Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C@@H:5]1[C@@H:8]([CH2:9][CH2:10][CH2:11][CH2:12][CH3:13])[O:7][C:6]1=[O:14])[CH2:2][CH2:3][CH3:4].[Li+].[CH3:16][Si]([N-][Si](C)(C)C)(C)C.IC>C1COCC1>[CH2:1]([C@:5]1([CH3:16])[C@H:8]([CH2:9][CH2:10][CH2:11][CH2:12][CH3:13])[O:7][C:6]1=[O:14])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCC[C@H]1OC(=O)[C@@H]1CCCC
Reactant: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CI
Product: CCCCC[C@@H]1OC(=O)[C@]1(C)CCCC
Temperature: -40 °C
Reaction time: 1.5 h
Yield: 72.9 %

Procedure:
A solution of β-lactone 3a (36.3 mg, 0.1835 mmol) in 1.9 mL THF was cooled to −78° C. and 370 μL of LiHMDS (0.367 mmol, 2.0 equiv, 1.0 M solution in THF) was added under a nitrogen atmosphere. After 1.5 h, 23 μL (0.367 mmol, 2.0 equiv) of iodomethane was added and the reaction warmed to −40° C. and stirred for an additional 45 min. The reaction mixture was concentrated in vacuo and purified by flash chromatography (0→15% Et2O: hexanes) to give β-lactone 8a (28.4 mg, 73%) as a colorless oil and as a mixture of cis/trans diastereomers (dr, 6:1). Data provided for major diastereomer: Rf(15% Et2O:hexanes) 0.64; IR (thin film) 1824 cm−1; 1H NMR (500 MHz, CDCl3) δ 4.18 (dd (major diast.), J=6.0, 8.5Hz, 1H), 1.63-1.78 (m, 2H), 1.45-1.53 (m, 2H), 1.39 (s, 3H), 1.24-1.39 (m, 10H), 0.89-0.94 (m, 6H); 13C NMR (500 MHz, CDCl3) 14.1, 14.2, 20.0, 22.1, 25.5, 25.6, 26.5, 30.3, 31.7, 35.9, 56.8, 84.5, 175.5; ESI LRMS Calcd. for C13H24O2Li [M+Li]: 219. Found: 219.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:8]([OH:10])=[O:9])[S:5][C:6]=1[Br:7].S(=O)(=O)(O)O.[CH3:16]O>>[Br:1][C:2]1[CH:3]=[C:4]([C:8]([O:10][CH3:16])=[O:9])[S:5][C:6]=1[Br:7]
Reactant: O=C(O)c1cc(Br)c(Br)s1
Reactant: CO
Agent: O=S(=O)(O)O
Product: COC(=O)c1cc(Br)c(Br)s1
Yield: 96.4 %

Procedure:
To a suspension of 23.75 g (83.06 mmol) of 4,5-dibromo-2-thiophencarboxylic acid in 235 mL of methanol was slowly added 15.5 mL (284 mol) of 98% sulfuric acid at room temperature. The mixture was refluxed for 23 hours. The resulting solution was concentrated to thick slurry under reduced pressure and diluted with 240 mL of dichloromethane. To this ice-cooled solution 190 mL of 17% NaOH was slowly added, under vigorous stirring. The aqueous layer was separated and extracted again with 120 mL of dichloromethane. The combined organic extracts were dried over Na2SO4 then concentrated to dryness to afford 24.02 g of product as an off-white solid.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:12][CH3:13])=[CH:9][CH:10]=2)[CH:5]=[CH:4][N:3]=1.[NH3:14]>C(O)CO.CO.[Cu-]=O>[CH3:13][O:12][C:8]1[CH:7]=[C:6]2[C:11](=[CH:10][CH:9]=1)[C:2]([NH2:14])=[N:3][CH:4]=[CH:5]2
Reactant: N
Reactant: COc1ccc2c(Cl)nccc2c1
Agent: O=[Cu-]
Solvent: CO
Solvent: OCCO
Product: COc1ccc2c(N)nccc2c1
Temperature: 120 °C
Yield: 72 %

