Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:6]=[C:7]([CH:13]=[CH:14][CH:15]=1)/[CH:8]=[CH:9]/[C:10]([OH:12])=O)(=[O:3])[CH3:2].[Cl:16][CH2:17][CH:18]1[C:26]2[C:21](=[CH:22][C:23]([N+:27]([O-:29])=[O:28])=[CH:24][CH:25]=2)[NH:20][CH2:19]1>>[C:1]([NH:4][C:5]1[CH:6]=[C:7]([CH:13]=[CH:14][CH:15]=1)/[CH:8]=[CH:9]/[C:10]([N:20]1[C:21]2[C:26](=[CH:25][CH:24]=[C:23]([N+:27]([O-:29])=[O:28])[CH:22]=2)[CH:18]([CH2:17][Cl:16])[CH2:19]1)=[O:12])(=[O:3])[CH3:2]
Reactant: CC(=O)Nc1cccc(/C=C/C(=O)O)c1
Reactant: O=[N+]([O-])c1ccc2c(c1)NCC2CCl
Product: CC(=O)Nc1cccc(/C=C/C(=O)N2CC(CCl)c3ccc([N+](=O)[O-])cc32)c1
Yield: 80 %

Procedure:
Similar reaction of (E)-3-(acetylamino)cinnamic acid and crude 3-chloromethyl-6-nitroindoline (6) (prepared as in Example 2) gave a crude product which was recrystallised from DMF/MeOH/H2O to give 1-[(E)-3-(acetylamino)cinnamoyl]-3-chloromethyl-6-nitroindoline (13) (80%), mp 229-230° C. 1H NMR [(CD3)2SO] δ10.06 (s, 1 H, NH), 8.97 (s, 1 H, H-7), 7.99 (dd, J=8.3, 2.3 Hz, 1 H, H-5), 7.86 (s, 1 H, H-2), 7.73-7.61 (m, 2 H, H-4,4′), 7.66 (d, J=15.3 Hz, 1 H, PhCH═CH), 7.53 (d, J=7.8 Hz, 1 H, H-6), 7.38 (t, J=7.9 Hz, 1 H, H-5), 7.08 (d, J=15.4 Hz, 1 H, PhCH═CH), 4.65 (t, J 10.0 Hz, 1 H, H-2), 4.33 (dd, J=10.7, 5.2 Hz, 1 H, H-2), 4.14-4.00 (m, 3 H, H-3, CH2Cl ), 2.07 (s, 3 H, CH3).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:16])[F:15])=[C:10]([O:18][CH2:19][CH3:20])[CH:9]=2)[CH:5]=[C:4]([C:21]([F:24])([F:23])[F:22])[N:3]=1.[Br:25][C:26]1[N:27]=[CH:28][NH:29][CH:30]=1>>[Br:25][C:26]1[N:27]=[CH:28][N:29]([C:2]2[N:7]=[C:6]([C:8]3[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:16])[F:15])=[C:10]([O:18][CH2:19][CH3:20])[CH:9]=3)[CH:5]=[C:4]([C:21]([F:24])([F:23])[F:22])[N:3]=2)[CH:30]=1
Reactant: Brc1c[nH]cn1
Reactant: CCOc1cc(-c2cc(C(F)(F)F)nc(Cl)n2)ccc1C(F)(F)F
Product: CCOc1cc(-c2cc(C(F)(F)F)nc(-n3cnc(Br)c3)n2)ccc1C(F)(F)F

Procedure:
The title compound was prepared from 2-chloro-4-(3-ethoxy-4-trifluoromethyl-phenyl)-6-trifluoromethyl-pyrimidine (example A.10) (0.5 g, 1.35 mmol) and commercially available 4-bromo-imidazole (0.30 g, 2.02 mmol) according to the general procedure IVa. Obtained as a white solid (0.47 g, 72%). MS (ISP) 483.0 [(M+H)+]; mp 147.5° C.
Reaction SMILES: [C:1]([NH:9][C:10]1[CH:27]=[CH:26][N:13]([C@@H:14]2[O:25][C@H:22]([CH2:23][OH:24])[C@@H:20]([OH:21])[C@H:15]2[O:16][CH2:17][CH2:18][CH3:19])[C:12](=[O:28])[N:11]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:29][O:30][C:31]1[C:32]([O:51][CH3:52])=[C:33]([CH:48]=[CH:49][CH:50]=1)[C:34](Cl)([C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1)[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1>>[C:1]([NH:9][C:10]1[CH:27]=[CH:26][N:13]([C@@H:14]2[O:25][C@H:22]([CH2:23][O:24][C:34]([C:41]3[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=3)([C:35]3[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=3)[C:33]3[CH:48]=[CH:49][CH:50]=[C:31]([O:30][CH3:29])[C:32]=3[O:51][CH3:52])[C@@H:20]([OH:21])[C@H:15]2[O:16][CH2:17][CH2:18][CH3:19])[C:12](=[O:28])[N:11]=1)(=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCCO[C@@H]1[C@H](O)[C@@H](CO)O[C@H]1n1ccc(NC(=O)c2ccccc2)nc1=O
Reactant: COc1cccc(C(Cl)(c2ccccc2)c2ccccc2)c1OC
Product: CCCO[C@@H]1[C@H](O)[C@@H](COC(c2ccccc2)(c2ccccc2)c2cccc(OC)c2OC)O[C@H]1n1ccc(NC(=O)c2ccccc2)nc1=O
Yield: 49 %

