Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[CH:4][C:3]=1[OH:12].[Cl:13][C:14]1[CH:15]=[C:16]([CH:20]=[CH:21][N:22]=1)[C:17](O)=[O:18].CCN=C=NCCCN(C)C>N1C=CC=CC=1>[Cl:13][C:14]1[CH:15]=[C:16]([CH:20]=[CH:21][N:22]=1)[C:17]([NH:1][C:2]1[CH:7]=[C:6]([C:8]([F:9])([F:10])[F:11])[CH:5]=[CH:4][C:3]=1[OH:12])=[O:18]
Reactant: O=C(O)c1ccnc(Cl)c1
Reactant: Nc1cc(C(F)(F)F)ccc1O
Agent: CCN=C=NCCCN(C)C
Solvent: c1ccncc1
Product: O=C(Nc1cc(C(F)(F)F)ccc1O)c1ccnc(Cl)c1
Temperature: 60 °C
Yield: 60.8 %

Procedure:
To a mixture of 0.71 g of 2-amino-4-(trifluoromethyl)phenol, 0.63 g of 2-chloroisonicotinic acid and 7 ml of pyridine, 1.05 g of WSC was added and stirred while heating at 60° C. for four hours. The reaction mixture was cooled to room temperature, and then concentrated under reduced pressure. Water was added to the residue, followed by extraction with ethyl acetate twice. The combined organic layers were washed with a saturated sodium chloride solution, dried over anhydrous sodium sulfate, and then concentrated under reduced pressure. The residue was subjected to silica gel column chromatography to give 0.77 g of 2-chloro-N-[2-hydroxy-5-(trifluoromethyl)phenyl]isonicotinamide.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([C:10]([C:12]2[CH:20]=[C:19]3[C:15]([C:16]([CH:29]=[CH:30][C:31]4[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=4)=[N:17][N:18]3COCC[Si](C)(C)C)=[CH:14][CH:13]=2)=[CH2:11])[CH:7]=[CH:8][CH:9]=1)([O-])=O.NC1C=C(C(C2C=C3C(C(C=CC4C=CC=CC=4)=NN3COCC[Si](C)(C)C)=CC=2)=C)C=CC=1>C(OCC)(=O)C.CCCCCC>[NH2:1][C:4]1[CH:5]=[C:6]([C:10]([C:12]2[CH:20]=[C:19]3[C:15]([C:16]([CH:29]=[CH:30][C:31]4[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=4)=[N:17][NH:18]3)=[CH:14][CH:13]=2)=[CH2:11])[CH:7]=[CH:8][CH:9]=1
Reactant: C=C(c1cccc([N+](=O)[O-])c1)c1ccc2c(C=Cc3ccccc3)nn(COCC[Si](C)(C)C)c2c1
Agent: C=C(c1cccc(N)c1)c1ccc2c(C=Cc3ccccc3)nn(COCC[Si](C)(C)C)c2c1
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: C=C(c1cccc(N)c1)c1ccc2c(C=Cc3ccccc3)n[nH]c2c1

