Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][N:11]=1)[C:5]([NH:7][CH3:8])=[O:6].Cl.CN[O:15][CH3:16].C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1.CCN(CC)CC>CN(C=O)C.O>[Cl:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][N:11]=1)[C:5]([N:7]([O:15][CH3:16])[CH3:8])=[O:6]
Reactant: CNC(=O)c1ccnc(Cl)c1
Reactant: CNOC
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: O
Product: CON(C)C(=O)c1ccnc(Cl)c1

Procedure:
2-Chloroisonicotinic acid (12-2, 2.0 g, 12.7 mmole), N,O-dimethylhydroxylamine hydrochloride (3.71 g, 38.1 mmole), EDC (2.92 g, 15.2 mmole), and HOBt (2.06 g, 15.2 mmole) were combined in dry DMF (40 mL). To this was added Et3N (8.9 mL, 63.47 mmole) at RT. After 60 hr the mixture was diluted with H2O and extracted with EtOAc (4×). The combined organic layers were washed with H2O, brine; then dried (MgSO4), filtered, and concentrated to give the titled compound as an amber oil which solidified on standing. The material was sufficiently pure for use in the next step. 1H-NMR (500 MHz, CDCl3) δ 8.47 (d, 1 H, J=5.13 Hz), 7.57 (s, 1 H), 7.45 (m, 1 H), 3.56 (s, 3 H), 3.38 (s, 3 H).
Reaction SMILES: [P:1]([O-:6])([O:4][CH3:5])[O:2][CH3:3].[CH3:7][C:8]([CH3:12])=[CH:9][CH:10]=[O:11].Cl>>[OH:11][C@@H:10]([P:1](=[O:6])([O:4][CH3:5])[O:2][CH3:3])[CH:9]=[C:8]([CH3:12])[CH3:7]
Reactant: COP([O-])OC
Reactant: CC(C)=CC=O
Agent: Cl
Product: COP(=O)(OC)[C@H](O)C=C(C)C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 72 %

Procedure:
The solution of ALB in tetrahydrofuran (0.1M, 0.40 ml) obtained in Example 1 was concentrated at room temperature for 1 hour under reduced pressure, then 0.4 ml of toluene was added thereto under an argon atmosphere. To this solution was added dimethyl phosphite (37 μl, 0.40 mmol) at room temperature. After stirring at room temperature for 30 minutes, the reaction vessel was cooled to -40° C., and it was maintained at this temperature for 15 minutes. Then 3-methyl-2-butenal (0.40 mmol) was added thereto. After reacting for 81 hours, 1N hydrochloric acid was added thereto to stop the reaction. The mixture was extracted with ethyl acetate (10 ml×three times), and the combined extracts were washed with brine and dried over Na2SO4. The solvent was distilled, and the residue was purified by flash column chromatography (acetone/hexane=1/5, on SiO2) to obtain dimethyl (S)-1-hydroxy-3-methyl-2-butenylphosphonate as a final product in a yield of 72%. The chemical reaction in this Example is shown in chemical formula 36.
Reaction SMILES: Cl[C:2]1[NH:3][C:4]([NH:11][C:12]2[CH:22]=[CH:21][C:15]([C:16]([O:18][CH2:19][CH3:20])=[O:17])=[CH:14][CH:13]=2)=[C:5]2[C:9]([N:10]=1)=[N:8][CH:7]=[N:6]2.[NH2:23][C:24]1[CH:34]=[CH:33][C:27]([C:28]([O:30][CH2:31][CH3:32])=[O:29])=[CH:26][CH:25]=1>>[CH2:31]([O:30][C:28]([C:27]1[CH:26]=[CH:25][C:24]([NH:23][C:2]2[N:10]=[C:9]3[C:5]([N:6]=[CH:7][NH:8]3)=[C:4]([NH:11][C:12]3[CH:22]=[CH:21][C:15]([C:16]([O:18][CH2:19][CH3:20])=[O:17])=[CH:14][CH:13]=3)[N:3]=2)=[CH:34][CH:33]=1)=[O:29])[CH3:32]
Reactant: CCOC(=O)c1ccc(N)cc1
Reactant: CCOC(=O)c1ccc(Nc2[nH]c(Cl)nc3ncnc2-3)cc1
Product: CCOC(=O)c1ccc(Nc2nc(Nc3ccc(C(=O)OCC)cc3)c3nc[nH]c3n2)cc1
Yield: 54.1 %