Procedure:
N4-Benzoyl-2'-O-propylcytidine (3.0 g, 0.007 mol) was treated with dimethoxytrityl chloride (1.5 g) as per the procedure of Example 72 to give 1.5 g of pure product. Anal. Calcd. for C40H42N3O8.1/2H2O: C, 68.45; H, 6.18; N, 5.99. Found: C, 68.39; H, 5.99; N, 5.95.
Reaction SMILES: Cl[C:2]1[C:11]2[N:12]=[CH:13][N:14]([CH2:15][C:16]([CH3:18])=[CH2:17])[C:10]=2[C:9]2[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=2[N:3]=1.[NH3:19]>>[CH3:18][C:16](=[CH2:17])[CH2:15][N:14]1[C:10]2[C:9]3[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=3[N:3]=[C:2]([NH2:19])[C:11]=2[N:12]=[CH:13]1
Reactant: N
Reactant: C=C(C)Cn1cnc2c(Cl)nc3ccccc3c21
Product: C=C(C)Cn1cnc2c(N)nc3ccccc3c21

Procedure:
The product 4-chloro-1-(2-methyl-2-propenyl)-1H-imidazo[4,5-c]quinoline from above was reacted with 18% methanolic ammonia as described in Example 10 below to yield a solid. The solid was extracted with hot ethanol, leaving an insoluble residue. The extracts were concentrated to about 20% of their original volume to provide white solid product, 1-(2-methyl-2-propenyl)-1H-imidazo[4,5-c]quinolin-4-amine, m.p. 290°-294° C. Analysis: Calculated for C14H14N4 : %C, 70.6; %H, 5.9; %N, 23.5; Found: %C, 70.6; %H, 6.0; %N, 23.6.
Reaction SMILES: C1(C(F)(F)F)C=CC=CC=1.[N+:11]([C:14]1[CH:15]=[C:16]([C:20]([F:23])([F:22])[F:21])[CH:17]=[CH:18][CH:19]=1)([O-])=O>>[NH2:11][C:14]1[CH:15]=[C:16]([C:20]([F:21])([F:22])[F:23])[CH:17]=[CH:18][CH:19]=1
Reactant: O=[N+]([O-])c1cccc(C(F)(F)F)c1
Solvent: FC(F)(F)c1ccccc1
Product: Nc1cccc(C(F)(F)F)c1

Procedure:
As another example, benzotrifluoride by nitration gives 3-nitrobenzotrifluoride which in turn by reduction gives 3-aminobenzotrifluoride. The latter can be reacted with phosgene to yield the 3-isocyanatobenzotrifluoride. In the subsequent reaction of the isocyanate with dimethylamine the 1-(3-trifluoromethylphenyl)-3-dimethyl-urea is obtained which is an important herbicide (DE-AS (German Examined Specification) No. 1206201).
Reaction SMILES: C([O:3][C:4]([C:6]1[S:7][C:8]2[C:17]3[N:16]=[C:15]([NH:18][C:19]4[CH:24]=[CH:23][CH:22]=[C:21]([S:25](=[O:28])(=[O:27])[NH2:26])[CH:20]=4)[N:14]=[CH:13][C:12]=3[CH:11]=[CH:10][C:9]=2[N:29]=1)=[O:5])C>CCO.[OH-].[Na+]>[S:25]([C:21]1[CH:20]=[C:19]([NH:18][C:15]2[N:14]=[CH:13][C:12]3[CH:11]=[CH:10][C:9]4[N:29]=[C:6]([C:4]([OH:5])=[O:3])[S:7][C:8]=4[C:17]=3[N:16]=2)[CH:24]=[CH:23][CH:22]=1)(=[O:28])(=[O:27])[NH2:26]
Reactant: CCOC(=O)c1nc2ccc3cnc(Nc4cccc(S(N)(=O)=O)c4)nc3c2s1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: NS(=O)(=O)c1cccc(Nc2ncc3ccc4nc(C(=O)O)sc4c3n2)c1
Temperature: 25 °C
Reaction time: 12 h
Yield: 102.5 %

