Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [SnH](CCCC)(CCCC)[CH2:2][CH2:3][CH2:4]C.CC(N=NC(C#N)(C)C)(C#N)C.[NH:26]1[C:34]2[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=2)[CH2:28][CH2:27]1>C1C=CC=CC=1>[CH:3]([N:26]1[C:34]2[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=2)[CH2:28][CH2:27]1)([CH3:4])[CH3:2]
Reactant: CCCC[SnH](CCCC)CCCC
Reactant: c1ccc2c(c1)CCN2
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: c1ccccc1
Product: CC(C)N1CCc2ccccc21

Procedure:
A three-hour addition of nBu3SnH (154 μL, 573 μmol) and AIBN (34 mg, 208 μmol) solution in benzene (1 mL) to a refluxing solution of the unpurified ketimine (125 mg, 521 μmol) in benzene (50 mL) delivered, after flash chromatography (30% CH2Cl2 Hexanes) 0.024 g (30%) of the desired indoline as a colorless oil. Rf=0.1 (30% CH2Cl2 Hexanes); IR (film) 3047, 1607 cm−1; 1H NMR (400 MHz, CDCl3) δ 7.04 (t, J=6.7 Hz, 2H), 6.59 (t, J=7.4 Hz, 1H), 6.42 (d, J=8.1 Hz, IH), 3.83 (sep, J=6.6 Hz, 1H), 3.33 (t, J=8.5 Hz, 2H), 2.93 (t, J=8.3 Hz, 2H), 1.15 (d, J=6.7 Hz, 6H); 13C NMR (100 MHz, CDCl3) ppm 151.5, 130.5, 127.5, 124.6, 117.1, 107.3, 46.0, 45.7, 28.4, 18.4; HRMS (EI) Exact mass calcd for C11H15N [M]+, 161.1204. Found 161.1201.
Reaction SMILES: [C:1]([O:5][C:6](=[O:24])[NH:7][CH2:8][C:9]1[C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=2[O:13][C:12]2[CH:20]=[CH:21][CH:22]=[CH:23][C:11]=2[CH:10]=1)([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].[CH2:27](Br)[C:28]#[CH:29].O>CN(C)C=O.[Cl-].[Na+].O.COC(C)(C)C>[C:1]([O:5][C:6](=[O:24])[N:7]([CH2:8][C:9]1[C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=2[O:13][C:12]2[CH:20]=[CH:21][CH:22]=[CH:23][C:11]=2[CH:10]=1)[CH2:29][C:28]#[CH:27])([CH3:4])([CH3:2])[CH3:3]
Reactant: C#CCBr
Reactant: CC(C)(C)OC(=O)NCC1=Cc2ccccc2Oc2ccccc21
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Solvent: COC(C)(C)C
Product: C#CCN(CC1=Cc2ccccc2Oc2ccccc21)C(=O)OC(C)(C)C
Reaction time: 0.25 h
Yield: 98.8 %