Procedure:
The procedure is carried out as in stage 2 of Example 1, using 238 mg of the product obtained in stage 1 of Example 1 and 660 mg of ethyl 4-aminobenzoate in place of trans-1,4-diaminocyclohexane. 181 mg of the expected product are thus obtained.
Reaction SMILES: I[C:2]1[CH:15]=[C:14]2[C:5]([C:6]3[CH:7]=[CH:8][C:9]([OH:16])=[CH:10][C:11]=3[CH2:12][CH2:13]2)=[CH:4][CH:3]=1.C(NC(C)C)(C)C.[CH2:24]([OH:28])[CH2:25][C:26]#[CH:27].Cl>C1COCC1.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.O>[OH:28][CH2:24][CH2:25][C:26]#[C:27][C:2]1[CH:15]=[C:14]2[C:5]([C:6]3[CH:7]=[CH:8][C:9]([OH:16])=[CH:10][C:11]=3[CH2:12][CH2:13]2)=[CH:4][CH:3]=1
Reactant: Oc1ccc2c(c1)CCc1cc(I)ccc1-2
Reactant: C#CCCO
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Agent: Cl
Solvent: CC(C)NC(C)C
Solvent: O
Solvent: C1CCOC1
Product: OCCC#Cc1ccc2c(c1)CCc1cc(O)ccc1-2
Reaction time: 1.5 h

Procedure:
9.0 g (24.6 mmol) of 7-iodo-9,10-dihydrophenanthren-2-ol are initially introduced in 100 ml of THF, 1.0 g (1.43 mmol) of bis(triphenylphosphine)palladium(II) chloride, 0.3 g (1.58 mmol) of copper(I) iodide and 11 ml of diisopropylamine are added, and subsequently a solution of 3.0 g (42.8 mmol) of but-3-yn-1-ol in 20 ml of THF is added dropwise at max. 30° C. with gentle cooling. The batch is left to stir at room temp. for 1.5 h, added to water and acidified using 2 N hydrochloric acid. The aqueous phase is separated off and extracted three times with ethyl acetate. The combined org. phases are washed with water, dried over sodium sulfate, and the solvent is removed in vacuo. The crude product is filtered through silica gel with dichloromethane/ethyl acetate (3:1) and recrystallised from toluene, giving 7-(4-hydroxybut-1-ynyl)-9,10-dihydrophenanthren-2-ol as colourless solid.
Reaction SMILES: [Cl:1][C:2]1[CH:12]=[CH:11][CH:10]=[CH:9][C:3]=1[C:4]([CH2:6][C:7]#[N:8])=O.O.[NH2:14][NH2:15]>C(O)C.C(OCC)(=O)C>[Cl:1][C:2]1[CH:12]=[CH:11][CH:10]=[CH:9][C:3]=1[C:4]1[CH:6]=[C:7]([NH2:8])[NH:14][N:15]=1
Reactant: N#CCC(=O)c1ccccc1Cl
Reactant: NN
Solvent: O
Solvent: CCO
Solvent: CCOC(C)=O
Product: Nc1cc(-c2ccccc2Cl)n[nH]1
Temperature: 20 °C

