Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([O-:3])=O.[Na+].C(O)=O.[O:8]1[CH:12]=[CH:11][CH:10]=[C:9]1[C:13]([N:15]1[C:24]2[C:19](=[CH:20][CH:21]=[C:22]([C:25]3[CH:30]=[CH:29][C:28]([S:31]([CH3:34])(=[O:33])=[O:32])=[CH:27][CH:26]=3)[CH:23]=2)[NH:18][C@@H:17]([CH3:35])[CH2:16]1)=[O:14]>>[O:8]1[CH:12]=[CH:11][CH:10]=[C:9]1[C:13]([N:15]1[C:24]2[C:19](=[CH:20][CH:21]=[C:22]([C:25]3[CH:30]=[CH:29][C:28]([S:31]([CH3:34])(=[O:32])=[O:33])=[CH:27][CH:26]=3)[CH:23]=2)[N:18]([CH:1]=[O:3])[C@@H:17]([CH3:35])[CH2:16]1)=[O:14]
Reactant: O=C[O-]
Reactant: C[C@H]1CN(C(=O)c2ccco2)c2cc(-c3ccc(S(C)(=O)=O)cc3)ccc2N1
Agent: [Na+]
Solvent: O=CO
Product: C[C@H]1CN(C(=O)c2ccco2)c2cc(-c3ccc(S(C)(=O)=O)cc3)ccc2N1C=O
Temperature: 25 °C
Reaction time: 5 h
Yield: 71.9 %

Procedure:
Sodium formate (14 mg, 0.200 mmol) and formic acid (46 mg, 1.0 mmol) were added to (S)-furan-2-yl(3-methyl-7-(4-(methylsulfonyl)phenyl)-3,4-dihydroquinoxaline-1(2H)-yl)methanone (0.2 M in 1,2-dichloroethane, 0.1 mL, 0.02 mmol) and shaken at room temperature for 5 h. The reaction was concentrated and the crude product was purified by mass-triggered preparatory HPLC. The product-containing fractions were combined and concentrated to afford (S)-4-(furan-2-carbonyl)-2-methyl-6-(4-(methylsulfonyl)phenyl)-3,4-dihydroquinoxaline-1(2H)-carbaldehyde (0.0061 g, 72%). MS (ESI, pos. ion) m/z 425.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.S(O)(=O)(=O)C.[Cl:12][CH2:13][CH2:14][CH2:15][O:16][C:17]12[CH:26]=[CH:25][CH:24]=[CH:23][CH:18]1[CH2:19][CH:20]2[CH2:21]O>C1(C)C=CC=CC=1.C(OCC)(=O)C>[Cl:12][CH2:13][CH2:14][CH2:15][O:16][C:17]12[CH:26]=[CH:25][CH:24]=[CH:23][CH:18]1[CH2:19][CH:20]2[CH2:21][N:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: C1CCNCC1
Reactant: OCC1CC2C=CC=CC21OCCCCl
Agent: CS(=O)(=O)O
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: ClCCCOC12C=CC=CC1CC2CN1CCCCC1

Procedure:
Piperidine (3.19 ml) is added to a solution of 3-(3-chloropropoxy)-1-hydroxymethylbenzocyclobutene mesylate (2.45 g) in toluene (32 ml) and the reaction mixture refluxed under nitrogen for about 12 hours. The reaction mixture is diluted with ethyl acetate and extracted with saturated NaHCO3 followed by saturated NaCl. The organic extract is dried, filtered and concentrated yielding the crude product used in the next step.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=O)=[CH:4][CH:3]=1.[CH:10]1([NH2:13])[CH2:12][CH2:11]1>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[N:13][CH:10]2[CH2:12][CH2:11]2)=[CH:4][CH:3]=1
Reactant: O=Cc1ccc(Cl)cc1
Reactant: NC1CC1
Solvent: Cc1ccccc1
Product: Clc1ccc(C=NC2CC2)cc1