Procedure:
1.0 9 (3.091 mmol) of dibenz(b,f]oxepin-10-ylmethyl-carbamic acid tert-butyl ester is placed in 10 ml of dimethylformamide, 0.22 g (4.636 mmol) of 55% sodium hydride suspension (in oil) is added at room temperature, the mixture is stirred for 15 minutes and then 0.279 ml (3.709 mmol) of propargyl bromide is added dropwise at room temperature. After 1 hour, water and a small amount of brine are carefully added and tert-butyl methyl ether is mixed in. The organic phase is washed 4× with water, dried over sodium sulfate and concentrated. 1.106 g (3.06 mmol)=98.8% of dibenz[b,f]oxepin-10-ylmethyl-prop-2-ynyl-carbamic acid tert-butyl ester are obtained in the form of a brown oil; TLC (silica gel; ethyl acetate/hexane=9:1; UV): Rf =0.45.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH:9]2[CH2:12][CH2:11][CH2:10]2)=[CH:4][C:3]=1[C:13]1[CH:14]=[C:15]([CH:29]=[CH:30][N:31]=1)[C:16]([NH:18][C@@H:19]1[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH2:22][CH2:21][CH2:20]1)=[O:17].[CH3:32][C:33]([CH3:62])([O:35][C:36](=[O:61])[CH2:37][CH2:38][O:39][CH2:40][CH2:41][O:42][CH2:43][CH2:44][O:45][CH2:46][CH2:47][O:48][CH2:49][CH2:50][CH2:51][C:52]1[CH:53]=[C:54]([CH:58]=[CH:59][CH:60]=1)[C:55](O)=[O:56])[CH3:34].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>CN(C=O)C>[CH:9]1([O:8][C:5]2[CH:6]=[CH:7][C:2]([NH:1][C:55]([C:54]3[CH:53]=[C:52]([CH2:51][CH2:50][CH2:49][O:48][CH2:47][CH2:46][O:45][CH2:44][CH2:43][O:42][CH2:41][CH2:40][O:39][CH2:38][CH2:37][C:36]([O:35][C:33]([CH3:62])([CH3:34])[CH3:32])=[O:61])[CH:60]=[CH:59][CH:58]=3)=[O:56])=[C:3]([C:13]3[CH:14]=[C:15]([C:16](=[O:17])[NH:18][C@@H:19]4[C:28]5[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=5)[CH2:22][CH2:21][CH2:20]4)[CH:29]=[CH:30][N:31]=3)[CH:4]=2)[CH2:12][CH2:11][CH2:10]1
Reactant: Nc1ccc(OC2CCC2)cc1-c1cc(C(=O)N[C@H]2CCCc3ccccc32)ccn1
Reactant: CC(C)(C)OC(=O)CCOCCOCCOCCOCCCc1cccc(C(=O)O)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)CCOCCOCCOCCOCCCc1cccc(C(=O)Nc2ccc(OC3CCC3)cc2-c2cc(C(=O)N[C@H]3CCCc4ccccc43)ccn2)c1
Temperature: 60 °C
Reaction time: 1 h
Yield: 34.4 %

Procedure:
To a mixture of (S)-2-(2-amino-5-cyclobutoxyphenyl)-N-(1,2,3,4-tetrahydronaphthalen-1-yl)isonicotinamide 132b (0.048 mmol, 20 mg), 3-(2,2-dimethyl-4-oxo-3,7,10,13,16-pentaoxanonadecan-19-yl)benzoic acid (0.053 mmol, 24 mg) and DIEA (0.29 mmol, 38 mg) in DMF (0.16 mL) was added HATU (0.053 mmol, 20 mg). The mixture was stirred at 60° C. for 1 h and purified by prep. TLC to give a yellow syrup (13.8 mg, 34%). MS (ES, m/z): 836.07 [M+H]+.
Reaction SMILES: C(N(CC)CC)C.[C:8]([NH:11][C:12](=[CH:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:13]([OH:15])=[O:14])(=[O:10])[CH3:9].[H][H]>CO>[C:8]([NH:11][C@@H:12]([C:13]([OH:15])=[O:14])[CH2:16][C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1)(=[O:10])[CH3:9]
Reactant: CC(=O)NC(=Cc1ccccc1)C(=O)O
Reactant: [H][H]
Solvent: CO
Solvent: CCN(CC)CC
Product: CC(=O)N[C@H](Cc1ccccc1)C(=O)O
Temperature: 40 °C
Reaction time: 22 h