Procedure:
A sealable tube was charged with 83E (770 mg, 3.98 mmol), copper (I) oxide (30 mg) and 12M NH3 in ethylene glycol (5 mL). The tube was sealed and the reaction was heated to 120° C. for 72 h. After cooling to rt, the reaction was diluted with methanol and was purified via preparative HPLC (MeOH/water/TFA) to provide 83F (832 mg, 72%). LC-MS: 175.23 (M+H)+.
Reaction SMILES: C(N(CC)CC)C.C(SCl)CCCCCCCCC.[C:20]1([CH3:47])[CH:25]=[CH:24][C:23]([N:26](SCCCCCCCCCC)[CH:27]=[N:28][C:29]2[CH:34]=[CH:33][C:32]([CH3:35])=[CH:31][CH:30]=2)=[CH:22][CH:21]=1>C1C=CC=CC=1>[C:32]1([CH3:35])[CH:33]=[CH:34][C:29]([NH:28][CH:27]=[N:26][C:23]2[CH:22]=[CH:21][C:20]([CH3:47])=[CH:25][CH:24]=2)=[CH:30][CH:31]=1
Reactant: CCCCCCCCCCSN(C=Nc1ccc(C)cc1)c1ccc(C)cc1
Agent: CCCCCCCCCCSCl
Solvent: c1ccccc1
Solvent: CCN(CC)CC
Product: Cc1ccc(N=CNc2ccc(C)cc2)cc1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
The N,N'-di-p-tolylformamidine which is prepared according to the above paragraph is then placed in a flask which is cooled to a temperature of about 0° C. by means of an ice bath. In addition, there was also present in the flask 100 grams of triethylamine and 200 cc. of benzene. When the mixture has reached the desired reduced temperature, decanesulfenyl chloride is slowly added dropwise accompanied by continuous stirring. Upon completion of the addition of the decanesulfenyl chloride, the mixture is stirred for an additional period of 1 hour and then allowed to warm to room temperature. Upon standing the desired product comprising N,N'-di-p-tolyl-N-decylthioformamidine crystallizes, is filtered, washed and recovered.
Reaction SMILES: [N:1]([C@@H:4]1[CH2:9][C@H:8]([O:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C@H:7]2[CH2:18][O:19][C@@H:5]1[O:6]2)=[N+]=[N-].C1CCCCC=1.[C:26](OC(=O)C)(=[O:28])[CH3:27]>CO.[Pd]>[C:26]([NH:1][C@@H:4]1[CH2:9][C@H:8]([O:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C@H:7]2[CH2:18][O:19][C@@H:5]1[O:6]2)(=[O:28])[CH3:27]
Reactant: [N-]=[N+]=N[C@@H]1C[C@H](OCc2ccccc2)[C@H]2CO[C@@H]1O2
Reactant: CC(=O)OC(C)=O
Agent: [Pd]
Solvent: CO
Solvent: C1=CCCCC1
Product: CC(=O)N[C@@H]1C[C@H](OCc2ccccc2)[C@H]2CO[C@@H]1O2
Reaction time: 2 h
Yield: 52 %