Procedure:
Under a nitrogen atmosphere, react 4-chlorobenzaldehyde (14.0 g) and cyclopropylamine (5.7 g) in anhydrous toluene (50 mL) in the presence of molecular sieves for 48 h. Filter the reaction mixture and concentrate the filtrate in vacuo at 60 C to give 4-chlorobenzylidene cyclopropylamine (By as a crystalline solid (15.98 g).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][N:10]=1)[C:5]([OH:7])=O.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CN1CCOCC1.[CH3:42][O:43][C:44]1[C:49]2[N:50]=[C:51]([NH2:53])[S:52][C:48]=2[C:47]([N:54]([CH3:62])[CH2:55][CH:56]2[CH2:61][CH2:60][O:59][CH2:58][CH2:57]2)=[CH:46][CH:45]=1>C1COCC1.C(OCC)(=O)C>[Br:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][N:10]=1)[C:5]([NH:53][C:51]1[S:52][C:48]2[C:47]([N:54]([CH3:62])[CH2:55][CH:56]3[CH2:61][CH2:60][O:59][CH2:58][CH2:57]3)=[CH:46][CH:45]=[C:44]([O:43][CH3:42])[C:49]=2[N:50]=1)=[O:7]
Reactant: COc1ccc(N(C)CC2CCOCC2)c2sc(N)nc12
Reactant: O=C(O)c1ccnc(Br)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN1CCOCC1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: COc1ccc(N(C)CC2CCOCC2)c2sc(NC(=O)c3ccnc(Br)c3)nc12
Reaction time: 5 h
Yield: 14.4 %

Procedure:
To a stirred solution of 99 mg (0.49 mmol) 2-bromo-isonicotinic acid in 3 ml THF were added 195 mg (0.51 mmol) HATU and 0.11 ml (0.98 mmol) N-methylmorpholine and stirring continued at 30° C. for 5 h. 75 mg (0.24 mmol) 4-methoxy-N7-methyl-N7-(tetrahydro-pyran-4-ylmethyl)-benzothiazole-2,7-diamine was then added and stirring continued at 40° C. for 16 h. The reaction mixture was then diluted with ethyl acetate and washed sequentially with 0.5 N hydrochloric acid, saturated sodium bicarbonate solution and brine. The organic phase was dried over sodium sulfate and concentrated in vactio. Flash chromatography (methanol/dichloromethane) followed by trituration in ether/hexane afforded 17 mg (14%) 2-bromo-N-{4-methoxy-7-[methyl-(tetrahydro-pyran-4-ylmethyl)-amino)-benzothiazol-2-yl}-isonicotinamide as a white crystalline solid. ES-MS m/e (%): 493 (M{81Br}+H+, 100), 491 (M{79Br}+H+, 95).
Reaction SMILES: [C:1]([CH2:9][C:10]([O:12]CC)=O)(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:15][O:16][C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([NH2:23])[CH:18]=1.Cl.O1CCOCC1.C(O)[C@H](O)[C@H]1OC(=O)C(O)=C1O>C1(C)C=CC=CC=1>[OH:12][C:10]1[C:20]2[C:19](=[CH:18][C:17]([O:16][CH3:15])=[CH:22][CH:21]=2)[N:23]=[C:1]([C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[CH:9]=1
Reactant: COc1cccc(N)c1
Reactant: CCOC(=O)CC(=O)c1ccccc1
Agent: Cl
Agent: O=C1O[C@H]([C@@H](O)CO)C(O)=C1O
Solvent: C1COCCO1
Solvent: Cc1ccccc1
Product: COc1ccc2c(O)cc(-c3ccccc3)nc2c1
Temperature: 280 °C