Procedure:
To a solution of 2-chlorobenzoylacetonitrile (400 g, 2.23 mol) in ethanol (9 L) was added hydrazine hydrate (221 g, 4.42 mol) over 15 minutes while maintaining internal reaction temperature at 15 to 25° C. The mixture was then heated at 75° C. for 20 hr. After cooling, the reaction was concentrated, in vacuo, to give a brown oil. The residue was dissolved in ethyl acetate (4 L), washed with half saturated brine (4 L), and then dried (Na2SO4) to a give a crude, dark orange solution of 5-(2-chlorophenyl)-2H-pyrazol-3-ylamine that was carried directly into the next reaciton: +ESI MS (M+1) 194.0.
Reaction SMILES: [CH3:1][C@:2]1([NH:21][C:22]2[CH:27]=[N:26][C:25]([C:28]([F:31])([F:30])[F:29])=[CH:24][N:23]=2)[CH2:6][CH2:5][CH2:4][C@@H:3]1[NH:7][C:8]([C:10]1[C:15](N2N=CC=N2)=[CH:14][CH:13]=[CH:12][N:11]=1)=[O:9].C[C@]1(NC2C=NC(C(F)(F)F)=CN=2)CCC[C@@H]1N.[CH2:50]([O:52]C1C(C(O)=O)=NC=CC=1)[CH3:51]>>[CH2:50]([O:52][C:15]1[C:10]([C:8]([NH:7][C@H:3]2[CH2:4][CH2:5][CH2:6][C@:2]2([CH3:1])[NH:21][C:22]2[CH:27]=[N:26][C:25]([C:28]([F:31])([F:30])[F:29])=[CH:24][N:23]=2)=[O:9])=[N:11][CH:12]=[CH:13][CH:14]=1)[CH3:51]
Reactant: C[C@]1(Nc2cnc(C(F)(F)F)cn2)CCC[C@@H]1NC(=O)c1ncccc1-n1nccn1
Reactant: CCOc1cccnc1C(=O)O
Agent: C[C@]1(Nc2cnc(C(F)(F)F)cn2)CCC[C@@H]1N
Product: CCOc1cccnc1C(=O)N[C@H]1CCC[C@]1(C)Nc1cnc(C(F)(F)F)cn1

Procedure:
Prepared according to the procedure for N-[(1S,2S)-2-methyl-2-{[5-(trifluoromethyl)pyrazin-2-yl]amino}cyclopentyl]-3-(2H-1,2,3-triazol-2-yl)pyridine-2-carboxamide (Example 77) from (1S,2S)-1-methyl-1-N-[5-(trifluoromethyl)pyrazin-2-yl]cyclopentane-1,2-diamine (Intermediate 25; 80 mg, 0.31 mmol) and 3-ethoxypyridine-2-carboxylic acid (CAS number 103878-09-7; 51 mg, 0.31 mmol) except this was purified by column chromatography (silica, 0-100% ethyl acetate/petrol) followed by reverse phase chromatography (C18 silica, 0-100% water (with 0.05% ammonia)/acetonitrile) to afford the title compound.
Reaction SMILES: O1C=CC(C(Cl)=O)=[CH:2]1.[CH3:9][C:10]1[C:31]([CH3:32])=[CH:30][C:13]2[NH:14][C:15]([C:17]3[C:21]([NH:22][C:23]([C:25]4[CH:29]=[CH:28][O:27][CH:26]=4)=[O:24])=[CH:20][NH:19][N:18]=3)=[N:16][C:12]=2[CH:11]=1>>[CH3:32][C:31]1[C:10]([CH3:9])=[CH:11][C:12]2[N:16]([CH3:2])[C:15]([C:17]3[C:21]([NH:22][C:23]([C:25]4[CH:29]=[CH:28][O:27][CH:26]=4)=[O:24])=[CH:20][NH:19][N:18]=3)=[N:14][C:13]=2[CH:30]=1
Reactant: O=C(Cl)c1ccoc1
Reactant: Cc1cc2nc(-c3n[nH]cc3NC(=O)c3ccoc3)[nH]c2cc1C
Product: Cc1cc2nc(-c3n[nH]cc3NC(=O)c3ccoc3)n(C)c2cc1C

Procedure:
By proceeding in a manner similar to Example 248 (a) above but using 3-furoylchloride there was prepared furan-3-carboxylic acid [3-(5,6-dimethyl-1H-benzoimidazol-2-yl)-1H-pyrazol-4-yl]-amide (80 mg) as a white solid. LC-MS (METHOD L): RT=7.10 minutes, 322.31 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][C:5]([C:8]([OH:10])=O)=[N:6][CH:7]=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.CCN(C(C)C)C(C)C.[CH:42]1([CH2:45][N:46]2[CH2:51][CH2:50][NH:49][CH2:48][CH2:47]2)[CH2:44][CH2:43]1>CN(C=O)C>[Br:1][C:2]1[CH:7]=[N:6][C:5]([C:8]([N:49]2[CH2:50][CH2:51][N:46]([CH2:45][CH:42]3[CH2:44][CH2:43]3)[CH2:47][CH2:48]2)=[O:10])=[N:4][CH:3]=1
Reactant: O=C(O)c1ncc(Br)cn1
Reactant: C1CN(CC2CC2)CCN1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(c1ncc(Br)cn1)N1CCN(CC2CC2)CC1
Temperature: 25 °C
Reaction time: 0.67 h
Yield: 28.9 %