Procedure:
A solution of 1,6-anhydro-2-azido-4-O-benzyl-2,3-dideoxy-β-D-ribo-hexopyranose (see Example 13) in methanol (20 ml) was subjected to transfer hydrogenation by heating under reflux with cyclohexene (7 ml) 5% and palladium on charcoal (0.5 g), added in three portions over a period of 6 h. Acetic anhydride (2.5 ml) was then added to the mixture at room temperature. After 2 h, the mixture was filtered, the filtrate was evaporated, and the residue chromatographed on silica gel to yield the title compound as a syrup (0.35 g, 52%), [α]D -28.7°; 13C-nmr data: 101.1 (C-1), 46.4 (C-2), 25.9 (C-3), 74.1 and 73.0 (C-4 and C-5), 65.8 (C-6), 70.5 (PhCH2O), 23.3 (NHCOCH3), 169.2 (NHCOCH3), 137.7 (q-aromatic), 128.5 (×2), 127.9, and 127.5 (×2, aromatic).
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]2[CH:10]=[C:9]([O:11][C:12]3[CH:13]=[CH:14][C:15]([CH3:32])=[C:16]([NH:18][C:19](=[O:31])[C:20]4[CH:25]=[CH:24][CH:23]=[C:22]([C:26]5([C:29]#[N:30])[CH2:28][CH2:27]5)[CH:21]=4)[CH:17]=3)[CH:8]=[CH:7][C:5]=2[N:6]=1.[CH:33]1([C:36](Cl)=[O:37])[CH2:35][CH2:34]1>CN(C)C(=O)C.C(OCC)(=O)C>[C:29]([C:26]1([C:22]2[CH:21]=[C:20]([CH:25]=[CH:24][CH:23]=2)[C:19]([NH:18][C:16]2[CH:17]=[C:12]([O:11][C:9]3[CH:8]=[CH:7][C:5]4[N:6]=[C:2]([NH:1][C:36]([CH:33]5[CH2:35][CH2:34]5)=[O:37])[S:3][C:4]=4[CH:10]=3)[CH:13]=[CH:14][C:15]=2[CH3:32])=[O:31])[CH2:27][CH2:28]1)#[N:30]
Reactant: Cc1ccc(Oc2ccc3nc(N)sc3c2)cc1NC(=O)c1cccc(C2(C#N)CC2)c1
Reactant: O=C(Cl)C1CC1
Solvent: CCOC(C)=O
Solvent: CC(=O)N(C)C
Product: Cc1ccc(Oc2ccc3nc(NC(=O)C4CC4)sc3c2)cc1NC(=O)c1cccc(C2(C#N)CC2)c1
Temperature: 25 °C
Reaction time: 10 h
Yield: 40.4 %

Procedure:
To a solution of N-{5-[(2-amino-1,3-benzothiazol-6-yl)oxy]-2-methylphenyl}-3-(1-cyanocyclopropyl)benzamide (300 mg, 0.681 mmol) in N,N-dimethylacetamide (3.0 mL) was added cyclopropanecarbonyl chloride (65 μL, 0.715 mmol), and the mixture was stirred at room temperature for 10 hr. To the reaction mixture was added cyclopropanecarbonyl chloride (30 μL, 0.33 mmol), and the mixture was further stirred at room temperature for 3 hr. The reaction mixture was diluted with ethyl acetate (100 mL), washed with 5% aqueous sodium hydrogencarbonate solution (100 mL) and saturated brine (100 mL), successively, and dried over anhydrous sodium sulfate. The insoluble material was filtered off, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane/ethyl acetate=70/30→0/100), and the obtained solution was concentrated under reduced pressure. The residue was triturated with ethyl acetate/diisopropyl ether to give the title compound (140 mg, 40%) as a colorless solid.
Reaction SMILES: [CH3:1][CH:2]([CH3:6])[C:3](=[S:5])[NH2:4].Cl[CH:8]([C:14]([CH3:16])=O)[C:9]([O:11][CH2:12][CH3:13])=[O:10]>C(O)C>[CH2:12]([O:11][C:9]([C:8]1[S:5][C:3]([CH:2]([CH3:6])[CH3:1])=[N:4][C:14]=1[CH3:16])=[O:10])[CH3:13]
Reactant: CCOC(=O)C(Cl)C(C)=O
Reactant: CC(C)C(N)=S
Solvent: CCO
Product: CCOC(=O)c1sc(C(C)C)nc1C
Yield: 93.8 %

Procedure:
A solution of 2-methylpropanethioamide (3.1 g, 30 mmol) and ethyl 2-chloroacetoacetate (3.29 g, 20 mmol) in ethanol (40 mL) was heated at reflux for 3 h. The reaction mixture was evaporated to dryness and the residue was taken up in dichloromethane (50 mL) and the solution was washed with saturated sodium bicarbonate solution (2×25 mL). The aqueous layers were back-washed with dichloromethane (25 mL), then the combined dichloromethane layers were dried (MgSO4), filtered and concentrated under vacuum. The residue was purified using a Waters Prep 500 apparatus (silica gel dual column; 10% ethyl acetate/hexanes). Evaporation of the appropriate fractions afforded 2-(1-methylethyl)-4-methylthiazole-5-carboxylic acid ethyl ester (4.0 g, 93% yield).
Reaction SMILES: [CH3:1][N:2](C)[CH:3]=[CH:4][C:5]([C:7]1[CH:8]=[C:9]([CH:14]=[CH:15][CH:16]=1)[C:10]([O:12][CH3:13])=[O:11])=O.CC(O)=O.C(N)=[NH:23].C[O-].[Na+]>CO>[N:2]1[CH:3]=[CH:4][C:5]([C:7]2[CH:8]=[C:9]([CH:14]=[CH:15][CH:16]=2)[C:10]([O:12][CH3:13])=[O:11])=[N:23][CH:1]=1
Reactant: N=CN
Reactant: COC(=O)c1cccc(C(=O)C=CN(C)C)c1
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: COC(=O)c1cccc(-c2ccncn2)c1
Yield: 62.2 %