Procedure:
A solution of ethyl benzoylacetate (b) (100.0 g, 0.52 mol), m-anisidine (a) (128.1 g, 1.04 mol) and 4 N HCl/dioxane (5.2 mL) in toluene (1.0 L) was refluxed for 6.25 h in a Dean-Stark apparatus. The cooled toluene solution was successively washed with aqueous 10% HCl (2×300 mL), 1 N NaOH (2×300 mL), H2O (300 mL) and brine (150 mL). The toluene phase was dried (MgSO4), filtered and concentrated under reduced pressure to give a 1.2:1.0 mixture of ester c and amide d (144.6 g, 45%/38% crude yield) as a dark brown oil. The crude oil was heated to 280° C. for 80 min while distilling generated EtOH. The cooled dark solid obtained was triturated with CH2Cl2 (200 mL). The suspension was filtered and the resulting solid washed with CH2Cl2 to give e (22.6 g, 17% from a) as a beige solid: 1H NMR (DMSO-d6) δ8.00 (d, J=9.0 Hz, 1H), 7.81-7.82 (m, 2H), 7.57-7.59 (m, 3H), 7.90 (d, J=2.2 Hz, 1H), 6.94 (dd, J=9.0, 2.2 Hz, 1H), 6.26 (s, 1H), 3.87 (s, 3H).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH:9]1[CH2:14][CH2:13][N:12]([C:15]([O:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[O:16])[CH2:11][CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].[CH2:27](I)[CH2:28][CH3:29].O>C1COCC1>[C:1]([O:5][C:6]([N:8]([CH2:27][CH2:28][CH3:29])[CH:9]1[CH2:10][CH2:11][N:12]([C:15]([O:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[O:16])[CH2:13][CH2:14]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)NC1CCN(C(=O)OCc2ccccc2)CC1
Reactant: CCCI
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CCCN(C(=O)OC(C)(C)C)C1CCN(C(=O)OCc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 22 h
Yield: 26.7 %

Procedure:
A solution of benzyl 4-[(tert-butoxycarbonyl)amino]piperidine-1-carboxylate obtained in Example (241a) (1.00 g, 2.99 mmol) in THF (5 mL) was added to a suspension of sodium hydride (55%) (261 mg, 5.98 mmol) in THF (25 mL) at 0° C. Subsequently, propyl iodide (1.46 mL, 15.0 mmol) was added at 0° C., and the mixture was stirred at room temperature for 22 hours. Thereafter, sodium hydride (55%) (130 mg, 2.99 mmol) and propyl iodide (0.58 mL, 5.98 mmol) were added, and the mixture was heated under reflux for 22 hours. Water was added to the reaction solution, and the mixture was extracted with ethyl acetate. Thereafter, the combined organic layers were washed with brine and dried over anhydrous magnesium sulfate. Following filtration, the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (elution solvent: hexane/ethyl acetate=5/1) to obtain 301 mg of the title compound as a pale yellow oily substance (27%).
Reaction SMILES: C[O:2][PH:3]([CH2:5][N:6]1[C:10](=[O:11])[C:9]2=[CH:12][CH:13]=[CH:14][CH:15]=[C:8]2[C:7]1=[O:16])=[O:4]>C(O)(=O)C.Br>[C:7]1(=[O:16])[N:6]([CH2:5][PH:3](=[O:2])[OH:4])[C:10](=[O:11])[C:9]2=[CH:12][CH:13]=[CH:14][CH:15]=[C:8]12
Reactant: CO[PH](=O)CN1C(=O)c2ccccc2C1=O
Agent: Br
Solvent: CC(=O)O
Product: O=C1c2ccccc2C(=O)N1C[PH](=O)O
Reaction time: 18 h

Procedure:
123 mg of [(RS)-4-methyl-2-[](S)-3-methyl-1-(methylcarbamoyl)butyl]carbamoyl]-4-methylpentyl](phthalimidomethyl)phosphinic acid methyl ester were dissolved in a mixture of 3 ml of acetic acid and 3 ml of 48% hydrogen bromide in acetic acid and the mixture was left to stand at room temperature for 18 hours. The solvent was removed by evaporation, the residue was dissolved in a mixture of 10 ml of toluene and 5 ml of acetone and the solution was evaporated. This procedure was repeated twice and the residue was then dissolved in a mixture of 5 ml of dichloromethane and 3 ml of acetone and the solution was evaporated. After drying under a high vacuum (0.1 mmHg), there were obtained 115 g of [(RS)-4-methyl-2-[[(S)-3-methyl-1-(methylcarbamoyl)butyl]carbamoyl[pentyl[-(phthalimidomethyl)phosphinic acid in the form of an off-white foam.
Reaction SMILES: [NH3:1].[C:2]([C:10]1[CH:11]=[C:12]2[C:16](=[CH:17][C:18]=1[O:19]C(=O)C)[CH:15]([C:23](Cl)=[O:24])[CH2:14][CH2:13]2)(=[O:9])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1>C1C=CC=CC=1>[C:2]([C:10]1[CH:11]=[C:12]2[C:16](=[CH:17][C:18]=1[OH:19])[CH:15]([C:23]([NH2:1])=[O:24])[CH2:14][CH2:13]2)(=[O:9])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: CC(=O)Oc1cc2c(cc1C(=O)c1ccccc1)CCC2C(=O)Cl
Reactant: N
Solvent: c1ccccc1
Product: NC(=O)C1CCc2cc(C(=O)c3ccccc3)c(O)cc21