Procedure:
To 5-bromopyrimidine-2-carboxylic acid (100 mg, 0.49 mmol) and TBTU (158 mg, 0.49 mmol) in anhydrous DMF 94.4. mL) was added DIPEA (0.36M in CH2Cl2, 1.4 mL, 0.49 mmol) and the reaction mixture stirred at RT for 40 min. N-cyclopropylmethylpiperazine (83 mg, 0.59 mmol) in anhydrous DMF (1 mL) was added and the reaction stirred at RT for 18 h. The reaction mixture was passed through a Si—NH2 cartridge (5 g), eluting with DMF and MeOH. The eluents were combined, concentrated in vacuo and purified by reverse phase preparative HPLC-MS to obtain (5-bromo-pyrimidin-2-yl)-(4-cyclopropylmethyl-piperazin-1-yl)-methanone as a pale yellow solid (46 mg, 29%).
Reaction SMILES: [CH:1]1([CH2:4][NH:5][CH2:6][CH2:7][CH3:8])[CH2:3][CH2:2]1.C[Al](C)C.C([O:15][C:16]([C:18]1[N:22]2[CH:23]=[C:24]([Cl:35])[N:25]([C:26]3[C:31]([CH3:32])=[CH:30][C:29]([CH3:33])=[CH:28][C:27]=3[CH3:34])[C:21]2=[N:20][C:19]=1[C:36]([F:39])([F:38])[F:37])=O)C.[C@H](O)(C([O-])=O)[C@@H](O)C([O-])=O.[Na+].[K+]>C1(C)C=CC=CC=1>[CH:1]1([CH2:4][N:5]([CH2:6][CH2:7][CH3:8])[C:16]([C:18]2[N:22]3[CH:23]=[C:24]([Cl:35])[N:25]([C:26]4[C:27]([CH3:34])=[CH:28][C:29]([CH3:33])=[CH:30][C:31]=4[CH3:32])[C:21]3=[N:20][C:19]=2[C:36]([F:38])([F:37])[F:39])=[O:15])[CH2:3][CH2:2]1
Reactant: CCOC(=O)c1c(C(F)(F)F)nc2n(-c3c(C)cc(C)cc3C)c(Cl)cn12
Reactant: CCCNCC1CC1
Agent: C[Al](C)C
Agent: O=C([O-])[C@H](O)[C@@H](O)C(=O)[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Product: CCCN(CC1CC1)C(=O)c1c(C(F)(F)F)nc2n(-c3c(C)cc(C)cc3C)c(Cl)cn12
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of N-cyclopropylmethylpropylamine (0.22 mL, 1.530 mmol) in toluene (1.5 mL) at 0° C. was added 2.0M solution of trimethylaluminum in toluene (0.77 mL, 1.530 mmol). The clear solution was warmed to room temperature and stirred for 1 h. A solution of 6-chloro-2-trifluoromethyl-7-(2,4,6-trimethyl-phenyl)-7H-imidazo[1,2-a]imidazole-3-carboxylic acid ethyl ester (37.7 mg, 0.094 mmol) in toluene (1.0 mL) was added at 0° C. via cannula. The reaction mixture was heated at 80° C. for 2 h. A solution of Rochelle's salt (2.0 mL) was added carefully at 0° C. and the mixture was vigorously stirred for 30 min. The crude product was extracted with ethyl acetate. The combined organic extracts were dried with MgSO4. The solvent was removed under reduced pressure and the crude product was purified by a reverse-phase preparative HPLC. Yield—39.5 mg (90%). LC/MS: tR=1.93 min., MS: [M+H]=467.
Reaction SMILES: [C:1]1([CH2:7][O:8][C:9]([N:11]2[CH2:16][CH2:15][CH2:14][CH2:13][C@H:12]2[C:17](O)=[O:18])=[O:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.O.C([O-])([O-])=O.[K+].[K+]>C1COCC1>[OH:18][CH2:17][C@@H:12]1[CH2:13][CH2:14][CH2:15][CH2:16][N:11]1[C:9]([O:8][CH2:7][C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)=[O:10]
Reactant: O=C(O)[C@@H]1CCCCN1C(=O)OCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Product: O=C(OCc1ccccc1)N1CCCC[C@H]1CO
Temperature: 25 °C
Reaction time: 8 h
Yield: 86.1 %