Procedure:
The atmosphere in a 25 mL-recovery flask was substituted with nitrogen, and 3 mL of deoxygenized methanol and triethylamine (20.9 μL, 0.15 mmol) were added to the flask as the reaction solvent. α-Acetamidocinnamic acid (0.20 g, 0.98 mmol) and [Rh(CLPL-S)(COD)]BF4 (3.95 mg, 0.0049 mmol) were weighed in a 50 mL-Pyrex (registered trade name) test tube for autoclaving, the tube was put into an autoclave together with a stirrer in the tube, and the atmosphere in the autoclave was substituted with nitrogen. The reaction solvent in a volume of 2 mL was added to the mixture, the atmosphere in the autoclave was sufficiently substituted with hydrogen, and then pressurized with 2 MPa of hydrogen, and the reaction mixture was stirred at 40° C. for 22 hours. After 22 hours, the atmosphere in the autoclave was returned to ordinary pressure, and the reaction mixture was concentrated in an evaporator. The concentrated residue was added with 5 mL of 2 M aqueous sodium hydroxide for dissolution, and the solution was washed with 5 mL of ethyl acetate. The aqueous layer was separated, and added with diluted hydrochloric acid until pH of the aqueous layer became lower than 2, and the produced oil was extracted with 10 mL of ethyl acetate. The organic layer was concentrated in an evaporator to obtain (R)-N-acetylphenylalanine quantitatively.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH2:15][CH2:16][CH2:17][N:18]3[CH2:23][CH2:22][N:21]([CH3:24])[CH2:20][C:19]3=[O:25])=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][N:3]=1.[Cl:26][C:27]1[CH:35]=[C:34]([C:36]#[C:37][CH2:38][CH2:39][O:40][CH3:41])[C:30]2[O:31][CH2:32][O:33][C:29]=2[C:28]=1[NH2:42].C[Si]([N-][Si](C)(C)C)(C)C.[Na+]>CN(C=O)C>[Cl:26][C:27]1[CH:35]=[C:34]([C:36]#[C:37][CH2:38][CH2:39][O:40][CH3:41])[C:30]2[O:31][CH2:32][O:33][C:29]=2[C:28]=1[NH:42][C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH2:15][CH2:16][CH2:17][N:18]3[CH2:23][CH2:22][N:21]([CH3:24])[CH2:20][C:19]3=[O:25])=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][N:3]=1
Reactant: COCCC#Cc1cc(Cl)c(N)c2c1OCO2
Reactant: COc1cc2c(Cl)ncnc2cc1OCCCN1CCN(C)CC1=O
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: CN(C)C=O
Product: COCCC#Cc1cc(Cl)c(Nc2ncnc3cc(OCCCN4CCN(C)CC4=O)c(OC)cc23)c2c1OCO2
Yield: 67.8 %

Procedure:
This was prepared by the method described in example 4 but using 1-{3-[(4-chloro-6-methoxyquinazolin-7-yl)oxy]propyl}-4-methylpiperazin-2-one (140 mg, 0.38 mmol), 5-chloro-7-(4-methoxybut-1-yn-1-yl)-1,3-benzodioxol-4-amine (107 mg, 0.42 mmol) and sodium bis(trimethylsilyl)amide (1.0M in THF, 0.81 ml) in DMF (2 ml). The crude product was purified by column chromatography on silica using increasing concentrations of methanol in dichloromethane as eluent. There was thus obtained the title compound (150 mg, 67%) as a pale orange solid; NMR Spectrum:(DMSOd6) 2.04 (quintet, 2H), 2.20 (s, 3H), 2.59 (t, 2H), 2.72 (t, 2H), 2.91 (s, 2H), 3.30 (s, 3H), 3.32 (t, 2H), 3.47 (t, 2H), 3.53 (t, 2H), 3.94 (s, 3H), 4.14 (t, 2H), 6.14 (s, 2H), 7.07 (s, 1H), 7.15 (s, 1H), 7.83 (s, 1H), 8.32 (s, 1H), 9.49 (s, 1H);
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[C:7]([C:12]([F:15])([F:14])[F:13])[CH:8]=[CH:9][CH:10]=2)[N:5]=[CH:4][C:3]=1[C:16]#[N:17].[NH2:18][C:19]1[CH:20]=[C:21](B(O)O)[CH:22]=[CH:23][CH:24]=1>>[NH2:18][C:19]1[CH:24]=[C:23]([C:2]2[C:11]3[C:6](=[C:7]([C:12]([F:15])([F:14])[F:13])[CH:8]=[CH:9][CH:10]=3)[N:5]=[CH:4][C:3]=2[C:16]#[N:17])[CH:22]=[CH:21][CH:20]=1
Reactant: N#Cc1cnc2c(C(F)(F)F)cccc2c1Cl
Reactant: Nc1cccc(B(O)O)c1
Product: N#Cc1cnc2c(C(F)(F)F)cccc2c1-c1cccc(N)c1

Procedure:
The title compound was prepared from 4-chloro-8-(trifluoromethyl)quinoline-3-carbonitrile and 3-aminophenylboronic acid according to the procedure of Example 1.
Reaction SMILES: [Br:1][C:2]1[C:3]([OH:14])=[C:4]([CH:7]=[C:8]([C:10]([CH3:13])([CH3:12])[CH3:11])[CH:9]=1)[CH:5]=[O:6].C(=O)([O-])[O-].[K+].[K+].[CH3:21][O:22][CH2:23][CH2:24][O:25][CH2:26]Cl>CN(C=O)C>[Br:1][C:2]1[C:3]([O:14][CH2:21][O:22][CH2:23][CH2:24][O:25][CH3:26])=[C:4]([CH:7]=[C:8]([C:10]([CH3:11])([CH3:13])[CH3:12])[CH:9]=1)[CH:5]=[O:6]
Reactant: CC(C)(C)c1cc(Br)c(O)c(C=O)c1
Reactant: COCCOCCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COCCOCOc1c(Br)cc(C(C)(C)C)cc1C=O
Temperature: 20 °C
Yield: 100.8 %