Procedure:
Dry ammonia is passed into a solution of 27 g of crude 5-benzoyl-6-acetoxy-indane-1-carboxylic acid chloride in 200 ml of anhydrous benzene at a temperature of 15°-20° C, with exclusion of moisture, until saturation is reached. The reaction solution is then evaporated to dryness in vacuo and the evaporation residue is partitioned between 200 ml of water and 3 times 200 ml of methylene chloride. The organic phases are washed until neutral, dried over sodium sulphate and evaporated in vacuo. Fractional crystallisation of the evaporation residue from hot dimethylformamide-water gives 5-benzoyl-6-hydroxy-indane-1-carboxylic acid amide of melting point 205°-207° C. The starting material can be obtained as follows. A solution of 20 g of 5-benzoyl-6-hydroxy-indane-1-carboxylic acid in 200 ml of acetic anhydride is heated to the reflux temperature for 4 hours. It is then evaporated to dryness in vacuo, 50 ml of toluene are added to the evaporation residue and the mixture is evaporated to dryness. This procedure is repeated twice more. The crude 5-benzoyl-6-acetoxy-indane-1-carboxylic acid thus obtained is used directly for further conversion.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:38])=[C:6]([N:8]2[C:15](=[O:16])[C:14]3[CH:13]=[C:12]([C:17]4[CH:18]=[C:19]([CH:23]=[CH:24][C:25]=4[O:26][CH3:27])[C:20]([OH:22])=O)[N:11]([CH:28]([CH3:30])[CH3:29])[C:10]=3[CH:9]2[C:31]2[CH:36]=[CH:35][C:34]([Cl:37])=[CH:33][CH:32]=2)[CH:7]=1.[CH3:39][S:40]([CH2:43][CH2:44][NH2:45])(=[O:42])=[O:41].CCN=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1.CCN(CC)CC>CN(C=O)C.O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:38])=[C:6]([N:8]2[C:15](=[O:16])[C:14]3[CH:13]=[C:12]([C:17]4[CH:18]=[C:19]([CH:23]=[CH:24][C:25]=4[O:26][CH3:27])[C:20]([NH:45][CH2:44][CH2:43][S:40]([CH3:39])(=[O:42])=[O:41])=[O:22])[N:11]([CH:28]([CH3:30])[CH3:29])[C:10]=3[CH:9]2[C:31]2[CH:32]=[CH:33][C:34]([Cl:37])=[CH:35][CH:36]=2)[CH:7]=1
Reactant: CS(=O)(=O)CCN
Reactant: COc1ccc(C(=O)O)cc1-c1cc2c(n1C(C)C)C(c1ccc(Cl)cc1)N(c1cc(Cl)ccc1C)C2=O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccc(C(=O)NCCS(C)(=O)=O)cc1-c1cc2c(n1C(C)C)C(c1ccc(Cl)cc1)N(c1cc(Cl)ccc1C)C2=O