Procedure:
6-(1-(3-Nitrophenyl)-vinyl)-3-styryl-1-[2-(trimethyl-silanyl)-ethoxymethyl]-1H-indazole was converted to 6-(1-(3-aminophenyl)-vinyl)-3-styryl-1-[2-(trimethyl-silanyl)-ethoxymethyl]-1H-indazole as described in Example 11, step (iv) (140 mg, 95%): Rf sm 0.59, p 0.46 (ethyl acetate-hexane 4:6); FTIR (thin film) 3460, 3366, 3223, 3084, 3028, 2952, 2894, 2246, 1616, 1601, 1581, 1489, 1474, 1448, 1359.1303, 1249, 1217, 1076, 961, 909, 860, 836, 733, 692 cm−1; 1H NMR (300 MHz, CDCl3) δ 7.96 (d, 1H, J=8.5 Hz), 7.59 (m, 3H), 7.50 (s, 1H), 7.46 (s, 1H), 7.40 (m, 2H), 7.30 (m, 1H), 7.25 (m, 1H), 7.14 (m, 1H), 6.77 (m, 1H), 6.68 (m, 2H); 13C NMR (75 MHz, CDCl3) δ 151.6, 147.7, 144.6, 143.9, 142.8, 142.4, 138.6, 132.8, 130.6, 130.2, 129.3, 128.0, 124.4, 123.6, 121.9, 121.5, 120.2, 116.4, 116.1, 110.8, 79.0, 67.9, 19.2, 0.0; HRMS (FAB) [M+Na]/z Calc'd 490.2291, found 490.2302.
Reaction SMILES: [N:1]1[C:10]2[C@H:9]([NH:11][CH2:12][CH2:13][CH2:14][CH2:15][N:16]3[C:24](=[O:25])[C:23]4[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=4)[C:17]3=[O:26])[CH2:8][CH2:7][CH2:6][C:5]=2[CH:4]=[CH:3][CH:2]=1.C(OC([N:34]1[C:38]2[CH:39]=[CH:40][CH:41]=[CH:42][C:37]=2[N:36]=[C:35]1[CH2:43]Cl)=O)(C)(C)C.C(N(C(C)C)CC)(C)C>C(#N)C.[I-].[K+]>[NH:34]1[C:38]2[CH:39]=[CH:40][CH:41]=[CH:42][C:37]=2[N:36]=[C:35]1[CH2:43][N:11]([C@H:9]1[C:10]2[N:1]=[CH:2][CH:3]=[CH:4][C:5]=2[CH2:6][CH2:7][CH2:8]1)[CH2:12][CH2:13][CH2:14][CH2:15][N:16]1[C:24](=[O:25])[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[C:17]1=[O:26]
Reactant: CC(C)(C)OC(=O)n1c(CCl)nc2ccccc21
Reactant: O=C1c2ccccc2C(=O)N1CCCCN[C@@H]1CCCc2cccnc21
Agent: [I-]
Agent: [K+]
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: O=C1c2ccccc2C(=O)N1CCCCN(Cc1nc2ccccc2[nH]1)[C@@H]1CCCc2cccnc21
Temperature: 50 °C
Reaction time: 22 h
Yield: 111.7 %

Procedure:
To a solution of 2-{4-[(R)-(5,6,7,8-tetrahydro-quinolin-8-yl)amino]-butyl}-isoindole-1,3-dione (135.3 g, 0.39 mol) and 2-chloromethyl-benzimidazole-1-carboxylic acid tert-butyl ester (103 g, 0.39 mol) in acetonitrile (780 mL) at room temperature was added diisopropylethylamine (101 mL, 0.58 mol) and potassium iodide (6.4 g, 0.04 mol) and the mixture heated to 50° C. for 3 hours. The mixture was then concentrated under reduced pressure and redissolved in methyl t-butyl ether (500 mL) and water (500 mL). The pH was adjusted to 2 with 6N HCl then the phases were separated. The aqueous layer was washed with methyl t-butyl ether (500 mL). The aqueous phase was stirred for 22 hours, adding 6N HCl as needed to maintain pH=2. The solution was basified to pH 10-11 with ION NaOH and extracted with toluene (2×1.5 L). The organic phase was washed with 1N NaOH (1×200 mL) and brine (1×200 mL). The organic phase was dried (Na2SO4), filtered and concentrated under reduced pressure to give 2-{4-[(R)-(1H-benzimidazol-2-ylmethyl)-5,6,7,8-tetrahydro-quinolin-8-yl-amino]-butyl}-isoindole-1,3-dione (209 g). 1H NMR (300 MHz, CDCl3, δ ppm) 0.75-1.75 (series of m, 5H), 1.80-2.10 (2m, 2H), 2.15-2.25 (m, 1H), 2.55-2.90 (m, 4H), 3.52 (t, 2H, J=7.0 Hz), 3.95-4.10 (m, 1H), 4.01 (d, 1H, J=17.0 Hz), 4.11 (d, 1H, J=17.0 Hz), 7.10-7.30 (m, 4H), 7.39 (d, 1H, J=7.5 Hz), 7.50-7.55 (m, 1H), 7.60-7.70 (m, 2H), 7.70-7.80 (m, 2H), 8.60 (d, 1H, J=3.5 Hz).
Reaction SMILES: S(=O)(=O)(O)O.[NH2:6][C:7]1[CH:8]=[N:9][N:10]([CH2:13][CH2:14][OH:15])[C:11]=1[NH2:12].[C:16]([O:20][C:21]([NH:23][CH2:24][C:25](ON1C(=O)CCC1=O)=[O:26])=[O:22])([CH3:19])([CH3:18])[CH3:17].C(N(C(C)C)C(C)C)C>C(Cl)Cl>[NH2:12][C:11]1[N:10]([CH2:13][CH2:14][OH:15])[N:9]=[CH:8][C:7]=1[NH:6][C:25](=[O:26])[CH2:24][NH:23][C:21]([O:20][C:16]([CH3:18])([CH3:17])[CH3:19])=[O:22]
Reactant: Nc1cnn(CCO)c1N
Reactant: CC(C)(C)OC(=O)NCC(=O)ON1C(=O)CCC1=O
Agent: O=S(=O)(O)O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NCC(=O)Nc1cnn(CCO)c1N
Temperature: 25 °C
Reaction time: 17 h
Yield: 80.8 %