Procedure:
The mixture of methyl 3-(3-dimethylaminopropenoyl)benzoate (1.4 g), formamidine-acetate (2.8 g) and 28% methanolic sodium methoxide (5.2 ml) in methanol (38 ml) was heated under reflux for 64 hours under stirring. The solvent was removed by concentration and to the residue was added water. The mixture was adjusted to pH 9 with 20% aqueous potassium carbonate solution and the mixture was extracted with ethyl acetate. The extract layer was washed with brine, dried over magnesium sulfate and evaporated in vacuo. The residue was triturated with the solution of diisopropyl ether and n-hexane and the precipitate was collected by filtration to give methyl 3-(pyrimidin-4-yl)benzoate (0.8 g).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([CH2:28][CH2:29]CS([O-])(=O)=O)[CH2:13][CH2:12][N:11]([C:14](=[O:27])[C:15]3[CH:20]=[C:19]([O:21][CH3:22])[C:18]([O:23][CH3:24])=[C:17]([O:25][CH3:26])[CH:16]=3)[CH2:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8].Cl.[CH:36]1[C:45]2[C:40](=[CH:41][CH:42]=[CH:43][CH:44]=2)[CH:39]=[CH:38][C:37]=1[C:46]1([C:52]([NH2:54])=[O:53])[CH2:51][CH2:50][NH:49][CH2:48][CH2:47]1>>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([CH2:28][CH2:29][N:49]3[CH2:48][CH2:47][C:46]([C:37]4[CH:38]=[CH:39][C:40]5[C:45](=[CH:44][CH:43]=[CH:42][CH:41]=5)[CH:36]=4)([C:52]([NH2:54])=[O:53])[CH2:51][CH2:50]3)[CH2:13][CH2:12][N:11]([C:14](=[O:27])[C:15]3[CH:20]=[C:19]([O:21][CH3:22])[C:18]([O:23][CH3:24])=[C:17]([O:25][CH3:26])[CH:16]=3)[CH2:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: COc1cc(C(=O)N2CCC(CCCS(=O)(=O)[O-])(c3ccc(Cl)c(Cl)c3)C2)cc(OC)c1OC
Reactant: NC(=O)C1(c2ccc3ccccc3c2)CCNCC1
Agent: Cl
Product: COc1cc(C(=O)N2CCC(CCN3CCC(C(N)=O)(c4ccc5ccccc5c4)CC3)(c3ccc(Cl)c(Cl)c3)C2)cc(OC)c1OC

Procedure:
Prepare by the method of example 3.3 using 2-[3-(3,4-dichloro-phenyl)-1-(3,4,5-trimethoxy-benzoyl)-pyrrolidin-3-yl]-ethyl-methanesulfonate (5 mmol) and 4-(naphth-2-yl)-piperidine-4-carboxylic acid amide hydrochloride (7.5 mmol, 1.5 eq.). Chromatograph on silica gel to give the title compound.
Reaction SMILES: [N:1]([O-])=O.[Na+].[CH3:5][O:6][C:7]1[CH:13]=[CH:12][C:10]([NH2:11])=[C:9]([CH3:14])[CH:8]=1>O.C(O)(=O)C>[CH3:5][O:6][C:7]1[CH:8]=[C:9]2[C:10](=[CH:12][CH:13]=1)[NH:11][N:1]=[CH:14]2
Reactant: O=N[O-]
Reactant: COc1ccc(N)c(C)c1
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: COc1ccc2[nH]ncc2c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 18 %

