH3:27])[CH:3]=1.[Br:28]Br.[OH-].[Na+].S(S([O-])=O)([O-])(=O)=O.[Na+].[Na+]>ClCCl.O>[CH3:27][C:19]1[CH:20]=[C:21]([C:22]#[N:23])[CH:24]=[C:25]([CH3:26])[C:18]=1[O:17][C:4]1[N:5]=[C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([C:15]#[N:16])=[CH:11][CH:10]=2)[N:7]=[C:2]([NH2:1])[C:3]=1[Br:28]
Reactant: BrBr
Reactant: Cc1cc(C#N)cc(C)c1Oc1cc(N)nc(Nc2ccc(C#N)cc2)n1
Agent: O=S([O-])S(=O)(=O)[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: O
Product: Cc1cc(C#N)cc(C)c1Oc1nc(Nc2ccc(C#N)cc2)nc(N)c1Br
Temperature: 2.5 °C
Reaction time: 4 h

Procedure:
4-[[6-amino-2-[(4-cyanophenyl)amino]-4-pyrimidinyl]oxy]-3,5-dimethyl-benzonitrile (10 gm) was dissolved in dichloromethane (100 ml) at 0 to 5° C. and then added bromine solution (4.7 gm in 50 ml of dichloromethane). The reaction mass was stirred for 4 hours at 0 to 5° C. and then added water (100 ml). The pH of the reaction mass was adjusted to 9 to 10 with sodium hydroxide solution (4N, 10 ml). Sodium metabisulphite solution (0.5 gm in 2 ml of water) was added to the reaction mass and pH of the reaction mass was maintained between 7.5 to 8.5 with sodium hydroxide solution (4N, 10 ml). The separated solid was filtered and dried at 50 to 55° C. to obtain crude etravirine.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:25]=[CH:26][N:27]=1)[C:5]([NH:7][C:8]1[S:9][C:10]2[C:16]([N:17]3[CH2:22][CH2:21][O:20][CH2:19][CH2:18]3)=[CH:15][CH:14]=[C:13]([O:23][CH3:24])[C:11]=2[N:12]=1)=[O:6].C(=O)([O-])[O-].[Cs+].[Cs+].[OH:34][CH:35]1[CH2:40][CH2:39][CH2:38][NH:37][CH2:36]1>>[OH:34][CH:35]1[CH2:40][CH2:39][CH2:38][N:37]([C:2]2[CH:3]=[C:4]([CH:25]=[CH:26][N:27]=2)[C:5]([NH:7][C:8]2[S:9][C:10]3[C:16]([N:17]4[CH2:22][CH2:21][O:20][CH2:19][CH2:18]4)=[CH:15][CH:14]=[C:13]([O:23][CH3:24])[C:11]=3[N:12]=2)=[O:6])[CH2:36]1
Reactant: COc1ccc(N2CCOCC2)c2sc(NC(=O)c3ccnc(Br)c3)nc12
Reactant: OC1CCCNC1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Product: COc1ccc(N2CCOCC2)c2sc(NC(=O)c3ccnc(N4CCCC(O)C4)c3)nc12

Procedure:
From 2-bromo-N-(4-methoxy-7-morpholin-4-yl-benzothiazol-2-yl)-isonicotinamide with cesium carbonate and 3-hydroxy-piperidine. ES-MS m/e (%): 470 (M+H+, 100).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([OH:12])=[C:6]([CH:11]=1)[C:7]([O:9]C)=O.O[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][NH:19][C:20](=[O:26])[O:21][C:22]([CH3:25])([CH3:24])[CH3:23]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:12][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][NH:19][C:20](=[O:26])[O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[C:6]([CH2:7][OH:9])[CH:11]=1
Reactant: COC(=O)c1cc(Cl)ccc1O
Reactant: CC(C)(C)OC(=O)NCCCCCO
Product: CC(C)(C)OC(=O)NCCCCCOc1ccc(Cl)cc1CO