Procedure:
A mixture of 3-bromo-5-(tert-butyl)-2-hydroxybenzaldehyde (3.99 g, 15.51 mmol) and anhydrous potassium carbonate (2.36 g, 17.10 mmol) in anhydrous DMF (20.0 mL) was stirred under nitrogen in a water bath (20° C.) to give an orange-yellow suspension. After stirring for 20 min, 2-methoxyethoxymethyl chloride (2.00 mL, 17.66 mmol, technical grade) was added drop wise (30 min) to above suspension while maintaining an internal temperature of 20° C. The reaction mixture was stirred at room temperature for 2.5 h to give a yellow-orange suspension. The reaction mixture was poured into ice-water (150 mL) and stirred at room temperature to give a yellow oily liquid, no solid formation was observed. After 30 min of stirring, the reaction mixture was extracted with dichloromethane (2×100 mL). The organic layer was removed, washed with water (1×50 mL) and dried over anhydrous magnesium sulfate, filtered and evaporated in vacuo to give a very pure product as an orange viscous liquid (5.40 g). 1H NMR (400 MHz; CDCl3): δ 1.29 (s, 9H, (CH3)3C—), 3.33 (s, 3H, CH3—O—), 3.53 (M, 2H, —CH2—CH2—O—), 3.98 (M, 2H, —CH2—CH2—O—), 5.25 (s, 2H, —O—CH2—O—), 7.79 (s, 2H, H-4 and H-6), 10.28 (s, 1H, —CHO). The 1H NMR spectrum of the sample was consistent with the suggested structure of the product.
Reaction SMILES: C(C1C=[CH:23][C:6]([CH2:7][S:8][C:9]2[CH:10]=[C:11]([O:19][CH2:20][O:21][CH3:22])[C:12](=[O:18])[N:13]([CH2:15][O:16][CH3:17])[CH:14]=2)=CC=1)C.ClC[C:27]1[CH:32]=[N:31]C=C[N:28]=1>>[CH3:22][O:21][CH2:20][O:19][C:11]1[C:12](=[O:18])[N:13]([CH2:15][O:16][CH3:17])[CH:14]=[C:9]([S:8][CH2:7][C:6]2[CH:23]=[N:31][CH:32]=[CH:27][N:28]=2)[CH:10]=1
Reactant: ClCc1cnccn1
Reactant: CCc1ccc(CSc2cc(OCOC)c(=O)n(COC)c2)cc1
Product: COCOc1cc(SCc2cnccn2)cn(COC)c1=O

Procedure:
Prepared as described for 5-[(4-ethylbenzyl)sulfanyl]-3-(methoxymethoxy)-1-(methoxymethyl)pyridin-2(1H)-one (Intermediate 17) but using 2-chloromethylpyrazine instead of 1-(chloromethyl)-4-ethylbenzene.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[NH:9][N:10]([CH3:21])[C:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[Cl:20])=[N:12][N:13]=1.Cl[C:23]1C=CC=CC=1C(NNC(=O)C1C=CC(C)=CC=1)=O>>[CH3:23][C:6]1[CH:5]=[CH:4][C:3]([C:8]2[NH:9][N:10]([CH3:21])[C:11]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=3[Cl:20])=[N:12][N:13]=2)=[CH:2][CH:7]=1
Reactant: Cc1ccc(C(=O)NNC(=O)c2ccccc2Cl)cc1
Reactant: CN1NC(c2ccccc2Cl)=NN=C1c1ccccc1Cl
Product: Cc1ccc(C2=NN=C(c3ccccc3Cl)N(C)N2)cc1