Procedure:
A solution of sodium nitrite (3.38 g, 49.0 mmol) in water (8.1 ml) was added to a solution of 4-methoxy-2-methylaniline (6.69 g, 48.8 mmol) in acetic acid (350 ml) in an ice-water bath while maintaining the temperature at 25° C. or lower, and stirred overnight at room temperature. Then, the reaction solution was poured into water and extracted with chloroform. The organic layer was washed with a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate and then distilled under reduced pressure to remove the solvent, and the resulting residue was purified by a silica gel column chromatography (eluent: chloroform/methanol=9/1) to obtain 5-methoxy-1H-indazole (1.30 g, 18%).
Reaction SMILES: C[O:2][C:3](=[O:24])[C@:4]([N:17]([CH2:19][CH:20]([OH:23])[CH2:21][OH:22])[CH3:18])([CH2:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[CH:11][CH:10]=1)[N:5]=[C:6]=[O:7].Cl>O1CCOCC1.O>[CH3:18][N:17]([C@@:4]([C:3]([OH:24])=[O:2])([CH2:8][C:9]1[CH:10]=[CH:11][C:12]([O:15][CH3:16])=[CH:13][CH:14]=1)[N:5]=[C:6]=[O:7])[CH2:19][CH:20]([OH:23])[CH2:21][OH:22]
Reactant: COC(=O)[C@](Cc1ccc(OC)cc1)(N=C=O)N(C)CC(O)CO
Agent: Cl
Solvent: O
Solvent: C1COCCO1
Product: COc1ccc(C[C@](N=C=O)(C(=O)O)N(C)CC(O)CO)cc1

Procedure:
The resultant compound from Example 115 (114 mg, 0.355 mmol) in dioxane (4 ml) and water (2 ml) at 0° C. was treated with LiOH monohydrate (42.0 mg, 1 mmol). After 90 min 2M HCl (0.6 ml, 1.2 mmol) was added and the mixture was evaporated to a form which was used without further purification; DCI-MS: (M+H)+ =327.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][CH:5]=1)([O-:3])=[O:2].C([O-])([O-])=O.[K+].[K+].Cl[CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>C(#N)C>[CH2:18]([O:10][C:7]1[CH:8]=[CH:9][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: ClCc1ccccc1
Reactant: O=[N+]([O-])c1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: O=[N+]([O-])c1ccc(OCc2ccccc2)cc1
Yield: 90.4 %

Procedure:
To a mixture of 4-nitrophenol (10.0 g, 71.9 mmol), K2CO3 (19.9 g, 143.9 mmol) and KI (2.6 g, 15.8 mmol) in acetonitrile was added chloromethylbenzene (10.0 g, 79.1 mmol) at RT. The resultant mixture was heated to reflux for 3 h. After removal of the solvent, the residue was dissolved in EtOAc. The combined organic extracts were washed with brine, dried (Na2SO4), filtered and concentrated to afford 4-benzyloxynitrobenzene (14.9 g, 90% yield). 1H NMR (400 MHz, CDCl3): δ 8.20 (d, J=8.0 Hz, 2H), 7.43-7.37 (m, 5H), 7.03 (d, J=8.0 Hz, 2H), 5.17 (s, 2H).
Reaction SMILES: [CH3:1][N:2](/[CH:4]=[N:5]/[C:6]1[S:7][C:8]([C:11]([OH:13])=O)=[CH:9][N:10]=1)[CH3:3].S(Cl)(Cl)=O.C(N(CC)CC)C.[CH:25]1([NH2:28])[CH2:27][CH2:26]1>>[CH:25]1([NH:28][C:11]([C:8]2[S:7][C:6](/[N:5]=[CH:4]/[N:2]([CH3:1])[CH3:3])=[N:10][CH:9]=2)=[O:13])[CH2:27][CH2:26]1
Reactant: NC1CC1
Reactant: CN(C)/C=N/c1ncc(C(=O)O)s1
Solvent: O=S(Cl)Cl
Solvent: CCN(CC)CC
Product: CN(C)/C=N/c1ncc(C(=O)NC2CC2)s1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a 100 mL flask was charged 2-{[(1E)-(dimethylamino) methylidene]amino}-1,3-thiazole-5-carboxylic acid 23-2 (0.56 g, 2.37 mmol) and thionyl chloride (5 mL). This suspension was refluxed for 75 minutes. At the end of this time the homogeneous solution was evaporated to dryness and the residue was flushed 2 times with CCl4. This residue was then dissolved in methylene chloride and triethylamine (1.20 g, 11.8 mmol) was added followed by cyclopropylamine (0.47 g, 8.29 mmol). The reaction was stirred overnight at 25° C. A precipitate was filtered off. Hi-Res MS: calc: 239.0961 found: 239.0959. 1H-NMR (DMSO): 8.36 ppm (s, 1H); 8.27 ppm (s, 1H); 7.83 ppm (s, 1H); 3.12 ppm (s, 3H); 2.98 ppm (s, 3H); 2.72 ppm (m, 1H); 0.67 ppm (m, 2H); 0.52 ppm (m, 2H).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([Br:8])=[CH:4][N:3]=1.[Cl:9][C:10]1[CH:17]=[CH:16][C:13]([CH:14]=O)=[CH:12][CH:11]=1.FC(F)(F)C(O)=O.C([SiH](CC)CC)C>C1(C)C=CC=CC=1>[Br:8][C:5]1[CH:6]=[CH:7][C:2]([NH:1][CH2:14][C:13]2[CH:16]=[CH:17][C:10]([Cl:9])=[CH:11][CH:12]=2)=[N:3][CH:4]=1
Reactant: Nc1ccc(Br)cn1
Reactant: O=Cc1ccc(Cl)cc1
Agent: CC[SiH](CC)CC
Solvent: Cc1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: Clc1ccc(CNc2ccc(Br)cn2)cc1