Procedure:
(2S)-1-{[(Phenylmethyl)oxy]carbonyl}-2-piperidinecarboxylic acid (1.0 g, 3.798 mmol) in THF (5 mL) was cooled to −18° C. and borane-THF complex (3.798 mL, 3.798 mmol) was added over 10 min. The mixture was allowed to warm to room temperature with stirring overnight, then cooled to 0° C., and water (4 mL) was added, followed by K2CO3 (1.4 g). The phases were separated, and the aqueous phase was extracted with Et2O (3×25 mL). The combined organic phase was washed with brine (1×25 mL) and dried over anhydrous MgSO4, filtered, and concentrated in vacuo to provide phenylmethyl (2S)-2-(hydroxymethyl)-1-piperidinecarboxylate (815 mg, 86%). LCMS: (M+H)+: 250.2.
Reaction SMILES: CCN(C(C)C)C(C)C.Cl[C:11]1[C:12]2[C:19]([C:20]3[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=3)=[C:18]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[O:17][C:13]=2[N:14]=[CH:15][N:16]=1.[NH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][OH:41]>CN(C=O)C.C(OCC)(=O)C>[CH3:27][O:26][C:23]1[CH:24]=[CH:25][C:20]([C:19]2[C:12]3[C:11]([NH:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][OH:41])=[N:16][CH:15]=[N:14][C:13]=3[O:17][C:18]=2[C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)=[CH:21][CH:22]=1
Reactant: NCCCCCCO
Reactant: COc1ccc(-c2c(-c3ccccc3)oc3ncnc(Cl)c23)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COc1ccc(-c2c(-c3ccccc3)oc3ncnc(NCCCCCCO)c23)cc1
Yield: 29.1 %

Procedure:
Add 1.15 g (8.9 mmol) DIEA to 1.0 g (3.0 mmol) 4-chloro-5-(4-methoxyphenyl)-6-phenylfuro[2,3-d]pyrimidine and 0.70 g (5.9 mmol) 6-aminohexanol in 10 ml DMF and heat for 4 h to 120° C. Then dilute the mixture with ethyl acetate, wash with water and dilute hydrochloric acid, dry, and concentrate by evaporation. Purify the residue by RP-HPLC (column: Gromsil 250 mm×40 mm, 10 μm; acetonitrile/water gradient: 0-3 min 5% acetonitrile, 3-34 min 5%→98% acetonitrile, 34-38 min 98% acetonitrile). 364 mg (29% of theor.) 6-{[5-(4-methoxyphenyl)-6-phenylfuro[2,3-d]pyrimidin-4-yl]amino}hexan-1-ol is obtained as a yellow oil, which solidifies after standing for 2 days.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH2:11][CH:10]([N:14]2[C:27]3[CH:26]=[C:25]([Cl:28])[CH:24]=[CH:23][C:22]=3[S:21][C:20]3[C:15]2=[CH:16][CH:17]=[CH:18][CH:19]=3)[CH2:9]1)=O)(C)(C)C.Cl>C(OCC)C.C(OCC)(=O)C>[Cl:28][C:25]1[CH:24]=[CH:23][C:22]2[S:21][C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[N:14]([CH:10]3[CH2:11][CH2:12][CH2:13][NH:8][CH2:9]3)[C:27]=2[CH:26]=1
Reactant: CC(C)(C)OC(=O)N1CCCC(N2c3ccccc3Sc3ccc(Cl)cc32)C1
Agent: Cl
Solvent: CCOCC
Solvent: CCOC(C)=O
Product: Clc1ccc2c(c1)N(C1CCCNC1)c1ccccc1S2
Temperature: 0 °C
Reaction time: 8 h
Yield: 127.8 %