Procedure:
By the method of Example 1 stages (b) and (c), the above compound was prepared from the product of stage (a) of this Example. Mp 152°-154° C.
Reaction SMILES: C[N:2]([CH3:12])[CH:3]=[CH:4][C:5]([C:7]1[CH:11]=[CH:10][O:9][CH:8]=1)=O.N[C:14]1[C:18]([C:19]#[N:20])=C[NH:16][N:15]=1>C(O)(=O)C>[O:9]1[CH:10]=[CH:11][C:7]([C:5]2[N:16]3[N:15]=[CH:14][C:18]([C:19]#[N:20])=[C:12]3[N:2]=[CH:3][CH:4]=2)=[CH:8]1
Reactant: N#Cc1c[nH]nc1N
Reactant: CN(C)C=CC(=O)c1ccoc1
Solvent: CC(=O)O
Product: N#Cc1cnn2c(-c3ccoc3)ccnc12

Procedure:
A mixture of 0.01 mole of 3-dimethylamino-1-(3-furyl)-2-propen-1-one and 0.01 mole of 3-aminopyrazole-4-carbonitrile in glacial acetic acid is heated at reflux temperature for 6 hours. The solvent is removed in vacuo and the residue purified as described for Example 1 to give the product of the example.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1.[Cl:14][C:15]1[CH:23]=[C:22]2[C:18]([C:19]([C:24](O)=[O:25])=[CH:20][NH:21]2)=[CH:17][CH:16]=1>>[Cl:14][C:15]1[CH:23]=[C:22]2[C:18]([C:19]([C:24]([N:11]3[CH2:12][CH2:13][N:8]([C:3]4[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=4[F:1])[CH2:9][CH2:10]3)=[O:25])=[CH:20][NH:21]2)=[CH:17][CH:16]=1
Reactant: O=C(O)c1c[nH]c2cc(Cl)ccc12
Reactant: Fc1ccccc1N1CCNCC1
Product: O=C(c1c[nH]c2cc(Cl)ccc12)N1CCN(c2ccccc2F)CC1

Procedure:
Following general procedure I, the coupling of (commercially available) 1-(2-fluoro-phenyl)-piperazine (described herein) with 6-chloro-1H-indole-3-carboxylic acid gave the title compound.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][C:6]([C:10]#[N:11])=[CH:7][CH:8]=2)[CH2:3][CH2:2]1.O=[C:13]1[CH2:17][CH2:16][N:15]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:14]1.CC(O)=O.[BH3-]C#N.[Na+]>CO>[C:10]([C:6]1[CH:5]=[C:4]2[C:9](=[CH:8][CH:7]=1)[N:1]([CH:17]1[CH2:13][CH2:14][N:15]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:16]1)[CH2:2][CH2:3]2)#[N:11]
Reactant: N#Cc1ccc2c(c1)CCN2
Reactant: CC(C)(C)OC(=O)N1CCC(=O)C1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCC(N2CCc3cc(C#N)ccc32)C1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a solution of indoline-5-carbonitrile (110 mg, 0.75 mmol) in 2.5 mL of MeOH was added tert-butyl 3-oxopyrrolidine-1-carboxylate (166 mg, 0.90 mmol) and HOAc (0.11 mL, 1.88 mmol) subsequently. After stirring at room temperature for 10 minutes, NaCNBH3 (57 mg, 0.90 mmol) was added and the mixture was then stirred at ambient temperature for 2 days. The volatiles were removed under vacuum. The residue was diluted with EtOAc, then washed with 1 N NaOH solution and brine, dried over Na2SO4, and evaporated in vacuo to afford the crude title compound for the next step use without further purification.
Reaction SMILES: [OH:1][C:2]1[C:10]([C:11]([OH:13])=[O:12])=[C:9]([O:14][CH3:15])[C:5]2[CH:6]=[CH:7][O:8][C:4]=2[C:3]=1[O:16][CH3:17].O.[OH-].[Na+].[H][H]>C(O)C.[Pd]>[OH:1][C:2]1[C:10]([C:11]([OH:13])=[O:12])=[C:9]([O:14][CH3:15])[C:5]2[CH2:6][CH2:7][O:8][C:4]=2[C:3]=1[O:16][CH3:17]
Reactant: [H][H]
Reactant: COc1c(C(=O)O)c(O)c(OC)c2occc12
Agent: [Pd]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: COc1c(O)c(C(=O)O)c(OC)c2c1OCC2
Yield: 73.4 %