Procedure:
To a suspension of 4,5-diamino-1-(2-hydroxyethyl)pyrazole sulfuric acid salt (1.20 g) and N-[2-(tert-butoxycarbonylamino)acetoxy]succinimide (1.35 g) in methylene chloride (20 ml) was added N-ethyldiisopropylamine (2.1 ml) under ice-cooling, and the mixture was stirred at room temperature for 17 hours. The reaction mixture was washed with water (40 ml), saturated aqueous sodium hydrogen carbonate solution (40 ml) and brine (40 ml). The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The oily residue was purified by column chromatography on silica gel eluting with 10% methanol/chloroform to give 5-amino-4-[2-(tert-butoxycarbonylamino)acetyl]amino-1-(2-hydroxyethyl)pyrazole (1.20 g) as a solid.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][CH:9]=[C:10]([C:16](=[O:19])[CH2:17][CH3:18])[C:11]([O:13]CC)=O)=[CH:4][CH:3]=1>C1C=CC(C2C=CC=CC=2)=CC=1.C1C=CC(OC2C=CC=CC=2)=CC=1>[Br:1][C:2]1[CH:3]=[C:4]2[C:5](=[CH:6][CH:7]=1)[N:8]=[CH:9][C:10]([C:16](=[O:19])[CH2:17][CH3:18])=[C:11]2[OH:13]
Reactant: CCOC(=O)C(=CNc1ccc(Br)cc1)C(=O)CC
Solvent: c1ccc(-c2ccccc2)cc1
Solvent: c1ccc(Oc2ccccc2)cc1
Product: CCC(=O)c1cnc2ccc(Br)cc2c1O
Temperature: 250 °C
Reaction time: 1.25 h
Yield: 73.7 %

Procedure:
Dowtherm A (200 mL) was heated to 240° C. Ethyl 2-(((4-bromophenyl)amino) methylene)-3-oxopentanoate (25.1 g, 77 mmol) was added portionwise. The reaction was then heated to 250° C. and stirred for 1.25 h. The reaction mixture was slowly cooled to room temperature and a precipitate formed. The suspension was diluted with hexanes (500 mL) and filtered to afford the desired product (15.9 g, 73%) as a tan solid: 1H NMR (300 MHz, DMSO-d6) δ 12.64 (br s, 1H), 8.56 (s, 1H), 8.30 (d, J=2.3 Hz, 1H), 7.88 (dd, J=8.8, 2.4 Hz, 1H), 7.61 (d, J=8.8 Hz, 1H), 3.10 (q, J=7.2 Hz, 2H), 1.05 (t, J=7.2 Hz, 3H).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:16])[CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[CH:4][CH:3]=1.[CH2:17]([O:24][CH2:25][CH2:26][O:27][CH2:28][CH2:29]Cl)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>>[CH2:17]([O:24][CH2:25][CH2:26][O:27][CH2:28][CH2:29][O:1][C:2]1[CH:3]=[CH:4][C:5]([C:8](=[O:16])[CH2:9][C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=2)=[CH:6][CH:7]=1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: ClCCOCCOCc1ccccc1
Reactant: O=C(Cc1ccccc1)c1ccc(O)cc1
Product: O=C(Cc1ccccc1)c1ccc(OCCOCCOCc2ccccc2)cc1