Procedure:
Intermediate I-31 was prepared from methyl 5-chloro-2-hydroxybenzoate and tert-butyl 5-hydroxypentylcarbamate analogously to Examples 24-26.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]([NH:10][C:11]2[S:12][C:13]([N:21]3[CH2:26][CH2:25][O:24][CH2:23][CH2:22]3)=[C:14]([C:16]3[O:17][CH:18]=[CH:19][CH:20]=3)[N:15]=2)=[O:9])[CH:5]=[CH:4][N:3]=1.[CH3:27][N:28]1[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]1.O>CN1C(=O)CCC1>[O:17]1[CH:18]=[CH:19][CH:20]=[C:16]1[C:14]1[N:15]=[C:11]([NH:10][C:8]([C:6]2[CH:5]=[CH:4][N:3]=[C:2]([N:31]3[CH2:32][CH2:33][N:28]([CH3:27])[CH2:29][CH2:30]3)[CH:7]=2)=[O:9])[S:12][C:13]=1[N:21]1[CH2:26][CH2:25][O:24][CH2:23][CH2:22]1
Reactant: O=C(Nc1nc(-c2ccco2)c(N2CCOCC2)s1)c1ccnc(Cl)c1
Reactant: CN1CCNCC1
Solvent: CN1CCCC1=O
Solvent: O
Product: CN1CCN(c2cc(C(=O)Nc3nc(-c4ccco4)c(N4CCOCC4)s3)ccn2)CC1
Temperature: 150 °C
Reaction time: 8 h
Yield: 4.9 %

Procedure:
Compound 39 (391 mg, 1.00 mmol) was dissolved in NMP (10 mL), and 1-methylpiperazine (1.11 mL, 10.0 mmol) was added thereto, followed by stirring overnight at 150° C. The reaction mixture was poured into water, followed by extraction with ethyl acetate. The organic layer was washed with a saturated aqueous solution of sodium chloride and dried over anhydrous magnesium sulfate, and then the solvent was distilled away under reduced pressure. The resulting residue was purified through silica gel column chromatography (chloroform:methanol=19:1) to afford the entitled Compound 41 (22.2 mg, 5%).
Reaction SMILES: Br[C:2]1[C:7]2[C:8](=[O:23])[C:9]3[C:10]([CH:21]=[CH:22][C:6]=2[CH:5]=[CH:4][CH:3]=1)=[N:11][CH:12]=[C:13]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[CH:14]=3.[CH3:24][S-:25].[Na+]>[Cu]Br>[CH3:24][S:25][C:2]1[C:7]2[C:8](=[O:23])[C:9]3[C:10]([CH:21]=[CH:22][C:6]=2[CH:5]=[CH:4][CH:3]=1)=[N:11][CH:12]=[C:13]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[CH:14]=3
Reactant: C[S-]
Reactant: O=c1c2cc(-c3ccccc3)cnc2ccc2cccc(Br)c12
Agent: [Cu]Br
Agent: [Na+]
Product: CSc1cccc2ccc3ncc(-c4ccccc4)cc3c(=O)c12
Temperature: 140 °C
Reaction time: 72 h

Procedure:
6-bromo-3-phenyl-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-5-one (15 mg, 0.04 mmol), sodium thiomethoxide (15 mg, 0.21 mmol) and copper (I) bromide (23 mg, 0.10 mmol) were combined in a dry flask. The flask was purged with argon and 0.5 mL of N,N-dimethylformamide were added. The solution was stirred and heated to 140° C. After 72 h, the reaction mixture was cooled to room temperature, diluted with EtOAc and washed with 5% HCl, brine and water. The organic layer was dried over sodium sulfate, filtered, concentrated and purified by reverse phase HPLC (30-100% acetonitrile/water gradient, 0.1% trifluoroacetic acid modifier) to afford the title compound. 1H NMR (600 MHz, CD3OD) δ 9.14 (d, 1H), 8.58 (d, 1M), 7.78 (d, 2H), 7.65 (m, 2H), 7.54 (t, 2H), 7.47 (m, 3H), 7.27 (d, 1H), 2.49 (s, 3H). LRMS (APCI) calculated for C21H16NOS [M+H]+, 330.0; found 330.1.
Reaction SMILES: [CH2:1]([S:3]([C:6]1[CH:11]=[CH:10][C:9]([C:12]2[C:17]([O:18][CH3:19])=[CH:16][CH:15]=[C:14](B3OC(C)(C)C(C)(C)O3)[CH:13]=2)=[C:8]([F:29])[CH:7]=1)(=[O:5])=[O:4])[CH3:2].Cl[C:31]1[C:32]2[N:39]=[CH:38][N:37]([CH2:40][CH3:41])[C:33]=2[N:34]=[N:35][CH:36]=1.C(=O)([O-])[O-].[Na+].[Na+]>O1CCOCC1.O.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[CH2:40]([N:37]1[C:33]2[N:34]=[N:35][CH:36]=[C:31]([C:14]3[CH:13]=[C:12]([C:9]4[CH:10]=[CH:11][C:6]([S:3]([CH2:1][CH3:2])(=[O:5])=[O:4])=[CH:7][C:8]=4[F:29])[C:17]([O:18][CH3:19])=[CH:16][CH:15]=3)[C:32]=2[N:39]=[CH:38]1)[CH3:41]
Reactant: CCn1cnc2c(Cl)cnnc21
Reactant: CCS(=O)(=O)c1ccc(-c2cc(B3OC(C)(C)C(C)(C)O3)ccc2OC)c(F)c1
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: CCn1cnc2c(-c3ccc(OC)c(-c4ccc(S(=O)(=O)CC)cc4F)c3)cnnc21
Temperature: 110 °C
Yield: 26 %