Procedure:
5 g of 6-hydroxy-4,7-dimethoxybenzofuran-5-carboxylic acid in 75 ml of ethanol/25 ml of H2O/0.8 g of NaOH are hydrogenated in the presence of 1 g of Pd/C (10%) under atmospheric pressure and at 50° C. until uptake of hydrogen is complete. The mixture is filtered, the ethanol is removed by distillation, the aqueous phase is acidified, and the solid is filtered off with suction. 3.7 g of product are obtained and reacted further without purification.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[C:6]([CH:12]=[CH:13][C:14]=1[O:15][CH2:16][CH3:17])[C:7]([O:9][CH2:10][CH3:11])=[O:8])[CH3:2].[N+:18]([O-])([OH:20])=[O:19]>CC(O)=O>[CH2:16]([O:15][C:14]1[C:4]([O:3][CH2:1][CH3:2])=[CH:5][C:6]([C:7]([O:9][CH2:10][CH3:11])=[O:8])=[C:12]([N+:18]([O-:20])=[O:19])[CH:13]=1)[CH3:17]
Reactant: O=[N+]([O-])O
Reactant: CCOC(=O)c1ccc(OCC)c(OCC)c1
Solvent: CC(=O)O
Product: CCOC(=O)c1cc(OCC)c(OCC)cc1[N+](=O)[O-]
Temperature: 50 °C
Yield: 93.8 %

Procedure:
According to the procedure described in Example 6A Step 2, to a solution of ethyl 3,4-diethoxybenzoate (6.43 g, 27 mmol) in AcOH (50 mL) was dropped fuming nitric acid (90%, 6.3 g) and the reaction was heated at 50° C. overnight, to afford ethyl 4,5-diethoxy-2-nitrobenzoate as a solid (7.175 g, 94%). 1H NMR (300 MHz, CDCl3) δ 7.44 (s, 1H), 7.05 (s, 1H), 4.37 (q, 2H), 4.18 (m, 4H), 1.50 (m, 6H), 1.35 (t, 3H); LC-MS (ESI) m/z 284 (M+H)+.
Reaction SMILES: [S:1]1[CH:5]=[C:4]([CH:6]=O)[N:3]=[N:2]1.[CH3:8][O:9][C:10]1[CH:17]=[C:16]([O:18][CH3:19])[CH:15]=[CH:14][C:11]=1[CH2:12][NH2:13].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)([O-])O.[Na+]>ClCCCl.ClCCl>[CH3:8][O:9][C:10]1[CH:17]=[C:16]([O:18][CH3:19])[CH:15]=[CH:14][C:11]=1[CH2:12][NH:13][CH2:6][C:4]1[N:3]=[N:2][S:1][CH:5]=1
Reactant: O=Cc1csnn1
Reactant: COc1ccc(CN)c(OC)c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: ClCCCl
Product: COc1ccc(CNCc2csnn2)c(OC)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 1,2,3-thiadiazole-4-carboxaldehyde (750 mg, 6.57 mmol) and 2,4-dimethoxybenzylamine (1086 μl, 7.23 mmol) in 1,2-dichloroethane (13.1 mL) at 0° C. was added molecular sieves (powdered, 4 A) (2.50 g, 6.57 mmol) followed by sodium triacetoxyborohydride (1950 mg, 9.20 mmol). The reaction was allowed to warm to room temperature with stirring overnight. Then, the resulting suspension was poured into dichloromethane (75 mL) and aqueous sodium hydrogen carbonate (saturated, 75 mL). The layers were mixed and then filtered through celite. The aqueous layer was then extracted with dichloromethane (3×50 mL) and the combined organics were dried over anhydrous Na2 SO4, filtered and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (EtOAc/Hexanes+1% triethylamine gradient) to afford the title compound as a pale yellow liquid. LRMS (APCI) calculated for C12H16N3O2S [M+H]+, 266.1; found 266.1.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]([N:10]2[CH2:15][CH2:14][CH:13]([N:16]3[CH2:20][CH2:19][CH2:18][CH2:17]3)[CH2:12][CH2:11]2)=[O:9])=[C:4]([O:21][CH3:22])[CH:3]=1.BrC1C=CC(C(O)=O)=C(OC)C=1.N1(C2CCNCC2)CCCC1.BrC1C(C)=C(C(N2CCC(N3CCCC3)CC2)=O)C=CC=1.[F:67][C:68]([F:79])([F:78])[C:69]1[CH:70]=[C:71](B(O)O)[CH:72]=[CH:73][CH:74]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>CN(C=O)C.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[CH3:22][O:21][C:4]1[CH:3]=[C:2]([C:73]2[CH:72]=[CH:71][CH:70]=[C:69]([C:68]([F:79])([F:78])[F:67])[CH:74]=2)[CH:7]=[CH:6][C:5]=1[C:8]([N:10]1[CH2:15][CH2:14][CH:13]([N:16]2[CH2:20][CH2:19][CH2:18][CH2:17]2)[CH2:12][CH2:11]1)=[O:9]
Reactant: COc1cc(Br)ccc1C(=O)N1CCC(N2CCCC2)CC1
Reactant: OB(O)c1cccc(C(F)(F)F)c1
Agent: [Pd]
Agent: C1CCN(C2CCNCC2)C1
Agent: COc1cc(Br)ccc1C(=O)O
Solvent: CN(C)C=O
Product: COc1cc(-c2cccc(C(F)(F)F)c2)ccc1C(=O)N1CCC(N2CCCC2)CC1