Procedure:
To a solution of 3-[5-(5-chloro-2-methyl-phenyl)-6-(4-chloro-phenyl)-1-isopropyl-4-oxo-1,4,5,6-tetrahydro-pyrrolo[3,4-b]pyrrol-2-yl]-4-methoxy-benzoic acid (Example 35) (0.147 mmol) in DMF (1 mL), were added 2-methanesulfonyl-ethylamine [49773-20-8] (0.183 mmol), EDC.HCl (0.183 mmol), HOBT.H2O (0.109 mmol) and Et3N (0.513 mmol) and the mixture was stirred at rt for 30 h. The mixture was diluted with H2O and extracted with CH2Cl2 (3×). The combined organic layers were washed with brine, dried (Na2SO4), filtered and concentrated. The residue was purified using a RediSep® silica gel column to afford the title compound as a white solid. tR: 4.84 min (HPLC 1); ESI-MS: tR=1.19 min, [M+H]+ 654/656/658 (LC-MS 1); TLC: Rf=0.22 (95:5 CH2Cl2/MeOH); 1H-NMR (d6-DMSO, 600 MHz): 8.69 (m, 1H), 7.96 (m, 1H), 7.82 (s, 1H), 7.79 (s, 1H), 7.38 (m, 2H), 7.25 (m, 2H), 7.22 (d, 1H), 7.15 (m, 1H), 7.10 (m, 1H), 6.52 (s, 1H), 6.26 (s, 1H), 3.92 (m, 1H), 3.82 (s, 3H), 3.64 (m, 2H), 3.36 (m, 2H), 3.02 (s, 3H), 1.93 (s, 3H), 1.31 (m, 3H), 0.45 (m, 3H).
Reaction SMILES: [C:1]([C:3]1[C:8]([CH3:9])=[CH:7][C:6]([N+:10]([O-])=O)=[CH:5][N:4]=1)#[N:2].[Cl-].[Ca+2].[Cl-]>C(O)C.[Fe]>[NH2:10][C:6]1[CH:7]=[C:8]([CH3:9])[C:3]([C:1]#[N:2])=[N:4][CH:5]=1
Reactant: Cc1cc([N+](=O)[O-])cnc1C#N
Agent: [Fe]
Agent: [Ca+2]
Agent: [Cl-]
Solvent: CCO
Product: Cc1cc(N)cnc1C#N
Reaction time: 1 h
Yield: 79.4 %

Procedure:
2-Cyano-3-methyl-5-nitropyridine (0.2 g, 1.23 mmol) was dissolved in 6 mL of 90% ethanol and calcium chloride (0.07 g, 0.64 mmol) was added followed by iron powder (0.62 g, 11.1 mmol, 325 Mesh). The heterogeneous mixture was stirred for one h. The mixture was filtered though Celite and concentrated to give compound 772B (0.13 g, 81%) as a light-brown solid.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[S:15][CH:16]=[C:17]([C:19](O)=[O:20])[CH:18]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[NH:53]1[CH:62]2[CH:57]([CH2:58][CH2:59][CH2:60][CH2:61]2)[CH2:56][CH2:55][CH2:54]1>C(#N)C>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][CH:11]([C:14]2[S:15][CH:16]=[C:17]([C:19]([N:53]3[C@@H:62]4[C@@H:57]([CH2:58][CH2:59][CH2:60][CH2:61]4)[CH2:56][CH2:55][CH2:54]3)=[O:20])[CH:18]=2)[CH2:12][CH2:13]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCC(c2cc(C(=O)O)cs2)CC1
Reactant: C1CCC2NCCCC2C1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CCC(c2cc(C(=O)N3CCC[C@@H]4CCCC[C@@H]43)cs2)CC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 101.1 %