Procedure:
is prepared according to example 4c starting from 1-(4-hydroxyphenyl)-2-phenyl ethanone (prepared according examples 4a-b)(10.0 g, 47.1 mmol) and 2-(2-benzyloxyethoxy)ethyl chloride (11.0 g, 51.8 mmol). The product was triturated three times with warm heptane to remove byproducts. Yield 9.6 g, 52%. 1H NMR (CDCl3): 3.60-3.79 (m, 4H), 3.85 (dist.t, 2H), 4.16 (dist.t, 2H), 4.20 (s, 2H), 4.56 (s, 2H), 6.92 (d, 2H), 7.20-7.41 (m, 10H), 7.96 (d, 2H).
Reaction SMILES: [C:1](OC(=O)C)(=[O:3])[CH3:2].[N:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[C:14]1[NH:18][C:17]2[CH:19]=[C:20]([CH:37]3[CH2:41][CH2:40][CH2:39][NH:38]3)[C:21]([O:23][C:24]3[CH:25]=[CH:26][C:27]([N:30]4[CH:35]=[CH:34][CH:33]=[CH:32][C:31]4=[O:36])=[N:28][CH:29]=3)=[CH:22][C:16]=2[N:15]=1>C(Cl)(Cl)Cl>[C:1]([N:38]1[CH2:39][CH2:40][CH2:41][CH:37]1[C:20]1[C:21]([O:23][C:24]2[CH:25]=[CH:26][C:27]([N:30]3[CH:35]=[CH:34][CH:33]=[CH:32][C:31]3=[O:36])=[N:28][CH:29]=2)=[CH:22][C:16]2[N:15]=[C:14]([C:9]3[CH:10]=[CH:11][CH:12]=[CH:13][N:8]=3)[NH:18][C:17]=2[CH:19]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)OC(C)=O
Reactant: O=c1ccccn1-c1ccc(Oc2cc3nc(-c4ccccn4)[nH]c3cc2C2CCCN2)cn1
Solvent: ClC(Cl)Cl
Product: CC(=O)N1CCCC1c1cc2[nH]c(-c3ccccn3)nc2cc1Oc1ccc(-n2ccccc2=O)nc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
0.003 ml of acetic anhydride was added to a chloroform (1 ml) solution of 5.8 mg of 5′-((2-pyridin-2-yl-6-pyrrolidin-2-yl-1H-benzimidazol-5-yl)oxy)-2H-1,2′-bipyridin-2-one enantiomer B obtained in Example 554, and the reaction liquid was stirred at room temperature for 30 minutes. The reaction solvent was evaporated away, and the resulting residue was purified through partitioning thin-layer chromatography (Kieselgel™ 60F254, Art 5744 (by Merck), chloroform/methanol=10/1) to obtain one chiral form of the entitled compound as a white solid.
Reaction SMILES: CS(C)=O.[S:5]1[CH:9]=[CH:8][N:7]=[C:6]1[NH:10][C:11](=O)[O:12]C1C=CC=CC=1.[NH2:20][C:21]1[CH:44]=[CH:43][C:24]([O:25][C:26]2[C:35]3[C:30](=[CH:31][C:32]([O:38][CH2:39][CH:40]4[CH2:42][O:41]4)=[C:33]([C:36]#[N:37])[CH:34]=3)[N:29]=[CH:28][CH:27]=2)=[CH:23][C:22]=1[F:45]>O>[C:36]([C:33]1[CH:34]=[C:35]2[C:30](=[CH:31][C:32]=1[O:38][CH2:39][CH:40]1[CH2:42][O:41]1)[N:29]=[CH:28][CH:27]=[C:26]2[O:25][C:24]1[CH:43]=[CH:44][C:21]([NH:20][C:11]([NH:10][C:6]2[S:5][CH:9]=[CH:8][N:7]=2)=[O:12])=[C:22]([F:45])[CH:23]=1)#[N:37]
Reactant: O=C(Nc1nccs1)Oc1ccccc1
Reactant: N#Cc1cc2c(Oc3ccc(N)c(F)c3)ccnc2cc1OCC1CO1
Solvent: O
Solvent: CS(C)=O
Product: N#Cc1cc2c(Oc3ccc(NC(=O)Nc4nccs4)c(F)c3)ccnc2cc1OCC1CO1
Temperature: 80 °C
Yield: 11.8 %