Procedure:
In analogy to the procedure described in example 1, (4-bromo-2-methoxy-phenyl)-(4-pyrrolidin-1-yl-piperidin-1-yl)-methanone (prepared from 4-bromo-2-methoxybenzoic acid and 4-pyrrolidin-1-yl-piperidine in analogy to the procedure described for the preparation of intermediate 2), was reacted with 3-trifluoromethyl-phenyl boronic acid, potassium phosphate solution and tetrakis-(triphenylphosphine)-palladium in DMF at 80° C. to give the title compound as colorless oil. MS: 433.2 (MH+).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:10]([O:11][CH2:12][C:13]([F:16])([F:15])[F:14])=[C:9]([C:17]([O:19]CC)=[O:18])[N:8]([CH2:22][C:23](=[O:32])[NH:24][C:25]2[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][N:26]=2)[N:7]=1)=[O:5])[CH3:2].Cl>C1COCC1.[OH-].[Na+]>[CH2:1]([O:3][C:4]([C:6]1[C:10]([O:11][CH2:12][C:13]([F:14])([F:15])[F:16])=[C:9]([C:17]([OH:19])=[O:18])[N:8]([CH2:22][C:23](=[O:32])[NH:24][C:25]2[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][N:26]=2)[N:7]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1nn(CC(=O)Nc2ccc(Cl)cn2)c(C(=O)OCC)c1OCC(F)(F)F
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CCOC(=O)c1nn(CC(=O)Nc2ccc(Cl)cn2)c(C(=O)O)c1OCC(F)(F)F
Reaction time: 16 h

Procedure:
To a solution of 400 mg 1-[(5-Chloro-pyridin-2-ylcarbamoyl)-methyl]-4-(2,2,2-trifluoro-ethoxy)-1H-pyrazole-3,5-dicarboxylic acid diethyl ester in 5 ml THF and 0.9 ml 1N NaOH were added. After standing for 16 h, the solution was acidified using 1 N HCl to pH 1. The precipitating product was collected by filtration and dried under reduced pressure. Yield: 142 mg.
Reaction SMILES: C([O:7][CH2:8][CH2:9][C@@H:10]1[C@@H:14]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[O:13][C:12]2([CH2:24][CH2:23][CH2:22][CH2:21]2)[O:11]1)(=O)C(C)(C)C.C(OCC[C@@H]1[C@@H](C2C=CC=CC=2)OC(CC)(CC)O1)(=O)C(C)(C)C>>[C:15]1([C@H:14]2[O:13][C:12]3([CH2:24][CH2:23][CH2:22][CH2:21]3)[O:11][C@@H:10]2[CH2:9][CH2:8][OH:7])[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1
Reactant: CC(C)(C)C(=O)OCC[C@H]1OC2(CCCC2)O[C@@H]1c1ccccc1
Agent: CCC1(CC)O[C@H](c2ccccc2)[C@@H](CCOC(=O)C(C)(C)C)O1
Product: OCC[C@H]1OC2(CCCC2)O[C@@H]1c1ccccc1
Yield: 80 %

