Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: ClC(OC(Cl)C)=O.[F:8][C:9]1[CH:32]=[C:31]([F:33])[CH:30]=[C:29]([F:34])[C:10]=1[C:11]([NH:13][C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([C:20]([CH:22]2[CH2:27][CH2:26][N:25](C)[CH2:24][CH2:23]2)=[O:21])[N:15]=1)=[O:12]>ClC(Cl)C>[F:34][C:29]1[CH:30]=[C:31]([F:33])[CH:32]=[C:9]([F:8])[C:10]=1[C:11]([NH:13][C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([C:20]([CH:22]2[CH2:23][CH2:24][NH:25][CH2:26][CH2:27]2)=[O:21])[N:15]=1)=[O:12]
Reactant: CN1CCC(C(=O)c2cccc(NC(=O)c3c(F)cc(F)cc3F)n2)CC1
Agent: CC(Cl)OC(=O)Cl
Solvent: CC(Cl)Cl
Product: O=C(Nc1cccc(C(=O)C2CCNCC2)n1)c1c(F)cc(F)cc1F
Yield: 29.3 %

Procedure:
Add 1-chloroethyl chloroformate (0.8 g) into a solution of 2,4,6-trifluoro-N-[6-(1-methyl-piperidin-4-ylcarbonyl)-pyridin-2-yl]-benzamide (0.216 g) in dichloroethane (10 mL) and heat at reflux for 1 hr. Then add more 1-chloroethyl chloroformate (1 mL) and heat at reflux overnight. Add methanol (10 mL) to the reaction mixture, concentrate to a small volume, dilute with methanol again, load onto an SCX column (10 g), wash with methanol, and elute with 2M NH3-methanol, evaporate and purify on a silica gel column (CH2Cl2 with 2 M NH3 in methanol) to obtain the title compound (61 mg). Mass spectrum (electric spray) m/z=364 (M+1); 1H NMR (CDCl3): 8.55 (d, J=8.1 Hz, 1H), 7.92 (dd, J=8.0, 8.0 Hz 1H), 7.84 (1H, J=8.0 Hz, 1H), 6.81 (m, 3H), 3.89 (m, 1H), 3.12 (br d, 2H), 2.81 (m, 2H), 1.85 (m, 2H), 1.74 (br, 2H), 1.61 (m, 2H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:20][C:21]([N:23]2[C:32]3[C:27](=[CH:28][C:29]([CH2:33][CH2:34][C:35]([O:37]CC)=[O:36])=[CH:30][CH:31]=3)[CH2:26][CH2:25][CH2:24]2)=[O:22])[CH:6]=[CH:7][C:8]=1[NH:9][C:10]([NH:12][C:13]1[C:14]([CH3:19])=[CH:15][CH:16]=[CH:17][CH:18]=1)=[O:11].O.[OH-].[Li+]>C(O)C.O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:20][C:21]([N:23]2[C:32]3[C:27](=[CH:28][C:29]([CH2:33][CH2:34][C:35]([OH:37])=[O:36])=[CH:30][CH:31]=3)[CH2:26][CH2:25][CH2:24]2)=[O:22])[CH:6]=[CH:7][C:8]=1[NH:9][C:10]([NH:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[CH3:19])=[O:11]
Reactant: CCOC(=O)CCc1ccc2c(c1)CCCN2C(=O)Cc1ccc(NC(=O)Nc2ccccc2C)c(OC)c1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: COc1cc(CC(=O)N2CCCc3cc(CCC(=O)O)ccc32)ccc1NC(=O)Nc1ccccc1C
Temperature: 20 °C
Reaction time: 3 h
Yield: 65.1 %

Procedure:
A solution of ethyl 3-(1-{[3-methoxy-4-[(2-toluidinocarbonyl)amino]phenyl}acetyl)-1,2,3,4-tetrahydroquinolin-6-yl)-propanoate (0.24 g, Reference Example 1) in anhydrous ethanol (4 ml), at 20° C., was treated dropwise with a solution of lithium hydroxide monohydrate (33 mg) in distilled water (1 ml). After stirring for 3 hours at 20° C. the reaction mixture was evaporated under reduced pressure (2.7 kPa) at 40° C. The residue was treated with distilled water (35 ml) and the resulting solution was washed twice with diethyl ether (20 ml), then acidified to pH 3 by addition of hydrochloric acid (0.8 ml, 1N) and then extracted twice with ethyl acetate (25 ml). The combined organic extracts were washed twice with water (5 ml), then dried over magnesium sulfate and then evaporated under reduced pressure (2.7 kPa) at 40° C. The resulting white foamy solid (191 mg) was subjected to chromatography on silica gel plates (4 plates, 20×20 cm, thickness=0.5 mm), eluting with a mixture of dichloromethane and methanol (9:1, v/v) to give the title compound (148 mg) as a white foamy solid. 1H NMR (300 MHz, (CD3)2SO): δ 1.81 (m, 2H); 2.27 (s, 3H); from 2.45-2.70 (m, 4H), 2.82 (t, J=7.5 Hz, 2H); 3.72 (t, J=6.5 Hz, 2H); 3.82 (s, 2H); 3.87 (s, 3H); 6.60-7.50 (m, 8H); 7.82 (d, J=8 Hz, 1H); 8.05 (d, J=8 Hz, 1H); 8.50 (s, 1H); 8.60 (s, 1H). MS (Electron Impact recorded on a Finnigan SSQ 7000 spectrometer at 70 eV) 501 (M+).
Reaction SMILES: CO.[C:3]1([NH:9][C:10](=[O:24])[NH:11][C:12]2[S:13][CH:14]=[C:15]([C:17](=[O:23])[C:18](OCC)=[O:19])[N:16]=2)[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[BH4-].[Na+].Cl>O1CCCC1>[OH:23][CH:17]([C:15]1[N:16]=[C:12]([NH:11][C:10]([NH:9][C:3]2[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=2)=[O:24])[S:13][CH:14]=1)[CH2:18][OH:19]
Reactant: CCOC(=O)C(=O)c1csc(NC(=O)Nc2ccccc2)n1
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Product: O=C(Nc1ccccc1)Nc1nc(C(O)CO)cs1
Temperature: 25 °C

Procedure:
7 ml of methanol were added dropwise, over a period of one hour, to a mixture comprising 1 g of ethyl 2-(3-phenylureido)thiazol-4-ylglyoxylate, 0.6 g of sodium borohydride and 20 ml of tetrahydrofuran kept heated under reflux. The resulting mixture was cooled to room temperature and acidified with 3N hydrochloric acid. The solvent was evaporated off under reduced pressure, and the residue was washed with water, giving the desired compound as a white powder.
Reaction SMILES: [H-].[Na+].[CH3:3]I.[OH:5][C:6]([C:11]1[CH:24]=[CH:23][C:22]2[C:13](=[C:14]3[C:19](=[CH:20][CH:21]=2)[CH:18]=[CH:17][CH:16]=[N:15]3)[N:12]=1)([CH3:10])[CH:7]([CH3:9])[CH3:8]>>[CH3:3][O:5][C:6]([C:11]1[CH:24]=[CH:23][C:22]2[C:13](=[C:14]3[C:19](=[CH:20][CH:21]=2)[CH:18]=[CH:17][CH:16]=[N:15]3)[N:12]=1)([CH3:10])[CH:7]([CH3:9])[CH3:8]
Reactant: CC(C)C(C)(O)c1ccc2ccc3cccnc3c2n1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Product: COC(C)(c1ccc2ccc3cccnc3c2n1)C(C)C
Yield: 100.3 %

Procedure:
By employing General Procedure II, NaH (0.020 g, 0.74 mmol), methyl iodide (0.046 mL, 0.74 mmol), and the corresponding 1-hydroxy-1,2-dimethylpropyl phenanthroline (0.052 g, 0.185 mmol), prepared as described by Example 4, were reacted to yield 0.052 g (70% yield) of the title methyl ether as a colorless oil: 1H NMR (300 MHz, CDCl3) δ9.24 (dd, J=4.40, 1.80 Hz, Hp9), 8.24 (dd, J=8.10, 1.80 Hz, Hp7), 8.11 (d, J=8.40 Hz, Hp4), 7.88 (d, J=8.40 Hz, Hp3), 7.81 and 7.74 (two d, J=8.80 Hz, Hp5 and Hp6), 7.60 (dd, J=8.10, 4.50 Hz, Hp8), 3.17 (s, OCH3), 2.25 (sep, J=6.80 Hz, CH(CH3)CH3),1.88 (s, CH3), 1.00 (d, J=6.60 Hz, CH(CH3)CH3), 0.71 (d, J=6.90 Hz, CH(CH3)CH3); 13C NMR (75 MHz) δ165.28, 150.46, 146.51, 145.13, 136.07, 135.76, 128.87, 127/39, 126.46, 126.07, 122.49, 121.06, 84.40, 51.25 39.10, 17.72, 17.43, 16.64; IR (CHCl3 2961 (C—H Ar), 2928 (CH), 866.4 (C—H Ar) cm−1; HRMS m/e Calcd for C18H21N2O (MH+): 281.1654, found 281.1651.
Reaction SMILES: [CH2:1]([Zn]CC)C.ClCI.[Si:9]([O:16][CH2:17][CH2:18][C:19](=[CH2:22])[CH2:20][OH:21])([C:12]([CH3:15])([CH3:14])[CH3:13])([CH3:11])[CH3:10].[NH4+].[Cl-]>C(Cl)Cl>[Si:9]([O:16][CH2:17][CH2:18][C:19]1([CH2:20][OH:21])[CH2:1][CH2:22]1)([C:12]([CH3:15])([CH3:14])[CH3:13])([CH3:10])[CH3:11]
Reactant: C=C(CO)CCO[Si](C)(C)C(C)(C)C
Reactant: CC[Zn]CC
Agent: ClCI
Agent: [Cl-]
Agent: [NH4+]
Solvent: ClCCl
Product: CC(C)(C)[Si](C)(C)OCCC1(CO)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 97.2 %

Procedure:
To a cold (0° C.), stirred solution of diethyl zinc (1.0 M in hexanes, 4.0 mL, 4.0 mmol) in CH2Cl2 (8 mL) was added neat ClCH2I (0.58 mL, 7.96 mmol) drop wise by syringe. After 1 hour, a solution of 4-(tert-butyldimethylsilyloxy)-2-methylene-butan-1-ol (0.395 g, 1.83 mmol) in CH2Cl2 (4 mL) was added by cannula. After 30 minutes, the reaction mixture was treated with saturated aqueous NH4Cl (10 mL), diluted with CH2Cl2 (12 mL), and warmed to room temperature. The phases were separated and the aqueous phase was extracted with CH2Cl2 (3×10 mL). The combined organic extracts were dried (Na2SO4) and concentrated. The crude material was purified by column chromatography on silica gel (9:1 hexanes-ethyl acetate) and provided 0.41 g (97%) of {1-[2-(tert-butyldimethylsilyloxy)-ethyl]-cyclopropyl}-methanol as a colorless oil.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:10]2[CH:22]([CH:23]3[CH2:27][CH2:26][CH2:25][CH2:24]3)[CH:21]3[C:12]([C:13]4[CH:14]=[CH:15][C:16]([C:28]([OH:30])=O)=[N:17][C:18]=4[CH2:19][CH2:20]3)=[N:11]2)[CH:5]=[CH:6][C:7]=1[C:8]#[N:9].Cl.[NH:32]1[CH2:37][CH2:36][S:35](=[O:39])(=[O:38])[CH2:34][CH2:33]1.CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>ClCCl.CN(C=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([N:10]2[CH:22]([CH:23]3[CH2:24][CH2:25][CH2:26][CH2:27]3)[CH:21]3[C:12]([C:13]4[CH:14]=[CH:15][C:16]([C:28]([N:32]5[CH2:37][CH2:36][S:35](=[O:39])(=[O:38])[CH2:34][CH2:33]5)=[O:30])=[N:17][C:18]=4[CH2:19][CH2:20]3)=[N:11]2)[CH:5]=[CH:6][C:7]=1[C:8]#[N:9]
Reactant: O=S1(=O)CCNCC1
Reactant: N#Cc1ccc(N2N=C3c4ccc(C(=O)O)nc4CCC3C2C2CCCC2)cc1Cl
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: N#Cc1ccc(N2N=C3c4ccc(C(=O)N5CCS(=O)(=O)CC5)nc4CCC3C2C2CCCC2)cc1Cl
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 76.2 %

Procedure:
In a dried reaction flask, 2-(3-chloro-4-cyanophenyl)-3-cyclopentyl-3,3a,4,5-tetrahydro-2H-pyrazolo[3,4-f]quinoline-7-carboxylic acid (0.421 g, 1.0 mmol), thiomorpholine-1,1-dioxide hydrochloride (0.223 g, 1.3 mmol), DIEA (0.26 mL, 1.49 mmol), and HATU (0.418 g, 1.1 mmol) were added to a mixed solvent of DMF (4 mL) and dichloromethane (8 mL). The mixture was stirred at room temperature for 1.5 hr and was concentrated under reduced pressure. Water was added to the residue. The mixture was filtered to produce a crude yellow solid, which was washed with methanol to obtain a purified product (0.410 g) in 76.2% yield.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][N:5]1[C:9]2[CH:10]=[CH:11][CH:12]=[C:13]3[CH:14]=[CH:15][CH:16]=[C:7]([C:8]=23)[S:6]1(=[O:18])=[O:17].C(N(CC)CC)C.[Cl:26][C:27]1[CH:32]=[CH:31][C:30]([CH:33]2[CH2:38][CH2:37][NH:36][CH2:35][CH2:34]2)=[CH:29][CH:28]=1>C1(C)C=CC=CC=1>[Cl:26][C:27]1[CH:32]=[CH:31][C:30]([CH:33]2[CH2:34][CH2:35][N:36]([CH2:2][CH2:3][CH2:4][N:5]3[C:9]4[CH:10]=[CH:11][CH:12]=[C:13]5[CH:14]=[CH:15][CH:16]=[C:7]([C:8]=45)[S:6]3(=[O:18])=[O:17])[CH2:37][CH2:38]2)=[CH:29][CH:28]=1
Reactant: O=S1(=O)c2cccc3cccc(c23)N1CCCCl
Reactant: Clc1ccc(C2CCNCC2)cc1
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: O=S1(=O)c2cccc3cccc(c23)N1CCCN1CCC(c2ccc(Cl)cc2)CC1
Temperature: 20 °C
Reaction time: 8 h
Yield: 31.8 %

Procedure:
The experiment is carried out as in Example 1, starting with 2-(3-chloropropyl)naphtho[1,8-cd]isothiazole 1,1-dioxide (2.81 g), triethylamine (1.4 cc) and 4-(4-chlorophenyl)piperidine (1.96 g) in toluene (30 cc). The mixture is heated for 8 hours at boiling point, then cooled to a temperature of about 20° C. Stirring is continued for 8 hours at this temperature. After purification by flash-chromatography on a silica column, under a current of argon at medium pressure (0.5-1.5 bar) with ethyl acetate as eluant, and recrystallization firstly from boiling acetonitrile (12 cc) and then from boiling acetonitrile (17 cc), 2-{3-[4-(4-chlorophenyl)piperidino]propyl}naphtho[1,8-cd]isothiazole 1,1-dioxide (1.4 g) is obtained, m.p. 111° C.
Reaction SMILES: C(=[N:14][C:15]1[CH:20]=[C:19]([C:21]2[N:25]3[N:26]=[C:27]([N:30]4[CH2:35][CH2:34][N:33](C(OC(C)(C)C)=O)[CH2:32][CH2:31]4)[CH:28]=[CH:29][C:24]3=[N:23][C:22]=2[C:43]2[CH:48]=[CH:47][C:46]([F:49])=[CH:45][CH:44]=2)[CH:18]=[CH:17][N:16]=1)(C1C=CC=CC=1)C1C=CC=CC=1>Cl>[F:49][C:46]1[CH:47]=[CH:48][C:43]([C:22]2[N:23]=[C:24]3[CH:29]=[CH:28][C:27]([N:30]4[CH2:31][CH2:32][NH:33][CH2:34][CH2:35]4)=[N:26][N:25]3[C:21]=2[C:19]2[CH:18]=[CH:17][N:16]=[C:15]([NH2:14])[CH:20]=2)=[CH:44][CH:45]=1
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc3nc(-c4ccc(F)cc4)c(-c4ccnc(N=C(c5ccccc5)c5ccccc5)c4)n3n2)CC1
Agent: Cl
Product: Nc1cc(-c2c(-c3ccc(F)cc3)nc3ccc(N4CCNCC4)nn23)ccn1
Temperature: 80 °C

Procedure:
A suspension of 0.80 (1.22 mmol) of tert-butyl 4-[3-[2-(benzhydrylideneamino)pyrid-4-yl]-2-(4-fluorophenyl)imidazo[1,2-b]pyridazin-6-yl]piperazine-1-carboxylate in 70 mL of aqueous hydrochloric acid is maintained at 80° C. for about 1 hour 30 minutes. After cooling, the aqueous phase is washed twice with diethyl ether and then basified by addition of ice-cold aqueous ammonia. The product is extracted with chloroform and the organic phase obtained is washed with water, dried over sodium sulfate and filtered, and the filtrate is concentrated under reduced pressure. The brown solid obtained is purified by chromatography on silica gel (35 g), eluting with a mixture of dichloromethane, methanol and aqueous ammonia (90/10/1). The product obtained is crystallized from 20 mL of refluxing acetonitrile to give 0.38 g of a white powder after cooling, filtering off and drying
Reaction SMILES: N1(C2[CH2:10][CH2:9][N:8]([CH2:11][C:12]3[S:13][C:14]4[N:15]=[C:16]([Cl:27])[N:17]=[C:18]([N:21]5[CH2:26][CH2:25][O:24][CH2:23][CH2:22]5)[C:19]=4[N:20]=3)[CH2:7][CH2:6]2)CCC1.[C:28]([O:32][C:33]([N:35]1CCNCC1)=[O:34])([CH3:31])([CH3:30])[CH3:29]>>[C:28]([O:32][C:33]([N:35]1[CH2:6][CH2:7][N:8]([CH2:11][C:12]2[S:13][C:14]3[N:15]=[C:16]([Cl:27])[N:17]=[C:18]([N:21]4[CH2:22][CH2:23][O:24][CH2:25][CH2:26]4)[C:19]=3[N:20]=2)[CH2:9][CH2:10]1)=[O:34])([CH3:31])([CH3:30])[CH3:29]
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: Clc1nc(N2CCOCC2)c2nc(CN3CCC(N4CCC4)CC3)sc2n1
Product: CC(C)(C)OC(=O)N1CCN(Cc2nc3c(N4CCOCC4)nc(Cl)nc3s2)CC1

Procedure:
Prepared according to the method used in the preparation of 2-(4-azetidin-1-ylpiperidin-1-ylmethyl)-5-chloro-7-morpholin-4-ylthiazolo[5,4-d]pyrimidine using piperazine-1-carboxylic acid tert-butyl ester in place of 4-azetidin-1-ylpiperidine. The title compound was obtained as a white solid (129 mg, 81%).
Reaction SMILES: [Cl:1][C:2]1[N:10]=[CH:9][N:8]=[C:7]2[C:3]=1[NH:4][CH:5]=[N:6]2.O[CH2:12][N:13]1[CH2:17][CH:16]([CH2:18][CH2:19][CH3:20])[CH2:15][C:14]1=[O:21].C(N(CC)C(=O)OCN1CC(CCC)CC1=O)C>C(#N)C>[Cl:1][C:2]1[N:10]=[CH:9][N:8]=[C:7]2[C:3]=1[N:4]=[CH:5][N:6]2[CH2:12][N:13]1[CH2:17][CH:16]([CH2:18][CH2:19][CH3:20])[CH2:15][C:14]1=[O:21]
Reactant: CCCC1CC(=O)N(CO)C1
Reactant: Clc1ncnc2nc[nH]c12
Agent: CCCC1CC(=O)N(COC(=O)N(CC)CC)C1
Solvent: CC#N
Product: CCCC1CC(=O)N(Cn2cnc3c(Cl)ncnc32)C1
Temperature: 25 °C

Procedure:
A solution of commercially available 6-chloro-7H-purine x74 (0.5 g, 3.23 mmol), 1-(hydroxymethyl)-4-propylpyrrolidin-2-one x2 (1 eq, 3.23 mmol, 0.508 g), and (2-oxo-4-propylpyrrolidin-1-yl)methyl diethylcarbamate x6 (0.1 eq, 83 mg, 0.32 mmol) in acetonitrile (5 ml) is heated 30 minutes in a microwave apparatus (Biotage, 150 W, 130° C.). After cooling to room temperature, the solvent is removed under reduced pressure and the crude product is purified by preparative chromatography leading to 600 mg of pure 1-[(6-chloro-9H-purin-9-yl)methyl]-4-propylpyrrolidin-2-one x75.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=O)[CH2:9][C:10]#[N:11])=[C:4]([CH3:13])[CH:3]=1.Cl.[CH3:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[NH:22][NH2:23]>C1(C)C=CC=CC=1>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10]([NH2:11])[N:22]([C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=3[CH3:15])[N:23]=2)=[C:4]([CH3:13])[CH:3]=1
Reactant: Cc1ccccc1NN
Reactant: Cc1cc(F)ccc1C(=O)CC#N
Agent: Cl
Solvent: Cc1ccccc1
Product: Cc1cc(F)ccc1-c1cc(N)n(-c2ccccc2C)n1
Temperature: 110 °C
Reaction time: 16 h
Yield: 15.7 %

Procedure:
To a solution of 3-(4-fluoro-2-methylphenyl)-3-oxopropanenitrile (2.0 g, 11.3 mmol) in toluene (10 mL) was added (2-methylphenyl)hydrazine hydrochloride (2.15 g, 13.5 mmol). The reaction was stirred at 110° C. for 16 h, and then cooled to rt. It was concentrated under reduced pressure, and the residue was purified by silica gel flash chromatography (2:1-1:1=hexanes:ethyl acetate) to afford the product as a yellow oil (500 mg, 16%). 1H NMR (400 MHz, DMSO-d6) δ 2.12 (s, 3H), 2.44 (s, 3H), 5.74 (s, 1H), 7.02-7.14 (m, 2H), 7.34-7.43 (m, 4H), 7.52 (dd, 1H); ES-MS m/z 282.4 (MH+); HPLC RT (min) 3.36
Reaction SMILES: [CH3:1][C:2]1([CH3:18])[O:6][C@@H:5]([C@@H:7]([C@@H:9]2[C@H:13]([CH2:14][OH:15])[O:12][C:11]([CH3:17])([CH3:16])[O:10]2)[OH:8])[CH2:4][O:3]1.[CH3:19][S:20](Cl)(=[O:22])=[O:21].C(=O)(O)[O-].[Na+].C(OCC)(=O)C>ClCCl.N1C=CC=CC=1>[CH3:1][C:2]1([CH3:18])[O:6][C@@H:5]([C@H:7]([O:8][S:20]([CH3:19])(=[O:22])=[O:21])[C@@H:9]2[C@H:13]([CH2:14][O:15][S:20]([CH3:19])(=[O:22])=[O:21])[O:12][C:11]([CH3:17])([CH3:16])[O:10]2)[CH2:4][O:3]1
Reactant: CC1(C)O[C@H]([C@@H](O)[C@H]2COC(C)(C)O2)[C@H](CO)O1
Reactant: CS(=O)(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Product: CC1(C)O[C@H]([C@@H](OS(C)(=O)=O)[C@H]2COC(C)(C)O2)[C@H](COS(C)(=O)=O)O1
Temperature: 0 °C
Reaction time: 5 h
Yield: 95.6 %

Procedure:
4.1 g (0.016 mol) of {(4R)-(2,2-dimethyl[1,3]dioxolan-4-yl)}-{(4R,5S)-(5-hydroxymethyl-2,2-dimethyl[1,3]dioxolan-4-yl)}-(S)-methanol from the aforementioned Experimental Example 2 were dissolved in a mixed solvent of 1.0 L dichloromethane and 25 mL pyridine. After cooling the mixture to 0° C., 18 mL (0.236 mol) of methanesulfonyl chloride were added and the resulting solution was stirred for 5 h at 0° C. Saturated sodium bicarbonate solution was added and the compound was extracted with chloroform. The extract was dried, filtered, and concentrated under reduced pressure. The concentrate was purified by silica gel column chromatography using the eluant hexane:ethyl acetate=2:1 to obtain 6.4 g (yield: 98%) of methanesulfonic acid {(4R)-(2,2-dimethyl[1,3]dioxolan-4-yl)}-{(4S,5S)-(5-methanesulfonyloxymethyl-2,2-dimethyl[1,3]dioxolan-4-yl)}-(S)methyl ester as an oil.
Reaction SMILES: [C:1]([O:4][C:5]1[C:6](Br)=[N:7][CH:8]=[CH:9][CH:10]=1)(=[O:3])[CH3:2].C(N(CC)CC)C.[C:19]([Si:21]([CH3:24])([CH3:23])[CH3:22])#[CH:20]>C1COCC1.[Cu]I.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>[C:1]([O:4][C:5]1[C:6]([C:20]#[C:19][Si:21]([CH3:24])([CH3:23])[CH3:22])=[N:7][CH:8]=[CH:9][CH:10]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)Oc1cccnc1Br
Reactant: C#C[Si](C)(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(=O)Oc1cccnc1C#C[Si](C)(C)C
Temperature: 25 °C
Reaction time: 18 h
Yield: 89.1 %

Procedure:
2-Bromopyridin-3-yl acetate (10 g, 46 mmol) was dissolved in THF (80 mL) and triethylamine (32 ml, 231 mmol), ethynyltrimethylsilane (19.5 ml, 139 mmol), and CuI (0.44 g, 2.3 mmol) were added. The mixture was degassed with argon for 15 minutes. PdCl2(PPh3)2 (1.6 g, 2.3 mmol) was added and the mixture stirred under argon at ambient temperature for 18 hours. The reaction was concentrated in vacuo, dissolved in 25% EtOAc in hexanes, filtered and purified over silica gel (25% ethyl acetate/hexanes) to afford 2-((trimethylsilyl)ethynyl)pyridin-3-yl acetate (9.7 g, 41 mmol).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.[N:11]1[CH:16]=[CH:15][C:14]([CH:17]([C:20]2[CH:21]=[CH:22][C:23]([C:26]([F:29])([F:28])[F:27])=[N:24][CH:25]=2)[CH2:18][NH2:19])=[CH:13][CH:12]=1>>[Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([NH:19][CH2:18][CH:17]([C:14]1[CH:13]=[CH:12][N:11]=[CH:16][CH:15]=1)[C:20]1[CH:21]=[CH:22][C:23]([C:26]([F:29])([F:27])[F:28])=[N:24][CH:25]=1)=[O:6]
Reactant: O=C(O)c1ccccc1Cl
Reactant: NCC(c1ccncc1)c1ccc(C(F)(F)F)nc1
Product: O=C(NCC(c1ccncc1)c1ccc(C(F)(F)F)nc1)c1ccccc1Cl

Procedure:
From 2-chlorobenzoic acid and 2-(pyridin-4-yl)-2-(2-(trifluoromethyl)pyridin-5-yl)ethanamine. LCMS (MH+): m/z=406.1, tR (minutes, Method F)=2.27
Reaction SMILES: CNC1N=C(C2C=CC=CN=2)C=C(C2C=NC=C(C#CC3N(C)C=NC=3)C=2)C=1.Br[C:30]1[CH:31]=[C:32]([C:36]2[CH:41]=[C:40]([NH:42][CH:43]3[CH2:45][CH2:44]3)[N:39]=[C:38]([C:46]3[CH:51]=[CH:50][CH:49]=[CH:48][N:47]=3)[CH:37]=2)[CH:33]=[N:34][CH:35]=1.[C:52]([C:54]1([OH:61])[CH2:59][CH2:58][N:57]([CH3:60])[CH2:56][CH2:55]1)#[CH:53]>>[CH:43]1([NH:42][C:40]2[N:39]=[C:38]([C:46]3[CH:51]=[CH:50][CH:49]=[CH:48][N:47]=3)[CH:37]=[C:36]([C:32]3[CH:33]=[N:34][CH:35]=[C:30]([C:53]#[C:52][C:54]4([OH:61])[CH2:59][CH2:58][N:57]([CH3:60])[CH2:56][CH2:55]4)[CH:31]=3)[CH:41]=2)[CH2:45][CH2:44]1
Reactant: Brc1cncc(-c2cc(NC3CC3)nc(-c3ccccn3)c2)c1
Reactant: C#CC1(O)CCN(C)CC1
Agent: CNc1cc(-c2cncc(C#Cc3cncn3C)c2)cc(-c2ccccn2)n1
Product: CN1CCC(O)(C#Cc2cncc(-c3cc(NC4CC4)nc(-c4ccccn4)c3)c2)CC1

Procedure:
is prepared analogously to Methyl-[5″-(3-methyl-3H-imidazol-4-ylethynyl)-[2,2′;4′,3″]terpyridin-6′-yl]-amine (Example 2.182) by replacing (5″-Bromo-[2,2′;4′,3″]terpyridin-6′-yl)-methyl-amine (Example 2.1; step1) with (5″-Bromo-[2,2′;4′,3″]terpyridin-6′-yl)-cyclopropyl-amine (Example 1.26) and by replacing 1-methyl-5-((trimethylsilyl)ethynyl)-1H-imidazole with 4-ethynyl-1-methylpiperidin-4-ol.
Reaction SMILES: C([O:5][C:6](=[O:26])[CH2:7][C@@H:8]([NH:16]S(C1C=CC(C)=CC=1)=O)[C@H:9]([CH3:15])[C@H:10]([CH3:14])[CH2:11][CH2:12][CH3:13])(C)(C)C.FC(F)(F)C(O)=O>CO>[NH2:16][C@@H:8]([C@H:9]([CH3:15])[C@H:10]([CH3:14])[CH2:11][CH2:12][CH3:13])[CH2:7][C:6]([OH:26])=[O:5]
Reactant: CCC[C@@H](C)[C@@H](C)[C@@H](CC(=O)OC(C)(C)C)NS(=O)c1ccc(C)cc1
Solvent: CO
Solvent: O=C(O)C(F)(F)F
Product: CCC[C@@H](C)[C@@H](C)[C@H](N)CC(=O)O
Reaction time: 2 h
Yield: 81.3 %

Procedure:
To the solution of (4R,5R)-4,5-dimethyl-(R)-3-(toluene-4-sulfinylamino)-octanoic acid tert-butyl ester (1.8 g, 4.71 mmol) in dry methanol (30 mL) at 0° C. under nitrogen was added excess trifluoroacetic acid (25 mL) and stirred for 2 hours at that temperature. The solution was concentrated to dryness followed by the addition of dry dichloromethane (20 mL) and trifluoroacetic acid (20 mL). The resulting mixture was stirred for 2 hours under nitrogen and concentrated to dryness. The residue was applied to BondElute SCX ion exchange resin and eluted with water until the eluent was at constant pH of 6.5. The resin was then eluted with a 1:1 solution of methanol and with 10% ammonium hydroxide solution. The ammonium hydroxide solution was evaporated and the residue was crystallized with methanol-acetonitrile mixture to afford the titled compound (0.717 g, 81.2% yield) as a white solid: 1H NMR (400 MHz, CD3OD-D) δ ppm 0.9 (m, 11H) 1.1 (m, 2H) 1.3 (m, 1H) 1.4 (m, 1H) 1.6 (m, 1H) 1.7 (m, 2H) 2.3 (dd, J=16.6, 10.0 Hz, 1H) 2.5 (dd, J=16.7, 3.5 Hz, 1H) 3.3 (m, 1H). MS, m/z (relative intensity): 188 [M+1H, 100%], 186 [M−1H, 100%].
Reaction SMILES: Br[C:2]1[N:3]=[C:4]([C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=2)[C:5]([NH2:12])=[N:6][C:7]=1[C:8]([F:11])([F:10])[F:9].CO.[C:22]([O:25][CH2:26]C)(=[O:24])C.[C]=O>C(N(CC)CC)C>[CH3:26][O:25][C:22]([C:2]1[C:7]([C:8]([F:11])([F:10])[F:9])=[N:6][C:5]([NH2:12])=[C:4]([C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=2)[N:3]=1)=[O:24]
Reactant: Nc1nc(C(F)(F)F)c(Br)nc1-c1ccc(Cl)cc1
Reactant: CCOC(C)=O
Agent: [C]=O
Solvent: CO
Solvent: CCN(CC)CC
Product: COC(=O)c1nc(-c2ccc(Cl)cc2)c(N)nc1C(F)(F)F

Procedure:
A mixture of 12.57 g 5-bromo-3-(4-chloro-phenyl)-6-trifluoromethyl-pyrazin-2-ylamine, 0.60 g palladium(II)chloride-dppf-dichloromethane complex, 75 ml methanol, 75 ml ethyl acetate and 10.0 ml triethylamine was heated to 110° C. in an autoclav under 70 bar of carbon monoxide for 20 h. The solvents were evaporated and the residue was purified by chromatography on silica gel with dichloromethane to yield 6.48 g of the title compound as off white solid. MS (M−H) at 330.1.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([NH:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([Br:23])[N:18]=2)[CH:12]=[CH:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:24]([C:26]1[N:27]=[CH:28][NH:29][CH:30]=1)=O.C([BH3-])#N.[Na+]>CO.[Cl-].[Zn+2].[Cl-]>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]([N:15]([CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([Br:23])[N:18]=2)[CH2:24][C:26]2[NH:27][CH:28]=[N:29][CH:30]=2)[CH:12]=[CH:13][CH:14]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Brc1cccc(CNc2cccc(OCc3ccccc3)c2)n1
Reactant: O=Cc1c[nH]cn1
Agent: [BH3-]C#N
Agent: [Cl-]
Agent: [Na+]
Solvent: CO
Product: Brc1cccc(CN(Cc2cnc[nH]2)c2cccc(OCc3ccccc3)c2)n1
Temperature: 40 °C
Reaction time: 8 h
Yield: 90.7 %

Procedure:
(3-Benzyloxy-phenyl)-(6-bromo-pyridin-2-ylmethyl)-amine (0.10 g, 0.27 mmol) was dissolved in methanol (2 ml). Then 4-formylimidazole (0.13 g, 1.35 mmol), zinc chloride (0.15 g, 1.08 mmol) and sodium cyanoborohydride (0.05 g, 0.81 mmol) were added and the reaction mixture was allowed to stir at 40° C. overnight. After cooling, the reaction mixture was poured onto ammoniumchloride/ice and extracted with ethyl acetate (2 times 50 ml). The organic layer was dried over magnesium sulfate and evaporated. The residue was purified using flash chromatography (SiO2; eluent: methanol/dichloromethane=1:9) to yield an off-white gum (0.11 g, 94%); MS (ISP): 451.1 ([81Br M+H]+), 449.1 ([79Br M+H]+).