Procedure:
After adding dimethylsulfoxide (1 ml) and phenyl N-(2-thiazolyl)carbamate (94 mg) to 4-(4-amino-3-fluorophenoxy)-7-oxiranylmethoxyquinoline-6-carbonitrile (100 mg), the mixture was heated at 80° C. for 90 minutes. Water was added and the precipitated crystals were filtered out to obtain the title compound (16 mg) as light yellow crystals.
Reaction SMILES: Br[CH2:2][CH:3]1[CH2:5][CH2:4]1.[P:6]([O:15]C(C)C)([O:11][CH:12]([CH3:14])[CH3:13])[O:7][CH:8]([CH3:10])[CH3:9]>C(OCC)(=O)C>[CH:8]([O:7][P:6]([CH2:2][CH:3]1[CH2:5][CH2:4]1)(=[O:15])[O:11][CH:12]([CH3:14])[CH3:13])([CH3:10])[CH3:9]
Reactant: BrCC1CC1
Reactant: CC(C)OP(OC(C)C)OC(C)C
Solvent: CCOC(C)=O
Product: CC(C)OP(=O)(CC1CC1)OC(C)C
Temperature: 144 °C
Yield: 94.3 %

Procedure:
Bromomethyl-cyclopropane (26.00 g, 0.193 mol) was added to triisopropyl phosphite (35.9 mL, 0.30 mol) at ambient temperature, under a nitrogen atmosphere. The resulting solution was stirred and heated at reflux (144° C. bath temperature) overnight. The reaction mixture was allowed to cool to ambient temperature and then ethyl acetate (350 mL) was added. The solution was washed with saturated sodium bicarbonate (350 mL) and then with saturated brine (2×350 mL). The organic phase was dried with magnesium sulfate, filtered, and concentrated by rotary evaporation and then under high vacuum to yield 39.96 g of cyclopropylmethyl-phosphonic acid diisopropyl ester (0.182 mol, 94% yield) as a colorless oil. 1H NMR (400 MHz, DMSO) δ 4.63-4.54 (m, 2H); 1.67-1.60 (d of d, 2H) 1.27-1.24 (d of d, 12H); 0.85-0.75 (m, 1H); 0.52-0.46 (m, 2H); 0.21-0.16 (m, 2H); ESMS (m/z): M+1)+ found, 221; (M+23)+ found, 243.
Reaction SMILES: Cl.[Cl:2][C:3]1[C:12]([Cl:13])=[CH:11][CH:10]=[C:9]2[C:4]=1[CH:5]=[CH:6][N:7]([CH2:15][CH:16]1[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]1)[C:8]2=[O:14].[C:22]1([C:28]2[CH:32]=[C:31]([CH:33]=O)[O:30][N:29]=2)[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCl.C(N(C(C)C)CC)(C)C>[Cl:2][C:3]1[C:12]([Cl:13])=[CH:11][CH:10]=[C:9]2[C:4]=1[CH:5]=[CH:6][N:7]([CH2:15][CH:16]1[CH2:21][CH2:20][N:19]([CH2:33][C:31]3[O:30][N:29]=[C:28]([C:22]4[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=4)[CH:32]=3)[CH2:18][CH2:17]1)[C:8]2=[O:14]
Reactant: O=c1c2ccc(Cl)c(Cl)c2ccn1CC1CCNCC1
Reactant: O=Cc1cc(-c2ccccc2)no1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: O=c1c2ccc(Cl)c(Cl)c2ccn1CC1CCN(Cc2cc(-c3ccccc3)no2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 52.5 %

Procedure:
The compound prepared in Example 77 (0.041 g), the compound prepared in Example 7 (0.026 g) and sodium triacetoxyborohydride (0.074 g) were suspended in dichloromethane (5 mL) and diisopropylethylamine (0.10 mL). The reaction mixture was stirred at room temperature overnight. The reaction mixture was diluted with dichloromethane and washed with a saturated aqueous sodium bicarbonate solution, dried over anhydrous magnesium sulfate and concentrated. The residue was purified by column chromatography on silica gel (ethyl acetate:hexane=3:1) to obtain the title compound (0.029 g) having the following physical data.
Reaction SMILES: [C:1]([N:3]=[C:4]([C:9]1[CH:10]=[N:11][CH:12]=[CH:13][CH:14]=1)OC(C)C)#[N:2].[C:15]1([CH2:21][CH2:22][CH2:23][NH2:24])[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>CO>[C:1]([NH:3][C:4]([C:9]1[CH:10]=[N:11][CH:12]=[CH:13][CH:14]=1)=[N:24][CH2:23][CH2:22][CH2:21][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)#[N:2]
Reactant: CC(C)OC(=NC#N)c1cccnc1
Reactant: NCCCc1ccccc1
Solvent: CO
Product: N#CNC(=NCCCc1ccccc1)c1cccnc1
Temperature: 25 °C
Reaction time: 0.83 h
Yield: 78.1 %