Procedure:
4-(4-Carboxy-thiophen-2-yl)-piperidine-1-carboxylic acid t-butyl ester (0.1 g, 0.32 mmol) was dissolved in acetonitrile (2 mL). Triethylamine (0.96 mmol), HATU (0.35 mmol) and decahydroquinoline (3:2 mixture of cis/trans-isomers; 2.5 mmol) were added and the reaction stirred at room temperature for 3 hours. The solvent was evaporated and the residue product was purified by flash chromatography on silica, eluting with 0-50% ethyl acetate in cyclohexane. The fractions containing the desired product were concentrated under vacuum to give the title compound (0.14 g). 1H NMR (400 MHz, CHCl3-d): δ 7.2 (s, 1H), 6.85 (s, 1H), 4.7 (m, 1H), 4.2 (m, 2H), 3.7 (m, 1H), 3.1-2.7 (m, 4H), 2.0-1.4 (m, 26H).
Reaction SMILES: [CH:1]([C:3]1[NH:4][C:5]([CH3:11])=[CH:6][C:7]=1[C:8]([OH:10])=O)=[O:2].C(N=C=NCCCN(C)C)C.C(N(CC)CC)C.[CH2:30]([N:32]([CH2:36][CH3:37])[CH2:33][CH2:34][NH2:35])[CH3:31]>CN(C)C=O.C(=O)(O)[O-].[Na+].[Cl-].[Na+].O>[CH2:30]([N:32]([CH2:36][CH3:37])[CH2:33][CH2:34][NH:35][C:8]([C:7]1[CH:6]=[C:5]([CH3:11])[NH:4][C:3]=1[CH:1]=[O:2])=[O:10])[CH3:31]
Reactant: CCN(CC)CCN
Reactant: Cc1cc(C(=O)O)c(C=O)[nH]1
Agent: CCN=C=NCCCN(C)C
Agent: O=C([O-])O
Agent: [Cl-]
Solvent: O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCN(CC)CCNC(=O)c1cc(C)[nH]c1C=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 2-formyl -5-methyl-1H-pyrrole-3-carboxylic acid (320 mg, 2.1 mmol) in dimethylformamide (3 mL) was added 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (483 mg, 1.2 equivl.), 1-hydroxybenzotriaole (340 mg, 1.2 equiv.), triethylamine (0.59 mL, 2 equiv.) and N,N-diethylethylenediamine (0.32 mL, 1.1 equiv.). After stirring at room temperature overnight, the reaction was diluted with saturated sodium bicarbonate and brine (with extra salt) and extracted with 10% methanol in dichloromethane. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate and concentrated to give 2-formyl-5-methyl-1H-pyrrole-3-carboxylic acid (2-diethylaminoethyl)-amide.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[N:4][C:5]([CH3:8])=[CH:6][CH:7]=1.[CH2:9](Cl)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.O>CN(C)C=O>[CH2:9]([O:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[N:4][CH:3]=1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: Cc1ccc(O)cn1
Reactant: ClCc1ccccc1
Solvent: CN(C)C=O
Solvent: O
Product: Cc1ccc(OCc2ccccc2)cn1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
140 g of 3-hydroxy-6-methylpyridine was dissolved in 1.4 L of dimethylformamide, and with cooling with ice, 178 ml of benzyl chloride was added to it and stirred overnight at room temperature. The reaction liquid was poured into water with ice, extracted with ethyl acetate, and the organic layer was washed with saturated saline water. After dried, the solvent was evaporated away under reduced pressure, and the residue was purified through silica gel column chromatography (developing solvent: hexane/ethyl acetate=40/1 to 2/1) to obtain 246.7 g of the entitled compound as an orange oil.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([S:11]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)(=[O:13])=[O:12])[C:6]([C:20]([O:22][CH2:23][CH3:24])=[O:21])=[C:5]2[S:25](Cl)(=[O:27])=[O:26].CCOC(C)=O.[NH3:35]>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([S:11]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)(=[O:13])=[O:12])[C:6]([C:20]([O:22][CH2:23][CH3:24])=[O:21])=[C:5]2[S:25]([NH2:35])(=[O:27])=[O:26]
Reactant: N
Reactant: CCOC(=O)c1c(S(=O)(=O)Cl)c2cc(Cl)ccc2n1S(=O)(=O)c1ccccc1
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CCOC(=O)c1c(S(N)(=O)=O)c2cc(Cl)ccc2n1S(=O)(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Through a 0° C. solution of the product from Example 1, Step C (96 mg, 0.21 mmols) in 5 mL of CH2Cl2, ammonia gas was bubbled for 3 minutes. The reaction was sealed, stirred for 30 minutes, warmed to room temperature and stirred 20 minutes more. This was poured into EtOAc and washed with water and brine. The solution was dried over Na2SO4 and concentrated in vacuo to give the titled compound. ESI+MS: 443 [M+H]+.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][CH2:15]O)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.N1C=CN=C1.[I:41]I>C1(C)C=CC=CC=1>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][CH2:15][I:41])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCC(CCO)CC1
Reactant: II
Agent: c1c[nH]cn1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)N1CCC(CCI)CC1
Reaction time: 8 h
Yield: 82.5 %