Procedure:
3-(2-Chlorophenothiazin-10-yl)piperidine-1-carboxylic acid tert-butyl ester (4.1 g, 9.83 mmol) was dissolved in diethyl ether (200 mL), and the solution cooled to 0° C. A solution of HCl in ethyl acetate (˜4 M, 30 mL) was slowly added. The mixture was allowed to warn to room temperature and stirred for 8 h. The solvent was removed under vacuum. The residue treated with HCl in ethyl acetate (˜4 M, 75 mL) and stirred overnight. The solvent was removed under vacuum to provide 2-chloro-10-piperidin-3-yl-10H-phenothiazine (3.98 g, 100%) as an off-white solid.
Reaction SMILES: [NH2:1][C:2]1[C:12]([F:13])=[CH:11][C:10]([C:14]2[CH:15]=[C:16]3[C:22]([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=4[O:29][CH3:30])=[CH:21][N:20]([S:31]([C:34]4[CH:39]=[CH:38][C:37]([CH3:40])=[CH:36][CH:35]=4)(=[O:33])=[O:32])[C:17]3=[N:18][CH:19]=2)=[CH:9][C:3]=1[C:4]([N:6]([CH3:8])[CH3:7])=[O:5].ClCCl.[C:44](=O)(O)[O-:45].[Na+].C(Cl)(Cl)=O>C1(C)C=CC=CC=1>[F:13][C:12]1[C:2]([N:1]=[C:44]=[O:45])=[C:3]([CH:9]=[C:10]([C:14]2[CH:15]=[C:16]3[C:22]([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=4[O:29][CH3:30])=[CH:21][N:20]([S:31]([C:34]4[CH:35]=[CH:36][C:37]([CH3:40])=[CH:38][CH:39]=4)(=[O:32])=[O:33])[C:17]3=[N:18][CH:19]=2)[CH:11]=1)[C:4]([N:6]([CH3:8])[CH3:7])=[O:5]
Reactant: COc1ccccc1-c1cn(S(=O)(=O)c2ccc(C)cc2)c2ncc(-c3cc(F)c(N)c(C(=O)N(C)C)c3)cc12
Reactant: O=C([O-])O
Agent: O=C(Cl)Cl
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: COc1ccccc1-c1cn(S(=O)(=O)c2ccc(C)cc2)c2ncc(-c3cc(F)c(N=C=O)c(C(=O)N(C)C)c3)cc12
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
In a scintillation vial was combined 125 mg (0.224 mmol) of 2-amino-3-fluoro-5-[3-(2-methoxy-phenyl)-1-(toluene-4-sulfonyl)-1H-pyrrolo[2,3-b]pyridin-5-yl]-N,N-dimethyl-benzamide, 2.0 mL dichloromethane, and 2.0 mL of a saturated aqueous solution of sodium bicarbonate. The vial was cooled to 0° C. in an ice bath and, under vigorous stirring, 601 μL (1.12 mmol) of a 20% phosgene in toluene solution was added. The reaction was stirred in the ice bath for 30 minutes and then stirred at room temperature for another 30 minutes. The layers were separated and organic layer was dried over sodium sulfate and concentrated to afford 3-fluoro-2-isocyanato-5-[3-(2-methoxy-phenyl)-1-(toluene-4-sulfonyl)-1H-pyrrolo[2,3-b]pyridin-5-yl]-N,N-dimethyl-benzamide as a brown foam.
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[N:11]=[C:10]([C:12]([NH:14][C:15]([CH2:23][CH3:24])([CH2:21][CH3:22])[C:16]([O:18]CC)=[O:17])=[O:13])[CH:9]=[CH:8][C:7]=2[C:25]([F:28])([F:27])[F:26])[CH2:3][CH2:2]1.[OH-].[Na+]>C1COCC1.CO>[CH:1]1([CH2:4][O:5][C:6]2[N:11]=[C:10]([C:12]([NH:14][C:15]([CH2:21][CH3:22])([CH2:23][CH3:24])[C:16]([OH:18])=[O:17])=[O:13])[CH:9]=[CH:8][C:7]=2[C:25]([F:28])([F:26])[F:27])[CH2:2][CH2:3]1
Reactant: CCOC(=O)C(CC)(CC)NC(=O)c1ccc(C(F)(F)F)c(OCC2CC2)n1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: CCC(CC)(NC(=O)c1ccc(C(F)(F)F)c(OCC2CC2)n1)C(=O)O
Temperature: 60 °C
Reaction time: 72 h
Yield: 100.6 %