Procedure:
Isopropyl N cyano-3-pyridinecarboximidate (0.60 g, 3.2 mmol) was dissolved in methanol (10 ml), and 3-phenylpropylamine (0.47 g, 3.5 mmol) was added. The mixture was stirred at room temperature for 50 minutes. After the reaction was completed, the reaction solution was concentrated under reduced pressure. The residual concentrate thus obtained was subjected to chromatography on a silica gel column (WAKO GEL C 200, 30 g) eluting with chloroform-methanol (100:1). The eluted fractions were concentrated under reduced pressure and crystallized from methanol-diethyl ether to give the title compound (0.67 g, 2.5 mmol, yield: 80%) as colorless needles.
Reaction SMILES: [CH3:1][C:2]([C:4]1[CH:9]=[C:8]([Cl:10])[CH:7]=[CH:6][C:5]=1[Cl:11])=[O:3].[Br:12]Br.C([O-])(O)=O.[Na+]>C(OCC)C>[Br:12][CH2:1][C:2]([C:4]1[CH:9]=[C:8]([Cl:10])[CH:7]=[CH:6][C:5]=1[Cl:11])=[O:3]
Reactant: BrBr
Reactant: CC(=O)c1cc(Cl)ccc1Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOCC
Product: O=C(CBr)c1cc(Cl)ccc1Cl
Temperature: 0 °C
Yield: 67.9 %

Procedure:
2,5-Dichloroacetophenone (20.9 g, 0.11 mol) was dissolved in diethyl ether (300 mL) and the reaction mixture was cooled to 0° C. Bromine (5.66 mL, 0.11 mol) was added slowly dropwise and the reaction mixture was allowed to warm to room temperature over 20 minutes. The reaction mixture was treated with saturated aqueous NaHCO3 solution (250 mL). The organic layer was separated, dried over MgSO4 and concentrated in vacuo, yielding the title compound (20.0 g, 68%) as a yellow oil. δH (d6-DMSO) 7.94 (dd, J 2.2, 0.3 Hz, 1H), 7.61 (m, 2H), 4.88 (s, 2H).
Reaction SMILES: [CH:1]([O:4][C:5]1[C:14]2[C:9](=[CH:10][C:11]([OH:17])=[C:12]([O:15][CH3:16])[CH:13]=2)[CH:8]=[C:7]([NH:18][C:19]2[CH:23]=[C:22]([CH3:24])[NH:21][N:20]=2)[N:6]=1)([CH3:3])[CH3:2].[CH3:25][O:26][CH2:27][CH2:28]Br>>[CH:1]([O:4][C:5]1[C:14]2[C:9](=[CH:10][C:11]([O:17][CH2:28][CH2:27][O:26][CH3:25])=[C:12]([O:15][CH3:16])[CH:13]=2)[CH:8]=[C:7]([NH:18][C:19]2[CH:23]=[C:22]([CH3:24])[NH:21][N:20]=2)[N:6]=1)([CH3:3])[CH3:2]
Reactant: COCCBr
Reactant: COc1cc2c(OC(C)C)nc(Nc3cc(C)[nH]n3)cc2cc1O
Product: COCCOc1cc2cc(Nc3cc(C)[nH]n3)nc(OC(C)C)c2cc1OC