Procedure:
To 2-(4′-(ethylsulfonyl)-2′-fluoro-6-methoxy-[1,1′-biphenyl]-3-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (Preparation 69, 90 mg, 0.21 mmol) in dioxane (2.5 mL) and water (1 mL) was added 4-chloro-7-ethyl-7H-imidazo[4,5-c]pyridazine (Preparation 8, 40 mg, 0.21 mmol) and sodium carbonate (68 mg, 0.64 mmol). The reaction was degassed and tetrakis(triphenylphosphine) palladium(0) (25 mg, 0.02 mmol) was added. The reaction was further degassed and then heated to 110° C. for 2 hours and then cooled to room temperature. The reaction mixture was diluted with EtOAc (40 mL) was passed through celite and the solvent removed in vacuo. The crude material was purified by reverse phase column chromatography eluting with a gradient of 0.1% formic acid in MeCN/water. The resulting residue was dissolved in DMSO (1 mL) and purified using preparative HPLC to give the title compound as a colourless solid in 26% yield, 24 mg.
Reaction SMILES: F[C:2]1[CH:9]=[C:8]([CH3:10])[CH:7]=[CH:6][C:3]=1[C:4]#[N:5].[H-].[Na+].[CH:13]([OH:16])([CH3:15])[CH3:14]>>[CH:13]([O:16][C:2]1[CH:9]=[C:8]([CH3:10])[CH:7]=[CH:6][C:3]=1[C:4]#[N:5])([CH3:15])[CH3:14]
Reactant: Cc1ccc(C#N)c(F)c1
Reactant: CC(C)O
Agent: [H-]
Agent: [Na+]
Product: Cc1ccc(C#N)c(OC(C)C)c1
Temperature: 50 °C

Procedure:
The 2-fluoro-4-methyl-benzonitrile (0.8 g, 3.99 mmol) was added in small portion to a mixture of NaH 60% (4 mol eq, 0.61 g) in isopropanol (30 mL). The reaction mixture was heated at 50° C. overnight. The solvent was distilled and water was added to the residue. The aqueous solution was extracted with EtOAc (3×25 mL) and the organic phases were evaporated at reduced pressure to give 30a as a deliquescent white solid (1.09 g, 6.22 mmol). 1HNMR (DMSO, 200 MHz) δ 1.21 (s, 3H), 1.28 (s, 3H), 2.10 (s, 3H), 4.89 (m, 1H), 7.41 (d, 1H), 7.55 (s, 1H), 7.89 (m, 1H).
Reaction SMILES: C1(C)C=CC=CC=1.[CH2:8]([NH:10][CH2:11][CH3:12])[CH3:9].[CH3:13][O:14][C:15]1[CH:23]=[CH:22][CH:21]=[CH:20][C:16]=1[C:17](Cl)=[O:18].Cl.C(NCC)C>O>[CH2:8]([N:10]([CH2:11][CH3:12])[C:17](=[O:18])[C:16]1[CH:20]=[CH:21][CH:22]=[CH:23][C:15]=1[O:14][CH3:13])[CH3:9]
Reactant: COc1ccccc1C(=O)Cl
Reactant: CCNCC
Agent: Cl
Solvent: Cc1ccccc1
Solvent: O
Product: CCN(CC)C(=O)c1ccccc1OC
Temperature: 0 °C
Yield: 94 %