Procedure:
Ethyl 2-(6-(cyclopropylmethoxy)-5-(trifluoromethyl)picolinamido)-2-ethylbutanoate (62 mg, 154 μmol) was dissolved in a mixture of 1 M aqueous sodium hydroxide solution (616 μL, 616 μmol), THF (600 μL) and MeOH (600 μL). The mixture was stirred at 60° C. for 3 d, poured onto ice water/brine/1N HCl (20 mL) and extracted with EtOAc (2×30 mL). The combined extracts were washed with ice water/brine (20 mL) and dried over Na2SO4. The solvent was removed in vacuo to give the title compound (58 mg, quant.) as a light yellow solid. MS: 373.1 [M−H]−.
Reaction SMILES: OC1C(=O)NN=C(CCC2C=CC=CC=2)C=1.C([O:24][C:25]1[N:26]=[N:27][C:28]([CH2:39][C:40]2[C:45]([F:46])=[CH:44][CH:43]=[CH:42][C:41]=2[Cl:47])=[CH:29][C:30]=1[O:31]CC1C=CC=CC=1)C1C=CC=CC=1>O1CCCC1>[Cl:47][C:41]1[CH:42]=[CH:43][CH:44]=[C:45]([F:46])[C:40]=1[CH2:39][C:28]1[CH:29]=[C:30]([OH:31])[C:25](=[O:24])[NH:26][N:27]=1
Reactant: Fc1cccc(Cl)c1Cc1cc(OCc2ccccc2)c(OCc2ccccc2)nn1
Agent: O=c1[nH]nc(CCc2ccccc2)cc1O
Solvent: C1CCOC1
Product: O=c1[nH]nc(Cc2c(F)cccc2Cl)cc1O

Procedure:
Prepared in the same way as 4-hydroxy-6-(2-phenylethyl)pyridazin-3(2H)-one (Example 1) from 3,4-bis(benzyloxy)-6-[(2-chloro-6-fluorophenyl)methyl]pyridazine (Intermediate 52) except that the solvent used for the hydrogenation was tetrahydrofuran and the product was recrystallised from a mixture of MTBE and heptanes.
Reaction SMILES: C1(=O)[N:5]([CH2:6][C:7](=[O:14])[CH2:8][CH2:9][C:10]([O:12]C)=[O:11])C(=O)C2=CC=CC=C12.[BrH:21]>>[BrH:21].[NH2:5][CH2:6][C:7](=[O:14])[CH2:8][CH2:9][C:10]([OH:12])=[O:11]
Reactant: COC(=O)CCC(=O)CN1C(=O)c2ccccc2C1=O
Agent: Br
Product: NCC(=O)CCC(=O)O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A stirred mixture of methyl 5-phthalimido-4-oxopentanoate (4.0 g, 14.5 mmol) [Z. Naturforsch. 41B, 1593-94 (1986)] and 48% hydrobromic acid (40 ml) was refluxed for 7 hrs, then cooled to room temperature and stored overnight in a refrigerator. Following filtering the residue was washed with water and the combined filtrates were evaporated to dryness on a rotary evaporator and titrated with diethyl ether (2×25 ml). The residue was filtered and dried over silica gel at 30° C. and 15 mm Hg in a drying pistol. The crude product was dissolved in methanol (10 ml) and 2-propanol (30 ml). Diethyl ether (150 ml) was added and the mixture was allowed to stand 2 hrs. The precipitate was filtered and dried as before, to give 2.5 g (81%), mp 137-140° C.
Reaction SMILES: [CH3:1][CH:2]1[C:7]([C:8]2[CH:13]=[CH:12][C:11]([N:14]([C:20](=[O:22])[CH3:21])[CH2:15][CH2:16][CH:17]([CH3:19])[CH3:18])=[C:10]([N+:23]([O-])=O)[CH:9]=2)=[N:6][NH:5][C:4](=[O:26])[CH2:3]1.O.NN>C(O)C.[Ni]>[CH3:1][CH:2]1[C:7]([C:8]2[CH:13]=[CH:12][C:11]([N:14]([C:20](=[O:22])[CH3:21])[CH2:15][CH2:16][CH:17]([CH3:18])[CH3:19])=[C:10]([NH2:23])[CH:9]=2)=[N:6][NH:5][C:4](=[O:26])[CH2:3]1
Reactant: CC(=O)N(CCC(C)C)c1ccc(C2=NNC(=O)CC2C)cc1[N+](=O)[O-]
Agent: [Ni]
Agent: NN
Solvent: O
Solvent: CCO
Product: CC(=O)N(CCC(C)C)c1ccc(C2=NNC(=O)CC2C)cc1N
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
6 gm of 5-methyl-6-{3-nitro-4-[N-acetyl-N-(3-methyl-butyl)-amino]-phenyl}-4,5-dihydro-2H-pyridazine-3-one were dissolved in 150 ml of ethanol. 4 gm of Raney-nickel and 3 ml of 98% hydrazine hydrate were added, and the solution was stirred for 30 minutes at room temperature. The catalyst was filtered off, the filtrate was evaporated, and the residue was processed further without further purification.
Reaction SMILES: [CH2:1]([C:4]1[CH:9]=[CH:8][C:7]([CH2:10][CH2:11][C:12]2[CH:17]=[CH:16][C:15]([Mg]Br)=[CH:14][CH:13]=2)=[CH:6][CH:5]=1)[CH2:2][CH3:3].Cl[C:21]1[CH:26]=[CH:25][C:24]([C@H:27]2[CH2:32][CH2:31][Si@H:30]([CH2:33][CH2:34][CH3:35])[CH2:29][CH2:28]2)=[CH:23][C:22]=1[F:36]>[Ni](Cl)Cl.C1(P(C2C=CC=CC=2)CCCP(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O1CCCC1>[CH2:33]([Si@H:30]1[CH2:31][CH2:32][C@H:27]([C:24]2[CH:25]=[CH:26][C:21]([C:15]3[CH:16]=[CH:17][C:12]([CH2:11][CH2:10][C:7]4[CH:8]=[CH:9][C:4]([CH2:1][CH2:2][CH3:3])=[CH:5][CH:6]=4)=[CH:13][CH:14]=3)=[C:22]([F:36])[CH:23]=2)[CH2:28][CH2:29]1)[CH2:34][CH3:35]
Reactant: CCC[Si@H]1CC[C@H](c2ccc(Cl)c(F)c2)CC1
Reactant: CCCc1ccc(CCc2ccc([Mg]Br)cc2)cc1
Agent: Cl[Ni]Cl
Agent: c1ccc(P(CCCP(c2ccccc2)c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CCCc1ccc(CCc2ccc(-c3ccc([C@H]4CC[Si@H](CCC)CC4)cc3F)cc2)cc1
Temperature: 50 °C
Reaction time: 20 h