Procedure:
To a solution of 1-(tert-butoxycarbonyl)-4-(2-hydroxyethyl)piperidine (458 mg, 2.0 mmol), Ph3P (785 mg, 3.0 mmol, 1.5 equiv.) and imidazole (204 mg, 3.0 mmol, 1.5 equiv.) in toluene (10 mL) was added I2 (761 mg, 3.0 mmol, 1.5 equiv.) at 0° C. The mixture was allowed to stand at room temperature overnight, before it was quenched with saturated Na2S2O3 solution. The product was extracted into CH2Cl2, and the organic layer was washed with brine and dried over Na2SO4. After concentration, the residue was purified by CC (SiO2, hexane/EtOAc 8:1, then 4:1). After removal of the solvents, 1-(tert-butoxycarbonyl)-4-(2-iodoethyl)piperidine (560 mg, 83%) was obtained as a colorless oil. 1H NMR (CDCl3, 400 MHz) δ 4.09 (br, 2H), 3.21 (t, 2H, J=7.2 Hz), 2.70 (t, 2H, J=12.0 Hz), 1.77 (q, 2H, J=7.2 Hz), 1.65 (d, 2H, J=12.8 Hz), 1.56 (m, 1H), 1.45 (s, 9H), 1.11 (m, 2H).
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][N:5]=[C:4]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([P:15]([CH3:18])([CH3:17])=[O:16])=[CH:11][C:10]=2[S:19]([CH:22]([CH3:24])[CH3:23])(=[O:21])=[O:20])[CH:3]=1.[CH3:25][O:26][C:27]1[CH:33]=[C:32]([N:34]2[CH2:39][CH2:38][CH:37]([N:40]3[CH2:45][CH2:44][N:43]([CH3:46])[CH2:42][CH2:41]3)[CH2:36][CH2:35]2)[CH:31]=[CH:30][C:28]=1[NH2:29]>COCCO>[CH3:17][P:15]([C:12]1[CH:13]=[CH:14][C:9]([NH:8][C:4]2[CH:3]=[C:2]([NH:29][C:28]3[CH:30]=[CH:31][C:32]([N:34]4[CH2:39][CH2:38][CH:37]([N:40]5[CH2:41][CH2:42][N:43]([CH3:46])[CH2:44][CH2:45]5)[CH2:36][CH2:35]4)=[CH:33][C:27]=3[O:26][CH3:25])[N:7]=[CH:6][N:5]=2)=[C:10]([S:19]([CH:22]([CH3:24])[CH3:23])(=[O:21])=[O:20])[CH:11]=1)([CH3:18])=[O:16]
Reactant: COc1cc(N2CCC(N3CCN(C)CC3)CC2)ccc1N
Reactant: CC(C)S(=O)(=O)c1cc(P(C)(C)=O)ccc1Nc1cc(Cl)ncn1
Solvent: COCCO
Product: COc1cc(N2CCC(N3CCN(C)CC3)CC2)ccc1Nc1cc(Nc2ccc(P(C)(C)=O)cc2S(=O)(=O)C(C)C)ncn1