Procedure:
To 2-Amino-5-bromopyridine (15, 6.10 g, 0.0352 mol) in toluene (90.0 mL) were added 4-chlorobenzaldehyde (40, 5.00 g, 0.0356 mol), trifluoroacetic acid (8.0 mL, 0.10 mol) and triethylsilane (16.5 mL, 0.103 mol). The reaction was heated to reflux for 48 hours. The reaction was concentrated, poured into aqueous potassium carbonate and extracted with ethyl acetate. The organic layer was washed with brine, dried over sodium sulfate and concentrated. The crude residue was crystallized with ethyl acetate to give compound (41, 6.8 g, 65.4%).
Reaction SMILES: [CH3:1]C(C)([O-])C.[K+].[Si:7]([O:14][CH2:15][CH2:16][C:17]([C:19]1[CH:24]=[CH:23][C:22]([Cl:25])=[C:21]([Cl:26])[CH:20]=1)=O)([C:10]([CH3:13])([CH3:12])[CH3:11])([CH3:9])[CH3:8].O>[Br-].C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C1C=CC=CC=1>[Si:7]([O:14][CH2:15][CH2:16][C:17]([C:19]1[CH:24]=[CH:23][C:22]([Cl:25])=[C:21]([Cl:26])[CH:20]=1)=[CH2:1])([C:10]([CH3:13])([CH3:12])[CH3:11])([CH3:9])[CH3:8]
Reactant: CC(C)(C)[Si](C)(C)OCCC(=O)c1ccc(Cl)c(Cl)c1
Reactant: CC(C)(C)[O-]
Agent: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Agent: [K+]
Solvent: O
Solvent: c1ccccc1
Product: C=C(CCO[Si](C)(C)C(C)(C)C)c1ccc(Cl)c(Cl)c1
Temperature: 25 °C
Reaction time: 9 h
Yield: 59.1 %