Procedure:
The substantially same method as described in Example 291 was conducted, except that 2-((2R,3R)-3-phenyl-1,4-dioxaspiro[4.4]nonan-2-yl)ethyl pivalate (Preparation example 292) was used instead of that 2-((4S,5S)-2,2-diethyl-5-phenyl-1,3-dioxolan-4-yl)ethyl pivalate (Preparation example 290), to obtain the title compound (0.9 g, 80˜95%)
Reaction SMILES: [C:1](Cl)(=[O:4])[CH:2]=[CH2:3].[NH2:6][C:7]1[CH:8]=[C:9]([CH:13]=[CH:14][CH:15]=1)[C:10]([NH2:12])=[O:11]>CC(C)=O>[C:1]([NH:6][C:7]1[CH:8]=[C:9]([CH:13]=[CH:14][CH:15]=1)[C:10]([NH2:12])=[O:11])(=[O:4])[CH:2]=[CH2:3]
Reactant: NC(=O)c1cccc(N)c1
Reactant: C=CC(=O)Cl
Solvent: CC(C)=O
Product: C=CC(=O)Nc1cccc(C(N)=O)c1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 44 %

Procedure:
Propenoyl chloride from Aldrich Chemical Company Ltd. (2.2 gm, 24.3 mMole) was added dropwise to an ice-cold solution of 3-aminobenzamide (5.0 gm, 36.8 mMole) in 30 ml of acetone. The mixture was stirred on ice for 30 minutes, and then the white precipitate was filtered off and washed with cold acetone and then with cold water to give 4.2 gm of white product. The product was crystallized from 25% aqueous dimethyl sulphoxide and the crystallized product had a melting point of 229° C. to 230° C. The overall yield was 44%.
Reaction SMILES: Cl([O-])=O.[Na+].[OH2:5].O.P([O-])(O)(O)=O.[Na+].[Cl:13][C:14]1[CH:15]=[C:16]([CH:19]=[CH:20][C:21]=1[CH2:22][CH:23]([CH3:25])[CH3:24])[CH:17]=[O:18]>O.C(O)(C)(C)C>[Cl:13][C:14]1[CH:15]=[C:16]([CH:19]=[CH:20][C:21]=1[CH2:22][CH:23]([CH3:25])[CH3:24])[C:17]([OH:5])=[O:18]
Reactant: O
Reactant: CC(C)Cc1ccc(C=O)cc1Cl
Agent: O=P([O-])(O)O
Agent: [Na+]
Agent: [O-][Cl+][O-]
Solvent: CC(C)(C)O
Product: CC(C)Cc1ccc(C(=O)O)cc1Cl
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A mixture of sodium chlorite (80% assay, 1.06 g, 0.0094 mol) and sodium dihydrogenphosphate dihydrate (3.33 g, 0.0213 mol) in demineralized water (10 mL) is added in two equal lots (one hr interval) to a solution of 3-chloro-4-isobutylbenzaldehyde (0.7 g, 0.0036 mol) in tert-butanol (10 mL) at room temperature. After completion of addition, stirring at room temperature is continued for 4 hrs. It is then extracted in ethyl acetate (2×30 mL). Combined organic layer is dried over sodium sulfate and concentrated under reduced pressure to give 3-chloro-4-isobutylbenzoic acid.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([OH:10])[CH:5]=[C:6]([CH3:9])[C:7]=1[CH3:8].Cl[CH2:12][C:13]([CH3:15])=[CH2:14].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[CH3:1][C:2]1[CH:3]=[C:4]([O:10][CH2:14][C:13](=[CH2:12])[CH3:15])[CH:5]=[C:6]([CH3:9])[C:7]=1[CH3:8]
Reactant: Cc1cc(O)cc(C)c1C
Reactant: C=C(C)CCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: C=C(C)COc1cc(C)c(C)c(C)c1

Procedure:
To a solution 20 g of 3,4,5-trimethylphenol in 150 ml of absolute acetone was added 22 ml of 3-chloro-2-methylpropene and 20.3 g of anhydrous potassium carbonate. After refluxing for 45 hours, the reaction mixture was filtered, washed with acetone, concentrated under reduced pressure and diluted with 200 ml of diethyl ether. The mixture was extracted three times with 50 ml of 2N hydrochloric acid and 50 ml of 20% aqueous solution of sodium hydroxide. The organic extract was dried over anhydrous magnesium sulfate, filtered and concentrated under the reduced pressure to afford a crude product. Final purification was carried by silica-gel column chromatography to afford 27 g of methallyl 3,4,5-trimethylphenyl ether as yellow oil.