Procedure:
8-(3-Sulfamoyl-phenylamino)-thiazolo[4,5-h]quinazoline-2-carboxylic acid ethyl ester (494 mg, 1.15mmol) was suspended in a mixture of EtOH (30 ml) and 1N sodium hydroxide (20 ml). The mixture was stirred at room temperature for 12 h. EtOH was removed in vacuo and the residual crude mixture was neutralised with 1N HCl (20 ml). The resulting solid was filtered and dried under vacuo to afford 0.473 g of a brownish solid. MS (ES+) 402, (ES−) 400. δH (d6 DMSO) 7.37 (2H, s), 7.50 (1H, d), 7.60 (1H, t), 8.06 (2H, s), 8.16 (1H, d), 8.62 (1H, s), 9.50 (1H, s), 10.52 (1H, s), 14.80 (1H, br s).
Reaction SMILES: [CH:1]1([C:4]2[CH:5]=[CH:6][C:7]([C:15]([OH:17])=O)=[N:8][C:9]=2[O:10][CH2:11][CH:12]2[CH2:14][CH2:13]2)[CH2:3][CH2:2]1.Cl.[NH2:19][C:20]([CH2:28][CH3:29])([CH2:26][CH3:27])[C:21]([O:23][CH2:24][CH3:25])=[O:22]>>[CH2:24]([O:23][C:21](=[O:22])[C:20]([NH:19][C:15]([C:7]1[CH:6]=[CH:5][C:4]([CH:1]2[CH2:2][CH2:3]2)=[C:9]([O:10][CH2:11][CH:12]2[CH2:13][CH2:14]2)[N:8]=1)=[O:17])([CH2:28][CH3:29])[CH2:26][CH3:27])[CH3:25]
Reactant: CCOC(=O)C(N)(CC)CC
Reactant: O=C(O)c1ccc(C2CC2)c(OCC2CC2)n1
Agent: Cl
Product: CCOC(=O)C(CC)(CC)NC(=O)c1ccc(C2CC2)c(OCC2CC2)n1

Procedure:
The title compound was synthesized in analogy to Example 1, using 5-cyclopropyl-6-cyclopropylmethyloxy-pyridine-2-carboxylic acid (Example 42 a) and ethyl 2-amino-2-ethylbutanoate hydrochloride (CAN 1135219-29-2) as starting materials. MS (EI): m/e=375.0 [M+H]+.
Reaction SMILES: O[CH:2]1[CH:9]2[CH:5]3[CH:6]([CH2:12][CH:3]1[CH2:4]3)[S:7](=[O:11])(=[O:10])[O:8]2.[CH2:13](Cl)Cl>>[CH:5]12[CH2:4][CH:3]([CH:2]=[CH:9]1)[CH2:12][CH:6]2[S:7]([O:8][CH3:13])(=[O:10])=[O:11]
Reactant: ClCCl
Reactant: O=S1(=O)OC2C(O)C3CC2C1C3
Product: COS(=O)(=O)C1CC2C=CC1C2