Procedure:
215 g (0.60 mole) of methyltriphenylphosphonium bromide and 54 g (0.48 mole) of potassium t-butoxide were added to 2 liters of dried benzene, and the mixture was stirred for 9 hours at room temperature. At the end of this time, 40 g (0.12 mole) of 3-(3,4-dichlorophenyl)-3-oxo-1-propanol t-butyldimethylsilyl ether [prepared as described in step (b) above] were dissolved in 800 ml of benzene and the resulting solution was slowly added dropwise to the mixture over a period of 2.5 hours. 1 liter of water was then added to the reaction mixture, and the mixture was stirred for 30 minutes, whilst ice-cooling. The organic layer was separated, and then washed with water and with a saturated aqueous solution of sodium chloride, after which it was dried over anhydrous sodium sulfate. The solvent was removed by distillation under reduced pressure, and the resulting residue was purified by silica gel column chromatography, using hexane as the eluent, to give 23.5 g of the title compound. The physicochemical properties of this product were the same as those of the product produced as described in Example 1(b).
Reaction SMILES: [CH2:1]([N:3]1[C:7]2[C:8]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=3)=[C:9]([F:12])[CH:10]=[CH:11][C:6]=2[N:5]=[C:4]1[C@@H:19]([NH2:21])[CH3:20])[CH3:2].[NH2:22][C:23]1[C:28]([C:29]#[N:30])=[C:27](Cl)[N:26]=[CH:25][N:24]=1.CCN(C(C)C)C(C)C>CC(O)C>[NH2:22][C:23]1[C:28]([C:29]#[N:30])=[C:27]([NH:21][C@H:19]([C:4]2[N:3]([CH2:1][CH3:2])[C:7]3[C:8]([C:13]4[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=4)=[C:9]([F:12])[CH:10]=[CH:11][C:6]=3[N:5]=2)[CH3:20])[N:26]=[CH:25][N:24]=1
Reactant: CCn1c([C@H](C)N)nc2ccc(F)c(-c3ccccn3)c21
Reactant: N#Cc1c(N)ncnc1Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(C)O
Product: CCn1c([C@H](C)Nc2ncnc(N)c2C#N)nc2ccc(F)c(-c3ccccn3)c21
Temperature: 80 °C
Reaction time: 16 h
Yield: 33 %

Procedure:
A mixture of (S)-1-(1-ethyl-6-fluoro-7-pyridin-2-yl-1H-benzoimidazol-2-yl)ethylamine (0.203 g, 0.715 mmol), 4-amino-6-chloropyrimidine-5-carbonitrile (0.11 g, 0.715 mmol) and DIPEA (0.65 mL, 3.58 mmol) in IPA (5 mL) was stirred at 80° C. in a sealed microwave tube for 16 hours. After cooling, the mixture was concentrated in vacuo and the residue was purified chromatography, (Si—PPC, gradient 0-5% MeOH in DCM), to give 410 as a solid (0.095 g, 33%). LCMS (Method K): RT 3.03 min [M+H]+ 403. 1H NMR (DMSO-d6, 400 MHz): δ 8.71-8.67 (1H, m), 7.96 (1H, s), 7.92 (1H, td, J=7.8, 1.9 Hz), 7.73 (1H, d, J=7.7 Hz), 7.70-7.62 (2H, m), 7.47 (1H, ddd, J=7.7, 5.0, 1.1 Hz), 7.25 (2H, br s), 7.12 (1H, dd, J=10.4, 8.8 Hz), 5.60 (1H, quin, J=7.2 Hz), 3.80-3.67 (2H, m), 1.55 (3H, d, J=6.8 Hz), 0.69 (3H, t, J=7.1 Hz)
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([CH2:8][N:9]2[CH:13]=[CH:12][N:11]=[CH:10]2)=[CH:4][C:3]=1[N+:14]([O-:16])=[O:15].[N:17]1[CH:22]=[CH:21][CH:20]=[C:19]([CH2:23][NH2:24])[CH:18]=1>C(O)C>[N:9]1([CH2:8][C:5]2[CH:6]=[CH:7][C:2]([NH:24][CH2:23][C:19]3[CH:18]=[N:17][CH:22]=[CH:21][CH:20]=3)=[C:3]([N+:14]([O-:16])=[O:15])[CH:4]=2)[CH:13]=[CH:12][N:11]=[CH:10]1
Reactant: O=[N+]([O-])c1cc(Cn2ccnc2)ccc1F
Reactant: NCc1cccnc1
Solvent: CCO
Product: O=[N+]([O-])c1cc(Cn2ccnc2)ccc1NCc1cccnc1
Reaction time: 4 h
Yield: 82 %