Procedure:
To the compound 6-chloro-N-[4-(dimethylphosphoryl)-2-(propan-2-ylsulfonyl)phenyl]pyrimidin-4-amine (0.16 mmol) in 1 mL of 2-methoxyethanol is added 2-methoxy-4-[4-(4-methylpiperazin-1-yl)piperidin-1-yl]aniline (prepared in Example 75: 0.71 g, 0.16 mmol). The mixture is stirred at 110° C. until formation of the desired compound. The mixture is basified with saturated sodium bicarbonate solution and extracted with limited amount of ethyl acetate. The compound can be purified by chromatography.
Reaction SMILES: Br[CH2:2][C:3]([CH3:31])([CH3:30])[CH2:4][NH:5][C:6]([C:8]1[CH:9]=[N:10][N:11]2[CH:16]=[CH:15][C:14]([N:17]3[CH2:21][CH2:20][CH2:19][C@@H:18]3[C:22]3[C:23]([OH:29])=[N:24][CH:25]=[C:26]([F:28])[CH:27]=3)=[N:13][C:12]=12)=[O:7].CC([O-])(C)C.[K+]>C1COCC1>[F:28][C:26]1[CH:27]=[C:22]2[C:23](=[O:29])[N:24]([CH:25]=1)[CH2:2][C:3]([CH3:31])([CH3:30])[CH2:4][NH:5][C:6](=[O:7])[C:8]1=[C:12]3[N:13]=[C:14]([CH:15]=[CH:16][N:11]3[N:10]=[CH:9]1)[N:17]1[C@@H:18]2[CH2:19][CH2:20][CH2:21]1
Reactant: CC(C)(CBr)CNC(=O)c1cnn2ccc(N3CCC[C@@H]3c3cc(F)cnc3O)nc12
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: CC1(C)CNC(=O)c2cnn3ccc(nc23)N2CCC[C@@H]2c2cc(F)cn(c2=O)C1
Temperature: 50 °C
Yield: 59.9 %

Procedure:
To a solution of (R)-N-(3-bromo-2,2-dimethylpropyl)-5-(2-(5-fluoro-2-hydroxypyridin-3-yl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide (30 mg, 0.061 mmol) in THF (5 mL) was added drop-wise potassium 2-methylpropan-2-olate (153 μL, 0.15 mmol). The reaction was heated at 50° C. for two hours. The solvent was removed under reduced pressure and the residue was purified by silica column chromatography, eluting with 10% MeOH/DCM to provide the title compound (15 mg, 60% yield). MS (apci) m/z=411.0 (M+H).
Reaction SMILES: [C:1]([CH:3]1[CH2:8][CH2:7][CH:6]([CH2:9][CH2:10][CH3:11])[CH2:5][CH2:4]1)#[CH:2].Br[C:13]1[CH:18]=[CH:17][C:16]([O:19][CH2:20][CH3:21])=[C:15]([F:22])[C:14]=1[F:23]>C(N(CC)CC)C.CC(OC)(C)C.Cl.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.[Cu]I>[CH2:20]([O:19][C:16]1[CH:17]=[CH:18][C:13]([C:2]#[C:1][CH:3]2[CH2:8][CH2:7][CH:6]([CH2:9][CH2:10][CH3:11])[CH2:5][CH2:4]2)=[C:14]([F:23])[C:15]=1[F:22])[CH3:21]
Reactant: CCOc1ccc(Br)c(F)c1F
Reactant: C#CC1CCC(CCC)CC1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Agent: Cl
Solvent: COC(C)(C)C
Solvent: CCN(CC)CC
Product: CCCC1CCC(C#Cc2ccc(OCC)c(F)c2F)CC1
Temperature: 50 °C

Procedure:
A mixture of 20.6 g (0.14 mol) of 1-ethynyl-4-propylcyclohexane, 25.0 g (0.11 mol) of 1-bromo-4-ethoxy-2,3-difluorobenzene, 2.22 g (3.16 mmol) of bis(triphenylphosphine)palladium(II) chloride and 603 mg (3.16 mmol) of copper(I) iodide in 440 ml of triethylamine is warmed at 50° C. for 19 h. After cooling, the mixture is diluted with MTBE and neutralised using dil. hydrochloric acid. The organic phase is separated off, and the aqueous phase is extracted with MTBE. The combined organic phases are washed with sodium chloride solution and dried using sodium sulfate. The solution is concentrated to dryness, and the residue is purified by column chromatography (SiO2, n-heptane:chlorobutane=9:1). The further purification is carried out by recrystallisation from n-heptane, giving 1-ethoxy-2,3-difluoro-4-(4-propylcyclohexylethynyl)benzene as a colourless solid (m.p. 64° C.). This has the phase sequence: C 64° C. I. The properties, extrapolated from a 10% solution in ZLI-4792, are: