Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O:2][C:3](=[O:39])[C:4]1[CH:9]=[CH:8][C:7]([CH:10]([NH:23][C:24]([NH:26][C:27]2[CH:32]=[C:31]([C:33]([F:36])([F:35])[F:34])[CH:30]=[C:29]([O:37][CH3:38])[CH:28]=2)=[O:25])[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[CH:17]2[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]2)=[CH:6][CH:5]=1.[OH-].[Na+].C(OCC)(=O)C>C(O)C>[CH:17]1([C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[CH:10]([NH:23][C:24]([NH:26][C:27]2[CH:32]=[C:31]([C:33]([F:35])([F:36])[F:34])[CH:30]=[C:29]([O:37][CH3:38])[CH:28]=2)=[O:25])[C:7]2[CH:6]=[CH:5][C:4]([C:3]([OH:39])=[O:2])=[CH:9][CH:8]=2)[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1
Reactant: COC(=O)c1ccc(C(NC(=O)Nc2cc(OC)cc(C(F)(F)F)c2)c2ccccc2C2CCCCC2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: CCOC(C)=O
Product: COc1cc(NC(=O)NC(c2ccc(C(=O)O)cc2)c2ccccc2C2CCCCC2)cc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 62.6 %

Procedure:
4-[1-(Cyclohexylphenyl)-3-(3-methoxy-5-trifluoromethylphenyl)ureidomethyl]benzoic acid methyl ester (3.0 g) was dissolved in absolute ethanol (50 mL), sodium hydroxide (4 N, 15 mL) was added and the reaction mixture was stirred at room temperature for 16 hours. The organic solvent was removed in vacuo, and additional water (50 mL) was added, pH was adjusted with hydrochloric acid (4 N) to acidic reaction and then ethyl acetate (200 mL) was added. The organic phase was washed with water (5×50 mL), dried (magnesium sulphate), filtered and evaporated in vacuo. The residue was recrystallised from acetonitrile (25 mL) to afford 4-[1-(cyclohexylphenyl)-3-(3-methoxy-5-trifluoromethylphenyl)ureidomethyl]benzoic acid (1.83 g) as crystals.
Reaction SMILES: [O:1]=[C:2]1[CH:7]=[CH:6][C:5]2[C:8](OS(C(F)(F)F)(=O)=O)=[CH:9][CH:10]=[CH:11][C:4]=2[O:3]1.[CH3:20][C:21]([Si:24]([O:27][CH2:28][CH2:29][CH2:30][CH2:31][C:32]#[CH:33])([CH3:26])[CH3:25])([CH3:23])[CH3:22]>>[CH3:23][C:21]([Si:24]([CH3:25])([CH3:26])[O:27][CH2:28][CH2:29][CH2:30][CH2:31][C:32]#[C:33][C:8]1[C:5]2[CH:6]=[CH:7][C:2](=[O:1])[O:3][C:4]=2[CH:11]=[CH:10][CH:9]=1)([CH3:20])[CH3:22]
Reactant: O=c1ccc2c(OS(=O)(=O)C(F)(F)F)cccc2o1
Reactant: C#CCCCCO[Si](C)(C)C(C)(C)C
Product: CC(C)(C)[Si](C)(C)OCCCCC#Cc1cccc2oc(=O)ccc12
Yield: 87 %

Procedure:
Using the procedure of example 120, trifluoromethanesulfonic acid 2-oxo-2H-1-benzopyran-5-yl ester from example 119 was converted to the title compound by reaction with (1,1-dimethylethyl)(5-hexynyloxy)dimethylsilane. The product was a solid, obtained in 87% yield.
Reaction SMILES: [F:1][C:2]1[C:3]2[N:4]([CH:20]=[N:21][CH:22]=2)[C:5]([NH:11][C:12]2[CH:17]=[CH:16][C:15]([I:18])=[CH:14][C:13]=2[F:19])=[C:6]([C:8](O)=[O:9])[CH:7]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.Cl.[OH:57][C@@H:58]([CH3:62])[CH2:59][O:60][NH-:61]>C1COCC1>[OH:57][C@@H:58]([CH3:62])[CH2:59][O:60][NH:61][C:8]([C:6]1[CH:7]=[C:2]([F:1])[C:3]2[N:4]([CH:20]=[N:21][CH:22]=2)[C:5]=1[NH:11][C:12]1[CH:17]=[CH:16][C:15]([I:18])=[CH:14][C:13]=1[F:19])=[O:9]
Reactant: C[C@H](O)CO[NH-]
Reactant: O=C(O)c1cc(F)c2cncn2c1Nc1ccc(I)cc1F
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: C[C@H](O)CONC(=O)c1cc(F)c2cncn2c1Nc1ccc(I)cc1F
Temperature: 25 °C
Reaction time: 18 h
Yield: 11.6 %

Procedure:
A suspension of 8-fluoro-5-(2-fluoro-4-iodo-phenylamino)-imidazo[1,5-a]pyridine-6-carboxylic acid (100 mg, 0.23 mmol), HATU (130 mg, 0.34 mmol), DIPEA (0.06 mL, 0.34 mmol) and (S)-2-hydroxy-propoxy-amide hydrochloride (44 mg, 0.34 mmol) in THF (1 mL) was stirred at room temperature for 18 hours. The reaction mixture was partitioned between ethyl acetate (5 mL) and 1M HCl, the organic layer was isolated and washed with saturated aqueous NaHCO3 (2×5 mL) and brine (2×5 mL), dried over Na2SO4, filtered and concentrated in vacuo. The resultant residue was subjected to reverse-phase preparative HPLC (Gemini 5 micron C18 250×21.20 mm column, 0.1% formic acid, gradient acetonitrile/water, 5 to 98%, ramp time 20 minutes) to afford the title compound as a yellow solid (13 mg, 8%). LCMS (method A): RT=8.13 min, [M+H]+=489. 1H NMR (DMSO-d6): 11.51 (1 H, broad), 8.95 (1 H, broad), 8.25 (1 H, s), 7.60 (1 H, s), 7.55 (1 H, d, J=10.7 Hz), 7.27 (1 H, d, J=8.4 Hz), 6.82 (1 H, d, J=11.1 Hz), 6.32 (1 H, t, J=8.8 Hz), 4.66 (1 H, broad), 3.64 (1 H, m), 3.43 (2 H, d, J=5.8 Hz), 0.94 (3 H, d, J=6.3 Hz).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:6]=[CH:7][C:8]2[CH:12]=[C:11]([C:13]3[C:18]([CH3:19])=[CH:17][N:16]=[C:15](Cl)[N:14]=3)[S:10][C:9]=2[CH:21]=1)=[O:4].[NH2:22][CH2:23][CH2:24][CH2:25][N:26]1[CH2:31][CH2:30][N:29]([CH3:32])[CH2:28][CH2:27]1>O1CCOCC1>[CH3:1][O:2][C:3]([C:5]1[CH:6]=[CH:7][C:8]2[CH:12]=[C:11]([C:13]3[C:18]([CH3:19])=[CH:17][N:16]=[C:15]([NH:22][CH2:23][CH2:24][CH2:25][N:26]4[CH2:27][CH2:28][N:29]([CH3:32])[CH2:30][CH2:31]4)[N:14]=3)[S:10][C:9]=2[CH:21]=1)=[O:4]
Reactant: COC(=O)c1ccc2cc(-c3nc(Cl)ncc3C)sc2c1
Reactant: CN1CCN(CCCN)CC1
Solvent: C1COCCO1
Product: COC(=O)c1ccc2cc(-c3nc(NCCCN4CCN(C)CC4)ncc3C)sc2c1
Temperature: 90 °C
Yield: 45.5 %

Procedure:
A mixture of 2-(2-chloro-5-methylpyrimidin-4-yl)-benzo[b]thiophene-6-carboxylic acid methyl ester (2.08 g, 6.50 mmol) and 1-(3-aminopropyl)-4-methylpiperazine (3.00 g, 19.0 mmol) in 1,4-dioxane (40 mL) is heated at 90° C. for 20 hours. The solvent is evaporated and the resulting residue is subjected to chromatography on silica gel, eluting with 2M NH3/CH3OH in dichloromethane 0-8%, to give the title compound (1.30 g, 72% yield). ES+(m/z) 460 [M+H].
Reaction SMILES: [C:1]1([S@@:7]([CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])(=[NH:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:16][C:17]1[CH:21]=[CH:20][O:19][C:18]=1[C:22]([NH:24][C:25]1[CH:26]=[C:27]([C:31]#[C:32][C:33]2[CH:34]=[N:35][CH:36]=[C:37]([CH:41]=2)[C:38](O)=[O:39])[CH:28]=[CH:29][CH:30]=1)=[O:23].Cl.CN(C)CCCN=C=NCC.Cl>CN(C=O)C.CN(C)C1C=CN=CC=1>[CH3:16][C:17]1[CH:21]=[CH:20][O:19][C:18]=1[C:22]([NH:24][C:25]1[CH:26]=[C:27]([C:31]#[C:32][C:33]2[CH:41]=[C:37]([C:38]([N:9]=[S@:7]([CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)=[O:8])=[O:39])[CH:36]=[N:35][CH:34]=2)[CH:28]=[CH:29][CH:30]=1)=[O:23]
Reactant: CCOC(=O)C[S@](=N)(=O)c1ccccc1
Reactant: Cc1ccoc1C(=O)Nc1cccc(C#Cc2cncc(C(=O)O)c2)c1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CN(C)C=O
Product: CCOC(=O)C[S@@](=O)(=NC(=O)c1cncc(C#Cc2cccc(NC(=O)c3occc3C)c2)c1)c1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 43.4 %

Procedure:
To a solution of ethyl (S)-(S-phenylsulfonimidoyl)acetate (139 mg, 0.61 mmol) in anhydrous DMF (3 mL) at room temperature was added 5-{3-[(3-Methyl-furan-2-carbonyl)-amino]-phenylethynyl}-nicotinic acid (233 mg), catalytic amount of 4-(dimethylamino)pyridine, and N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (141 mg). The reaction mixture was stirred at room temperature for 30 min. The reaction was then poured into aqueous HCl (0.5%) and extracted with EtOAc. After the aqueous layer was separated, solid sodium chloride was added and the resulting aqueous mixture was extracted again with EtOAc. The organic layers were combined, washed with brine (1×), saturated aqueous NaHCO3 (1×), then brine (1×), and finally dried with sodium sulfate. The upper solution was decanted, concentrated, and the yellow oily residue was subject to a column chromatography (silica gel, gradient elution EtOAc-Hex from 1:5 to 1:1.5) to give the title compound as a white foam (147 mg, 43%).
Reaction SMILES: [CH:1]1([Mg]Br)[CH2:5][CH2:4][CH2:3][CH2:2]1.[C:8]([CH2:12][C:13]1([CH2:20][CH3:21])[C:18](=[O:19])[CH:17]=[CH:16][CH2:15][CH2:14]1)([O:10][CH3:11])=[O:9]>C1COCC1.S(C)C>[C:8]([CH2:12][C:13]1([CH2:20][CH3:21])[CH2:14][CH2:15][CH:16]([CH:1]2[CH2:5][CH2:4][CH2:3][CH2:2]2)[CH2:17][C:18]1=[O:19])([O:10][CH3:11])=[O:9]
Reactant: CCC1(CC(=O)OC)CCC=CC1=O
Reactant: Br[Mg]C1CCCC1
Solvent: CSC
Solvent: C1CCOC1
Product: CCC1(CC(=O)OC)CCC(C2CCCC2)CC1=O
Reaction time: 1.5 h
Yield: 73.9 %

Procedure:
Following the procedure of Paquette et al., J. Am. Chem. Soc., 103, 1831 (1981) a solution of cyclopentylmagnesium bromide (222.5 mmol, 111.2 ml of 2M in Et2O), in 481 ml of dry THF under nitrogen was cooled to -78° C. and treated dropwise with a solution of 120.4 mmol (24.75 g) of CuBr.Me2S in 170 ml of Me2S. After 1.5 hours at -78° C., a solution of the enone, 6-carbomethoxymethyl-6-ethyl-2-cyclohexene-1-one prepared in Example 1, Step (c), (40.77 mmol, 8 g) in 80 ml of THF was added dropwise. After 1.5 hours, TLC indicated the consumption of enone and the reaction was quenched with 250 ml of 1M HCl (aq.) and extracted with 2×100 ml of CH2Cl2 and 2×100 ml of petroleum ether. Drying (Na2SO4) and flash chromatography afforded 8.027 g (30.13 mmol, 74%) of pale yellow oil containing a mixture of diastereomers. This material was combined with another batch to give 11.04 g and this was separated by preparative HPLC to afford 2.96 g of a less polar isomer and 4.3 g of a more polar isomer.
Reaction SMILES: Cl[CH2:2][C:3]1[CH:20]=[CH:19][C:6]2[N:7]([CH2:17][CH3:18])[C:8](=[O:16])[C:9]([CH3:15])([CH3:14])[C:10](=[O:13])[N:11]([CH3:12])[C:5]=2[CH:4]=1.[C-:21]#[N:22].[Na+].O>CN(C=O)C>[CH2:17]([N:7]1[C:8](=[O:16])[C:9]([CH3:15])([CH3:14])[C:10](=[O:13])[N:11]([CH3:12])[C:5]2[CH:4]=[C:3]([CH2:2][C:21]#[N:22])[CH:20]=[CH:19][C:6]1=2)[CH3:18]
Reactant: [C-]#N
Reactant: CCN1C(=O)C(C)(C)C(=O)N(C)c2cc(CCl)ccc21
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCN1C(=O)C(C)(C)C(=O)N(C)c2cc(CC#N)ccc21
Reaction time: 8 h
Yield: 78.2 %

Procedure:
To a solution of 7-chloromethyl-1-ethyl-3,3,5-trimethyl-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione (1.11 g) in DMF (15 ml) was added sodium cyanide (0.59 g) at room temperature, the mixture was stirred overnight. Water was added to the reaction mixture, followed by extraction using ethyl acetate. The organic layer was dried with magnesium sulfate, and was condensed under reduced pressure to give the title compound (0.84 g) as a pale yellow oil.
Reaction SMILES: Br[C:2]1[N:6]([CH3:7])[CH:5]=[N:4][C:3]=1[C:8]1[CH:13]=[C:12]([C:14]#[N:15])[CH:11]=[CH:10][N:9]=1.[F:16][C:17]1[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[C:20](B(O)O)=[CH:19][CH:18]=1>>[F:16][C:17]1[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[C:20]([C:2]2[N:6]([CH3:7])[CH:5]=[N:4][C:3]=2[C:8]2[CH:13]=[C:12]([C:14]#[N:15])[CH:11]=[CH:10][N:9]=2)=[CH:19][CH:18]=1
Reactant: OB(O)c1ccc(F)c2ccccc12
Reactant: Cn1cnc(-c2cc(C#N)ccn2)c1Br
Product: Cn1cnc(-c2cc(C#N)ccn2)c1-c1ccc(F)c2ccccc12

Procedure:
The title compound was prepared from 2-(5-bromo-1-methyl-1H-imidazol-4-yl)pyridine-4-carbonitrile (PREPARATION 2) and 4-fluoronaphthalene-1-boronic acid according to the procedure for the preparation of Example 3, part A. [M+H] Calc'd for C20H13FN4, 329. Found, 329.
Reaction SMILES: [CH2:1]1[C:9]2[CH:8]=[CH:7][CH:6]=[C:5]([OH:10])[C:4]=2[CH2:3][CH2:2]1.[N+:11]([O-])([OH:13])=[O:12]>C(O)(=O)C>[OH:10][C:5]1[C:4]2[CH:3]=[CH:2][CH2:1][C:9]=2[CH:8]=[CH:7][C:6]=1[N+:11]([O-:13])=[O:12]
Reactant: Oc1cccc2c1CCC2
Reactant: O=[N+]([O-])O
Solvent: CC(=O)O
Product: O=[N+]([O-])c1ccc2c(c1O)C=CC2
Reaction time: 0.5 h

Procedure:
The starting material, 4-indanol (i.e., Formula 5) is dissolved in an organic acid, preferably glacial acetic acid, at a temperature in the range of about 20°-30° C., preferably about room temperature. To this solution is added in a gradual manner a solution of concentrated nitric acid (about 1 to 2 molar equivalents, preferably about 1.5 molar equivalents) in an organic acid, preferably glacial acetic acid. The reaction mixture is stirred for a period of about 15 minutes to 1 hour, preferably about 30 minutes, at a temperature in the range of 20°-30° C., preferably about room temperature. When the reaction is substantially complete, the 4-hydroxy-5-nitrobenzocyclopentene of Formula 6 is isolated and purified by conventional means, preferably by flash column chromatography.
Reaction SMILES: C(C1C=C([CH2+]=NC2C=C[C:15]([O:16]C3C=CN=C(C(NC)=O)C=3)=[CH:14]C=2F)N(C2C=CC=C(CO)C=2)N=1)(C)(C)C.[C:38]([C:42]1[CH:46]=[C:45]([NH:47][C:48]([NH:50][C:51]2[CH:67]=[CH:66][C:54]([O:55][C:56]3[CH:61]=[CH:60][N:59]=[C:58]([C:62]([NH:64][CH3:65])=[O:63])[CH:57]=3)=[CH:53][C:52]=2[F:68])=[O:49])[N:44]([C:69]2[CH:74]=[CH:73][CH:72]=[C:71]([CH2:75][OH:76])[CH:70]=2)[N:43]=1)([CH3:41])([CH3:40])[CH3:39].C(Cl)(=O)C>ClCCl>[C:15]([O:76][CH2:75][C:71]1[CH:72]=[CH:73][CH:74]=[C:69]([N:44]2[C:45]([NH:47][C:48](=[O:49])[NH:50][C:51]3[CH:67]=[CH:66][C:54]([O:55][C:56]4[CH:61]=[CH:60][N:59]=[C:58]([C:62](=[O:63])[NH:64][CH3:65])[CH:57]=4)=[CH:53][C:52]=3[F:68])=[CH:46][C:42]([C:38]([CH3:41])([CH3:39])[CH3:40])=[N:43]2)[CH:70]=1)(=[O:16])[CH3:14]
Reactant: CNC(=O)c1cc(Oc2ccc(N=[CH2+]c3cc(C(C)(C)C)nn3-c3cccc(CO)c3)c(F)c2)ccn1
Reactant: CNC(=O)c1cc(Oc2ccc(NC(=O)Nc3cc(C(C)(C)C)nn3-c3cccc(CO)c3)c(F)c2)ccn1
Solvent: ClCCl
Solvent: CC(=O)Cl
Product: CNC(=O)c1cc(Oc2ccc(NC(=O)Nc3cc(C(C)(C)C)nn3-c3cccc(COC(C)=O)c3)c(F)c2)ccn1
Temperature: 0 °C
Reaction time: 1 h
Yield: 30 %

Procedure:
To a 0° C. solution of example 1, (4-{4-[({3-tert-butyl-1-[3-(hydroxymethyl)phenyl]-1H-pyrazol-5-yl}carbamoyl)amino]-3-fluorophenoxy}-N-methylpyridine-2-carboxamide, (1.00 g, 1.88 mmol) in dichloromethane (15 mL) was added dropwise acetyl chloride (0.15 mL, 2.07 mmol). The reaction mixture was allowed to stir at 0° C. for 1 h. The reaction mixture was quenched with water and extracted with CH2Cl2. The combined organic layer was dried and concentrated. The crude material was purified via column chromatography (CH2Cl2:2M NH3 in MeOH, 97:3) to afford 0.32 g (30%) of the desired product as a white powder. MS m/z 575.1 (M+H)+; Retention time (LC-MS): 3.55 min.
Reaction SMILES: [H-].[Na+].[CH3:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([N:11]2[CH2:16][CH2:15][N:14]([CH2:17][C:18]3[C:26]4[C:21](=[N:22][CH:23]=[CH:24][CH:25]=4)[NH:20][CH:19]=3)[CH2:13][CH2:12]2)=[CH:7][CH:6]=1.[CH3:27]I.O>CN(C)C=O>[CH3:3][O:4][C:5]1[CH:6]=[CH:7][C:8]([N:11]2[CH2:16][CH2:15][N:14]([CH2:17][C:18]3[C:26]4[C:21](=[N:22][CH:23]=[CH:24][CH:25]=4)[N:20]([CH3:27])[CH:19]=3)[CH2:13][CH2:12]2)=[CH:9][CH:10]=1
Reactant: CI
Reactant: COc1ccc(N2CCN(Cc3c[nH]c4ncccc34)CC2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccc(N2CCN(Cc3cn(C)c4ncccc34)CC2)cc1
Temperature: 25 °C
Yield: 78.6 %

Procedure:
Sodium hydride (80% dispersion in oil; 0.13 g, 4.3 mmol) was added to a solution of 3-(4-(4-methoxyphenyl)piperazin-1-yl)methyl-1H-pyrrolo[2,3-b]pyridine (1.06 g, 3.29 mmol) in dimethylformamide (30 ml) at 0° C. The cooling bath was removed and the mixture stirred at room temperature for an hour. Methyl iodide (0.22 ml, 3.53 mmol) was added and the reaction mixture stirred for 2 h at room temperature. The mixture was poured into water (300 ml), extracted with ethyl acetate (2×150 ml), and the extracts washed with brine (150 ml). The combined extracts were dried (MgSO4) and evaporated to give a yellow solid. Purification by flash chromatography, eluting with 5% then 7.5% methanol in dichloromethane, gave the title compound (0.87 g, 79%). Recrstallisation from ethyl acetate/petrol (60°-80° C.) gave fine needles, m.p. 92°-94° C.; (Found: C, 71.25; H, 7.18; N, 16.49. C20H24N4O requires C, 71.40; H, 7.19; N, 16.65%); δH (CDCl3) 2.65 (4H, m, 2×piperazinyl CH2), 3.09 (4H, m, 2×piperazinyl CH2), 3.74 (2H, s, CH2N), 3.75 (3H, s, ArOCH3), 3.87 (3H, s, N--CH3), 6.85 (4H, m, ArH), 7.05 (1H, dd, J 7.8, 4.7 Hz, 5-H), 7.15 (1H, br s, 2H), 8.04 (1H, dd, J 7.8, 1.5 Hz, 4-H), and 8.33 (1H, dd, J 4.7, 1.5 Hz, 6-H); m/z (CI+, NH3) 337 (M+1)+.
Reaction SMILES: [F:1][C:2]([F:16])([F:15])[C:3]1[C:4]([N:9]2[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]2)=[N:5][CH:6]=[CH:7][CH:8]=1.[Br:17]Br>ClCCl>[Br:17][C:7]1[CH:8]=[C:3]([C:2]([F:1])([F:15])[F:16])[C:4]([N:9]2[CH2:10][CH2:11][NH:12][CH2:13][CH2:14]2)=[N:5][CH:6]=1
Reactant: BrBr
Reactant: FC(F)(F)c1cccnc1N1CCNCC1
Solvent: ClCCl
Product: FC(F)(F)c1cc(Br)cnc1N1CCNCC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a suspension of 1-(3-trifluoromethyl-pyridin-2-yl)-piperazine (230 mg, 1 mmol, Oakwood Products) in dichloromethane (5 mL) was added a solution of bromine in dichloromethane (1.5 mL, 1 M, 1.5 mmol). The reaction mixture was stirred at 25° C. for 2 h. The precipitated yellow solid was filtered, washed with small amount of methanol and dried in vacuo to give the title compound as a yellow amorphous solid. MS (ESI, pos. ion) m/z: 311 (M+1).
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][C:7]([CH2:11][N:12]3[C:16]4=[N:17][C:18]([C:21](=O)[CH3:22])=[CH:19][N:20]=[C:15]4[N:14]=[N:13]3)=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.Cl.[CH2:25]([O:27][NH2:28])[CH3:26]>>[CH2:25]([O:27]/[N:28]=[C:21](/[C:18]1[N:17]=[C:16]2[N:12]([CH2:11][C:7]3[CH:6]=[C:5]4[C:10](=[CH:9][CH:8]=3)[N:1]=[CH:2][CH:3]=[CH:4]4)[N:13]=[N:14][C:15]2=[N:20][CH:19]=1)\[CH3:22])[CH3:26]
Reactant: CCON
Reactant: CC(=O)c1cnc2nnn(Cc3ccc4ncccc4c3)c2n1
Agent: Cl
Product: CCO/N=C(\C)c1cnc2nnn(Cc3ccc4ncccc4c3)c2n1
Yield: 61 %

Procedure:
The title compound was prepared from 1-(1-(quinolin-6-ylmethyl)-1H-[1,2,3]triazolo[4,5-b]pyrazin-6-yl)ethanone (22.4) and O-ethylhydroxylamine hydrochloride in 61% yield using the same procedure as described in the synthesis of example 22. 1H-NMR (400 MHz, DMSO-d6), δ ppm 9.31 (s, 1H), 8.89 (m, 1H), 8.35 (d, 1H), 8.01 (m, 2H), 7.82 (d, 1H), 7.53 (dd, 1H), 6.20 (s, 2H), 4.34 (q, 2H), 2.32 (s, 3H), 1.24 (t, 3H). LCMS (method B): [MH]+=348, tR=2.59 min.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:22]=[CH:21][C:10]2[C:11]([C:14]3[CH:19]=[CH:18][C:17]([Br:20])=[CH:16][CH:15]=3)=[N:12][S:13][C:9]=2[CH:8]=1.[CH3:23][NH:24][CH2:25][C:26]#[CH:27]>>[Br:20][C:17]1[CH:18]=[CH:19][C:14]([C:11]2[C:10]3[CH:21]=[CH:22][C:7]([O:6][CH2:5][CH2:4][CH2:3][CH2:2][N:24]([CH3:23])[CH2:25][C:26]#[CH:27])=[CH:8][C:9]=3[S:13][N:12]=2)=[CH:15][CH:16]=1
Reactant: C#CCNC
Reactant: BrCCCCOc1ccc2c(-c3ccc(Br)cc3)nsc2c1
Product: C#CCN(C)CCCCOc1ccc2c(-c3ccc(Br)cc3)nsc2c1

Procedure:
According to the method in example 6, 6-(4-Bromo-butoxy)-3-(4-bromo-phenyl)-benzo[d]isothiazole and Methyl-prop-2-ynyl-amine were converted to yield {4-[3-(4-Bromo-phenyl)-benzo[d]isothiazol-6-yloxy]-butyl-methyl-prop-2-ynyl-amine as light yellow oil, MS: 429(MH+, 1Br).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[N:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([C:14]3[C:15]([C:20](O)=[O:21])=[CH:16][CH:17]=[CH:18][CH:19]=3)=[CH:10][C:9]=2[F:23])=[CH:4][N:3]=1.[NH:24]1[CH2:29][CH2:28][CH:27]([OH:30])[CH2:26][CH2:25]1>>[NH2:1][C:2]1[N:3]=[CH:4][C:5]([C:8]2[CH:13]=[CH:12][C:11]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=3[C:20]([N:24]3[CH2:29][CH2:28][CH:27]([OH:30])[CH2:26][CH2:25]3)=[O:21])=[CH:10][C:9]=2[F:23])=[N:6][CH:7]=1
Reactant: OC1CCNCC1
Reactant: Nc1cnc(-c2ccc(-c3ccccc3C(=O)O)cc2F)cn1
Product: Nc1cnc(-c2ccc(-c3ccccc3C(=O)N3CCC(O)CC3)cc2F)cn1

Procedure:
The title compound was prepared using methods analogous to those described in Step C of Example 504 using 4′-(2-aminopyrazin-5-yl)-3′-fluoro-[1,1′-biphenyl]-2-carboxylic acid and piperidin-4-ol. MS (ESI): mass calcd. for C22H21FN4O2, 392.16; m/z found, 393.1 [M+H]+. 1H NMR (400 MHz, CDCl3) Complex due to the presence of multiple conformations on the NMR time-scale, peaks listed for identification purposes only: δ 8.54 (d, J=13.9), 8.11-8.05 (m), 7.98-7.83 (m), 7.47-7.27 (m), 6.72 (s), 4.68 (s), 4.24-4.05 (m), 3.76-3.53 (m), 3.27-3.18 (m), 2.91-2.80 (m), 2.62-2.51 (m), 1.82 (m), 1.69 (m), 1.51-1.45 (m), 1.26-1.18 (m), 0.48-0.41 (m).
Reaction SMILES: C(O[C:4](=[C:11]1[C:19]2[C:14](=[CH:15][CH:16]=[C:17]([N+:20]([O-:22])=[O:21])[CH:18]=2)[NH:13][C:12]1=[O:23])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)C.[OH:24][CH2:25][CH2:26][N:27]([CH2:30][CH2:31][C:32]1[CH:37]=[CH:36][C:35]([NH:38]NC2C=CC=CC=2)=[CH:34][CH:33]=1)[CH2:28][CH3:29]>CN(C=O)C>[OH:24][CH2:25][CH2:26][N:27]([CH2:30][CH2:31][C:32]1[CH:33]=[CH:34][C:35]([NH:38]/[C:4](=[C:11]2\[C:12](=[O:23])[NH:13][C:14]3[C:19]\2=[CH:18][C:17]([N+:20]([O-:22])=[O:21])=[CH:16][CH:15]=3)/[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=2)=[CH:36][CH:37]=1)[CH2:28][CH3:29]
Reactant: CCN(CCO)CCc1ccc(NNc2ccccc2)cc1
Reactant: CCOC(=C1C(=O)Nc2ccc([N+](=O)[O-])cc21)c1ccccc1
Solvent: CN(C)C=O
Product: CCN(CCO)CCc1ccc(N/C(=C2\C(=O)Nc3ccc([N+](=O)[O-])cc32)c2ccccc2)cc1

Procedure:
Prepared analogously to Example 89 from 3-(1-ethoxy-1-phenyl-methylidene)-5-nitro-2-indolinone and {4-[2-(N-(2-hydroxyethyl)-N-ethyl-amino)-ethyl]-phenylamino}-aniline in DMF.
Reaction SMILES: [CH2:1]1[O:10][C:9]2[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][C:3]=2[O:2]1.[CH:11](O)=[O:12]>>[O:10]1[C:9]2[CH:8]=[CH:7][C:5]([NH:6][CH:11]=[O:12])=[CH:4][C:3]=2[O:2][CH2:1]1
Reactant: O=CO
Reactant: Nc1ccc2c(c1)OCO2
Product: O=CNc1ccc2c(c1)OCO2

Procedure:
Was prepared according to Example 2 from 3,4-(methylenedioxy)aniline and formic acid.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:8]2[NH:7][C:6]3[CH2:11][CH2:12][N:13]([CH3:15])[CH2:14][C:5]=3[C:4]=2[CH:3]=1.[CH3:16][C:17]1[CH:18]=[N:19][CH:20]=[C:21]([CH:23]=[CH2:24])[CH:22]=1.[OH-].[K+]>CN1C(=O)CCC1>[Cl:1][C:2]1[CH:10]=[CH:9][C:8]2[N:7]([CH2:24][CH2:23][C:21]3[CH:20]=[N:19][CH:18]=[C:17]([CH3:16])[CH:22]=3)[C:6]3[CH2:11][CH2:12][N:13]([CH3:15])[CH2:14][C:5]=3[C:4]=2[CH:3]=1
Reactant: CN1CCc2[nH]c3ccc(Cl)cc3c2C1
Reactant: C=Cc1cncc(C)c1
Agent: [K+]
Agent: [OH-]
Solvent: CN1CCCC1=O
Product: Cc1cncc(CCn2c3c(c4cc(Cl)ccc42)CN(C)CC3)c1

Procedure:
The title compound is prepared from a mixture of 8-chloro-2,3,4,5-tetrahydro-2-methyl-1H-pyrido[4,3-b]indole, 3-methyl-5-vinylpyridine and KOH (5-7 equiv) in NMP at a temperature ranging between 25 deg C. to 100 deg C. The product obtained is isolated by preparative HPLC.
Reaction SMILES: [C:1]1([OH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:8][O:9][CH:10]([O:13][CH3:14])[CH2:11]Br.C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[CH3:8][O:9][CH:10]([O:13][CH3:14])[CH2:11][O:7][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: COC(CBr)OC
Reactant: Oc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(COc1ccccc1)OC

Procedure:
A mixture of 31.3 g of phenol, 60.0 g of bromoacetaldehyde dimethyl acetal and 80 g of potassium carbonate was heated at 150° C. in 300 ml of dimethylformamide. After 4.5 hours the reaction mixture was cooled, added to water, and extracted with diethyl ether. Separation, drying and evaporation of the organic phase gave the crude product. Vacuum distillation, bp 88°-98° C./1 mm yielded the title compound as a colourless oil.
Reaction SMILES: [F:1][C:2]1[C:11]2[CH:12]([NH:14][CH2:15][CH2:16][CH2:17][C@H:18]3[O:22][C:21](=[O:23])[N:20]([C:24]4[CH:25]=[CH:26][C:27]5[S:32][CH2:31][C:30](=[O:33])[NH:29][C:28]=5[CH:34]=4)[CH2:19]3)[CH2:13][N:9]3[C:10]=2[C:5]([CH:6]=[CH:7][C:8]3=[O:35])=[CH:4][CH:3]=1.[Si:36]([O:43][CH2:44][CH:45]=O)([C:39]([CH3:42])([CH3:41])[CH3:40])([CH3:38])[CH3:37]>>[C:39]([Si:36]([CH3:38])([CH3:37])[O:43][CH2:44][CH2:45][N:14]([CH2:15][CH2:16][CH2:17][C@H:18]1[O:22][C:21](=[O:23])[N:20]([C:24]2[CH:25]=[CH:26][C:27]3[S:32][CH2:31][C:30](=[O:33])[NH:29][C:28]=3[CH:34]=2)[CH2:19]1)[CH:12]1[C:11]2=[C:10]3[C:5](=[CH:4][CH:3]=[C:2]2[F:1])[CH:6]=[CH:7][C:8](=[O:35])[N:9]3[CH2:13]1)([CH3:42])([CH3:41])[CH3:40]
Reactant: CC(C)(C)[Si](C)(C)OCC=O
Reactant: O=C1CSc2ccc(N3C[C@@H](CCCNC4Cn5c(=O)ccc6ccc(F)c4c65)OC3=O)cc2N1
Product: CC(C)(C)[Si](C)(C)OCCN(CCC[C@@H]1CN(c2ccc3c(c2)NC(=O)CS3)C(=O)O1)C1Cn2c(=O)ccc3ccc(F)c1c32
Yield: 43 %

Procedure:
Starting from the compound of Example 13 and tert-butyldimethylsilyloxy-acetaldehyde and using procedure E, the title compound was obtained as a yellow foam (57 mg; 43% yield).