Procedure:
An 22-ml tetrahydrofuran solution of 1.05M 4-(2-(4-n-propylphenyl)ethyl)phenyl magnesium bromide was dripped into a mixture of 5.44 g of trans-4-(4-chloro-3-fluorophenyl) -1-n-propyl-1-silacyclohexane, 80 mg of 1,3-bis(diphenylphosphino)propane nickel (II) chloride and 30 ml of tetrahydrofuran, and the resulting mixture was stirred for 20 hours at 50° C. After a conventional after treatment, the reaction mixture was purified by means of silica-gel chromatography to obtain 6.42 g (yield 70%) of the target product.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[CH:5]=[CH:4][N:3]=1.C(=O)([O-])[O-].[K+].[K+].[Br:15][C:16]1[NH:20][CH:19]=[N:18][CH:17]=1.O>CN(C=O)C>[Br:15][C:16]1[N:20]([C:6]2[CH:5]=[CH:4][N:3]=[C:2]([Cl:1])[N:7]=2)[CH:19]=[N:18][CH:17]=1
Reactant: Brc1cnc[nH]1
Reactant: Clc1ccnc(Cl)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: Clc1nccc(-n2cncc2Br)n1
Temperature: 0 °C
Yield: 23.1 %

Procedure:
To a solution of 2,4-dichloropyrimidine (0.447 g, 3 mmol) in anhydrous DMF (4 ml) was added potassium carbonate (0.415 g, 3 mmol). The reaction mixture was cooled (0° C.) under an inert atmosphere before the addition of 5-bromo-1-H-imidazole (0.441 g, 3 mmol) as solution in DMF (2 ml). The reaction was then allowed to stir at this temperature for a further 3 hours whereupon water (3 ml) was added. The resultant white precipitate was removed from the mixture by filtration and washed with water before being dried to give the title compound as a white solid (0.18 g, 23%) which was suitably pure to be used without further purification. m/z (LC-MSW, ESP):259.2,261.2 (bromine isotopes) [M+H]+, R/T=3.47 mins.