Procedure:
Similar procedure as described in example 328 was used, starting from 1-Isopropoxy-7-methoxy-3-(5-methyl-1H-pyrazol-3-ylamino)-isoquinolin-6-ol and 2-bromoethyl methyl ether to give [1-Isopropoxy-7-methoxy-6-(2-methoxy-ethoxy)-isoquinolin-3-yl]-(5-methyl-1H-pyrazol-3-yl)-amine. LC-MS m/e 387(MH+).
Reaction SMILES: [NH2:1][C:2]1[C:7]([NH:8][CH2:9][C:10]#[CH:11])=[CH:6][C:5]([N:12]2[C:20](=[O:21])[C:19]3[CH2:18][CH2:17][CH2:16][CH2:15][C:14]=3[C:13]2=[O:22])=[C:4]([F:23])[CH:3]=1.[N:24]([O-])=O.[Na+].O>C(O)(=O)C>[F:23][C:4]1[C:5]([N:12]2[C:13](=[O:22])[C:14]3[CH2:15][CH2:16][CH2:17][CH2:18][C:19]=3[C:20]2=[O:21])=[CH:6][C:7]2[N:8]([CH2:9][C:10]#[CH:11])[N:24]=[N:1][C:2]=2[CH:3]=1
Reactant: C#CCNc1cc(N2C(=O)C3=C(CCCC3)C2=O)c(F)cc1N
Reactant: O=N[O-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: C#CCn1nnc2cc(F)c(N3C(=O)C4=C(CCCC4)C3=O)cc21
Reaction time: 0.17 h
Yield: 11.5 %

Procedure:
2-[4-Amino-2-fluoro-5-(2-propynylamino)phenyl]-4,5,6,7-tetrahydro-2H-isoindole-1,3-dione (0.59 g) was dissolved in acetic acid (1.9 ml), and sodium nitrite (0.13 g) was added thereto at a temperature of 10° to 15° C. After stirring for 10 minutes, the reaction mixture was admixed with water and extracted with ethyl acetate. The extract was washed with water and an aqueous solution of sodium bicarbonate, dried and concentrated. The residue was purified by silica gel thin layer chromatography using a mixture of ethyl acetate and hexane (1:2 by volume) as an eluent to give 2-[5-fluoro-1-(2-propynyl)benzotriazol-6-yl]-4,5,6,7-tetrahydro-2H-isoindole-1,3-dione (0.07 g) as a resinous material.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[O:12][C:13]1[CH:18]=[CH:17][C:16]([C:19](=[O:32])[NH:20][CH2:21][CH:22]([C:25]3[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=3)[O:23][CH3:24])=[CH:15][CH:14]=1)[O:8][CH2:7][CH2:6][CH:5]2[C:33]([O:35]CC)=[O:34].[OH-].[Na+]>C1COCC1.C(O)C>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[O:12][C:13]1[CH:18]=[CH:17][C:16]([C:19](=[O:32])[NH:20][CH2:21][CH:22]([C:25]3[CH:26]=[CH:27][C:28]([Cl:31])=[CH:29][CH:30]=3)[O:23][CH3:24])=[CH:15][CH:14]=1)[O:8][CH2:7][CH2:6][CH:5]2[C:33]([OH:35])=[O:34]
Reactant: CCOC(=O)C1CCOc2cc(Oc3ccc(C(=O)NCC(OC)c4ccc(Cl)cc4)cc3)c(Cl)cc21
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Product: COC(CNC(=O)c1ccc(Oc2cc3c(cc2Cl)C(C(=O)O)CCO3)cc1)c1ccc(Cl)cc1
Reaction time: 16 h
Yield: 90.4 %