Procedure:
Into a three-necked flask (200 ml), a toluene solution (56 g) containing diethylamine (25.80 g; 0.352 moles) was placed. While the flask was cooled with ice water and the solution was stirred, a toluene solution (30 g) of 2-methoxybenzoyl chloride (2.00 g; 0.117 moles) was added dropwise over 30 minutes. After the addition was completed, water was added to the resultant mixture, and diethylamine and diethylamine hydrochloride in excess amounts were removed. The obtained toluene layer was dehydrated with MgSO4. Then, the solvent was removed by distillation, and a light yellow liquid was obtained (the obtained amount: 22.81 g; the yield: 94%).
Reaction SMILES: [C:1]([CH2:4][O:5][C:6](=[O:20])[C@:7]([NH:18][NH2:19])([CH3:17])[CH2:8][C:9]1[CH:14]=[CH:13][C:12]([OH:15])=[C:11]([OH:16])[CH:10]=1)(O)=O.BrCC[CH2:24][C:25]([O:27]CC1C=CC(OC)=CC=1OC)=[O:26]>>[OH:16][C:11]1[CH:10]=[C:9]([CH2:8][C@@:7]([NH:18][NH2:19])([CH3:17])[C:6]([O:5][CH2:4][CH2:1][CH2:24][C:25]([OH:27])=[O:26])=[O:20])[CH:14]=[CH:13][C:12]=1[OH:15]
Reactant: C[C@@](Cc1ccc(O)c(O)c1)(NN)C(=O)OCC(=O)O
Reactant: COc1ccc(COC(=O)CCCBr)c(OC)c1
Product: C[C@@](Cc1ccc(O)c(O)c1)(NN)C(=O)OCCCC(=O)O
Yield: 41 %

Procedure:
Following the procedure described for preparation of compound 229, and substituting tert-butyl bromomethyl acetate with 2,4-dimethoxybenzyl γ-bromobutyrate, provided the title compound (41% over 2 steps) as a colorless thick liquid. 1H NMR (400 MHz, CD3OD): δ1.45 (3H, s), 1.95 (2H, q), 2.35 (2H, t), 2.86(2H, m), 4.21 (2H, m), 6.46 (1H, dd), 6.56(1H, d), 6.68 (1H, d). MS (ESI) m/z 313.21 (M+H+) and 311.18 (M−H−).
Reaction SMILES: [CH3:1][CH:2]([CH3:32])[CH2:3][C@H:4]([NH:21][C:22]1[CH:31]=[CH:30][C:25]([C:26]([O:28]C)=[O:27])=[CH:24][N:23]=1)[C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:13][N:12]=2)=[CH:7][CH:6]=1.O1CCCC1.[OH-].[Li+]>CO>[CH3:1][CH:2]([CH3:32])[CH2:3][C@H:4]([NH:21][C:22]1[CH:31]=[CH:30][C:25]([C:26]([OH:28])=[O:27])=[CH:24][N:23]=1)[C:5]1[CH:6]=[CH:7][C:8]([C:11]2[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:18])[F:19])=[CH:13][N:12]=2)=[CH:9][CH:10]=1
Reactant: COC(=O)c1ccc(N[C@@H](CC(C)C)c2ccc(-c3ccc(C(F)(F)F)cn3)cc2)nc1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: CC(C)C[C@H](Nc1ccc(C(=O)O)cn1)c1ccc(-c2ccc(C(F)(F)F)cn2)cc1
Temperature: 50 °C

Procedure:
A mixture of (S)-methyl 6-[(3-methyl-1-{4-[5-(trifluoromethyl)pyridin-2-yl]phenyl}butyl)amino]nicotinate (53.0 g, 119.5 mmol) was dissolved in methanol (239 ml) and tetrahydrofuran (120 ml) and treated with aqueous lithium hydroxide (120 ml, 239 mmol, 2.0M). An additional aliquot of methanol was added to homogenize the mixture (110 ml, ˜2 ml/g). The reaction was heated to 50° C. for 12 h. The reaction was concentrated in vacuo, and the crude residue was diluted with water (500 ml). The solution was vigorously stirred and slowly acidified with aqueous 1.0M hydrochloric acid (240 ml, to approximately pH 5.0). The precipitated solid was collected by filtration and the remaining solid was dissolved with ethyl acetate and transferred into a separate flask. The crude solid was dried in vacuo and used directly for further transformations.