Procedure:
(a-3) A mixture of 4.4 parts of 1-[(4-fluoro-3-nitrophenyl)methyl]-1H-imidazole, 4.33 parts of 3-pyridinemethanamine and 80 parts of absolute ethanol was stirred for 4 hours at reflux temperature. The reaction mixture was evaporated. 50 Parts of water were added to the residue. The product was extracted twice with 130 parts of trichloromethane. The combined trichloromethane layers were dried, filtered and evaporated. The residue was crystallized from 48 parts of 2-propanol. The product was filtered off and dried, yielding 5.1 parts (82%) of N-[4-(1H-imidazol-1-ylmethyl)-2-nitrophenyl]-3-pyridinemethanamine; mp. 171.0° C. (int. 71).
Reaction SMILES: [CH:1]1([C:4]2[C:12]([N:13]([CH2:18][CH2:19][CH2:20][OH:21])[S:14]([CH3:17])(=[O:16])=[O:15])=[CH:11][C:10]3[C:6](=[C:7]([C:36]([NH:38][CH3:39])=[O:37])[N:8]([C:22]4[CH:27]=[CH:26][C:25]([NH:28]C5C=CC=CC=5F)=[CH:24][CH:23]=4)[N:9]=3)[CH:5]=2)[CH2:3][CH2:2]1.BrC1C=CC(N2C(C(NC)=O)=C3C(C=C(N(CCCO)S(C)(=O)=O)C(C4CC4)=C3)=N2)=CC=1.[F:72][C:73]1[CH:79]=[CH:78][C:76](N)=[CH:75][CH:74]=1>>[CH:1]1([C:4]2[C:12]([N:13]([CH2:18][CH2:19][CH2:20][OH:21])[S:14]([CH3:17])(=[O:15])=[O:16])=[CH:11][C:10]3[C:6](=[C:7]([C:36]([NH:38][CH3:39])=[O:37])[N:8]([C:22]4[CH:23]=[CH:24][C:25]([NH:28][C:76]5[CH:78]=[CH:79][C:73]([F:72])=[CH:74][CH:75]=5)=[CH:26][CH:27]=4)[N:9]=3)[CH:5]=2)[CH2:3][CH2:2]1
Reactant: CNC(=O)c1c2cc(C3CC3)c(N(CCCO)S(C)(=O)=O)cc2nn1-c1ccc(Nc2ccccc2F)cc1
Reactant: Nc1ccc(F)cc1
Agent: CNC(=O)c1c2cc(C3CC3)c(N(CCCO)S(C)(=O)=O)cc2nn1-c1ccc(Br)cc1
Product: CNC(=O)c1c2cc(C3CC3)c(N(CCCO)S(C)(=O)=O)cc2nn1-c1ccc(Nc2ccc(F)cc2)cc1

Procedure:
5-Cyclopropyl-2-{4-[(4-fluorophenyl)amino]phenyl}-6-[(3-hydroxypropyl)(methylsulfonyl)amino]-N-methyl-2H-indazole-3-carboxamide (ii) was prepared similarly to Compound (5) (Method C, Step b) from 2-(4-bromophenyl)-5-cyclopropyl-6-[(3-hydroxypropyl)(methylsulfonyl)amino]-N-methyl-2H-indazole-3-carboxamide (i) using 4-fluoroaniline instead of 2-fluoroaniline.
Reaction SMILES: [NH2:1][C:2]1[N:3]=[CH:4][C:5]2[NH:6][C:7]3[C:12]([C:13]=2[CH:14]=1)=[CH:11][CH:10]=[CH:9][CH:8]=3.Br[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20]Br.C1(C2CCCCCCCCCC=2)CCCCCCCCNN=1>O1CCCC1.C(O)C>[N:1]1([C:2]2[N:3]=[CH:4][C:5]3[NH:6][C:7]4[C:12]([C:13]=3[CH:14]=2)=[CH:11][CH:10]=[CH:9][CH:8]=4)[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1
Reactant: Nc1cc2c(cn1)[nH]c1ccccc12
Reactant: BrCCCCCBr
Agent: C1=C(C2=NNCCCCCCCC2)CCCCCCCCC1
Solvent: CCO
Solvent: C1CCOC1
Product: c1ccc2c(c1)[nH]c1cnc(N3CCCCC3)cc12
Yield: 6.6 %

Procedure:
549 mg of 3-amino-β-carboline are refluxed for 4 hours with 1.5 g of 1,5-dibromopentane and 1 g of diazabicycloundecene in 25 ml of tetrahydrofuran and 5 ml of absolute ethanol. After evaporation, the product is chromatographed on silica gel with cyclohexane/ethyl acetate=1:1 as eluant. 50 mg of 3-piperidino-β-carboline are obtained as oil.