Procedure:
To a solution of ethyl 6-chloro-7-(4-(2-(4-chlorophenyl)-2-methoxyethylcarbamoyl)phenoxy)chroman-4-carboxylate (0.067 g, 0.12 mmol) in 3:1 THF/ethanol (2 ml) was added 1M sodium hydroxide (0.26 ml, 0.26 mmol). The reaction was stirred for 16 hours, and then concentrated, diluted with water, and acidified with 1M hydrochloric acid. The mixture was extracted twice with EtOAc, and the combined organic layers were washed with saturated sodium chloride, dried over anhydrous sodium sulfate, filtered, and concentrated to yield 56 mg of the title compound (88% yield).
Reaction SMILES: [CH2:1]([C@@H:4]1[CH2:9][CH2:8][CH2:7][C@H:6]([OH:10])[CH2:5]1)[CH:2]=[CH2:3].[H-].[Na+].I[CH2:14][C:15]1[N:16]=[C:17]([C:21]2[CH:26]=[CH:25][CH:24]=[C:23]([CH3:27])[CH:22]=2)[O:18][C:19]=1[CH3:20].CCOCC>CN(C)C=O>[CH2:1]([C@@H:4]1[CH2:9][CH2:8][CH2:7][C@H:6]([O:10][CH2:14][C:15]2[N:16]=[C:17]([C:21]3[CH:26]=[CH:25][CH:24]=[C:23]([CH3:27])[CH:22]=3)[O:18][C:19]=2[CH3:20])[CH2:5]1)[CH:2]=[CH2:3]
Reactant: C=CC[C@@H]1CCC[C@H](O)C1
Reactant: Cc1cccc(-c2nc(CI)c(C)o2)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOCC
Product: C=CC[C@@H]1CCC[C@H](OCc2nc(-c3cccc(C)c3)oc2C)C1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
2 g of cis-3-allylcyclohexanol are dissolved in 30 ml of dimethylformamide, and 750 mg of sodium hydride (60% strength suspension in paraffin oil) are added. After 30 minutes, 6.7 g of 4-iodomethyl-5-methyl-2-(3-methylphenyl)oxazole, dissolved in 20 ml of dimethylformamide, are added dropwise. The mixture is stirred at room temperature for 1 hour. 200 ml of methy tert-buthyl ether are then added to the reaction mixture, and the mixture is washed three times with water. The organic phase is dried over magnesium sulfate and the solvent is then removed under reduced pressure. The residue is purified by RP-HPLC. This gives 1.56 g of 4-(cis-3-allylcyclohexyloxymethyl)-2-(3-methylphenyl)-5-methyloxazole as an oil. C21H27NO2 (325.45), MS (ESI): 326 (M+H+), Rf(n-heptane:ethylacetate=2:1)=0.28.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:11])[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][N:6]=1.[N:12]([O-])=[O:13].[Na+].O>CC(O)=O>[CH3:1][O:2][C:3](=[O:11])[C:4](=[N:12][OH:13])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][N:6]=1
Reactant: COC(=O)Cc1ccccn1
Reactant: O=N[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: COC(=O)C(=NO)c1ccccn1
Reaction time: 0.67 h
Yield: 9755.6 %

Procedure:
To a solution of pyridin-2-yl-acetic acid methyl ester (8.9 ml, 0.66 mmol) in AcOH (16 mL) at 0° C. with stirring, an aqueous solution of sodium nitrite (4.67 g, 0.66 mmol in 14 mL) was added portion wise. After addition was completed stirring was continued for 40 min at room temperature. Water (30 mL) was added and the mixture was stirred for additional 1 h. The mixture was concentrated to remove most of the AcOH and basidified to pH 8˜9 with Na2CO3 aq. extracted with EtOAc (3×). The combined organics were dried over MgSO4, filtered, and concentrated in vacuo. Drying in a vacuum oven affords Hydroxyimino-pyridin-2-yl-acetic acid methyl ester (11.6 g, 97%) as an off-white solid, m/z 181.6 [M+1]+
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[CH:10][C:6]([C:7](Cl)=[O:8])=[CH:5][CH:4]=1.C(N(CC)CC)C.[C:19]1([CH2:25][CH2:26][CH2:27][NH2:28])[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>C(Cl)Cl>[C:19]1([CH2:25][CH2:26][CH2:27][NH:28][C:7](=[O:8])[C:6]2[CH:10]=[CH:11][C:3]([O:2][CH3:1])=[CH:4][CH:5]=2)[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: NCCCc1ccccc1
Reactant: COc1ccc(C(=O)Cl)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1ccc(C(=O)NCCCc2ccccc2)cc1
Temperature: 25 °C

Procedure:
To a solution of p-methoxybenzoyl chloride (37.8 g, .222 mol) in CH2Cl2 (200 ml) at 0°, is added triethylamine (22.5 g, .222 mol) followed by the slow addition of 3-phenylpropylamine (20 g,.148 mol) dissolved in CH2Cl2 (100 ml). The reaction is allowed to warm to room temperature over several hours. The solvent is removed in vacuo, and the residue is dissolved in EtOAc (500 ml) and 2N HCl (500 ml). The EtOAc is separated, washed with 2NHCl (350 ml), H2O (350 ml), saturated NaHCO3 solution (350 ml), and saturated NaCl solution (350 ml); dried over MgSO4 ; and evaporated. The resulting light brown solid is purified by chromatography (SiO2 ;1:9 EtOAc/hexanes, 1:4 EtOAc/hexanes) yielding N-(3-phenylpropyl)-4-methoxybenzamide as creamy solid.