Procedure:
According to Example 1 described in JP-A-2007-31355, 2-hydroxy-4-oxa-5-thiatricyclo[4.2.1.03,7]nonane 5,5-dioxide was synthesized. Specifically, firstly, into a four-necked flask having an inner volume of 5 L equipped with a stirrer, a thermometer and a dropping funnel, methyl 5-norbornene-2-sulfonate (128.8 g, purity: 92.1%) which was obtained in the above-described Comparative Example 1 and methylene chloride (2650 g) were charged. m-Chlorobenzoic acid (200.0 g) was charged slowly under stirring in a state cooled with an ice bath so that the inner temperature of the reaction system did not rise to 5° C. or higher. After confirming disappearance of methyl 5-norbornene-2-sulfonate, 20% by mass sodium sulfite aqueous solution (687.1 g) was added dropwise so that the inner temperature of the reaction system was maintained in a range of 5 to 10° C. After that, the organic layer was washed with a saturated sodium hydrogen carbonate aqueous solution (500 g) three times. By concentrating the resultant organic layer under the reduced pressure, methyl 5,6-epoxynorbornane-2-sulfonate (125.9 g, purity was 87.2% as a peak area percentage in gas chromatography analysis) was obtained.
Reaction SMILES: CS(O[CH:6]([C:22]1[CH:27]=[CH:26][C:25]([Br:28])=[CH:24][CH:23]=1)[CH2:7][CH2:8][CH:9](OS(C)(=O)=O)[C:10]1[CH:15]=[CH:14][C:13]([Br:16])=[CH:12][CH:11]=1)(=O)=O.[CH:29]1([C:32]2[CH:38]=[CH:37][C:35]([NH2:36])=[CH:34][CH:33]=2)[CH2:31][CH2:30]1>CN(C=O)C>[Br:16][C:13]1[CH:14]=[CH:15][C:10]([CH:9]2[CH2:8][CH2:7][CH:6]([C:22]3[CH:27]=[CH:26][C:25]([Br:28])=[CH:24][CH:23]=3)[N:36]2[C:35]2[CH:37]=[CH:38][C:32]([CH:29]3[CH2:31][CH2:30]3)=[CH:33][CH:34]=2)=[CH:11][CH:12]=1
Reactant: CS(=O)(=O)OC(CCC(OS(C)(=O)=O)c1ccc(Br)cc1)c1ccc(Br)cc1
Reactant: Nc1ccc(C2CC2)cc1
Solvent: CN(C)C=O
Product: Brc1ccc(C2CCC(c3ccc(Br)cc3)N2c2ccc(C3CC3)cc2)cc1
Temperature: 50 °C
Reaction time: 3 h
Yield: 75.6 %

Procedure:
The product from Example 42B (3.14 g, 5.64 mmol) and 4-cyclopropylaniline (6.01 g, 45.2 mmol) were combined in DMF (20 mL). The mixture was stirred at 50° C. under nitrogen for 3 hours. The reaction mixture was partitioned between 1M HCl and ethyl acetate. The organic layer was washed with brine three times, dried with sodium sulfate, filtered and evaporated. The residue was purified by chromatography on silica gel eluting with ethyl acetate/hexane (0.5% to 1%) to give the title compound (2.12 g, 76%) as a mixture of stereoisomers as a sticky solid.
Reaction SMILES: [C:1]([C:3]1[CH:32]=[CH:31][C:6]2[N:7]=[C:8]([CH:10]([OH:30])[C:11]3[C:19]([O:20][CH3:21])=[CH:18][C:17]([CH3:22])=[C:16]4[C:12]=3[CH:13]=[CH:14][N:15]4C(OC(C)(C)C)=O)[S:9][C:5]=2[CH:4]=1)#[N:2].C([O-])([O-])=O.[Cs+].[Cs+].[BH4-].[Na+]>C1COCC1.CO>[OH:30][CH:10]([C:11]1[C:19]([O:20][CH3:21])=[CH:18][C:17]([CH3:22])=[C:16]2[C:12]=1[CH:13]=[CH:14][NH:15]2)[C:8]1[S:9][C:5]2[CH:4]=[C:3]([C:1]#[N:2])[CH:32]=[CH:31][C:6]=2[N:7]=1
Reactant: COc1cc(C)c2c(ccn2C(=O)OC(C)(C)C)c1C(O)c1nc2ccc(C#N)cc2s1
Agent: O=C([O-])[O-]
Agent: [BH4-]
Agent: [Cs+]
Solvent: C1CCOC1
Solvent: CO
Product: COc1cc(C)c2[nH]ccc2c1C(O)c1nc2ccc(C#N)cc2s1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
tert-Butyl 4-((6-cyanobenzo[d]thiazol-2-yl)(hydroxy)methyl)-5-methoxy-7-methyl-1H-indole-1-carboxylate (40 mg, 0.089 mmol) and Cs2CO3 (145 mg, 0.445 mmol) were mixed in THF (0.5 mL) and MeOH (0.5 mL), and stirred at 65° C. for 2 hours. NaBH4 (67 mg, 1.78 mmol) was added to the reaction mixture and stirred at rt for 1 hour to reduce the oxidative by-products. The reaction mixture was then concentrated dissolved in MeOH and purified with HPLC (HC-B) to provide the title compound. 1H NMR (400 MHz, CD3OD) δ ppm 8.45 (d, J=1.01 Hz, 1H) 7.92 (d, J=8.59 Hz, 1H) 7.73 (dd, J=8.59, 1.52 Hz, 1H) 7.15 (d, J=3.28 Hz, 1H) 6.62-6.88 (m, 2H) 6.42 (d, J=3.03 Hz, 1H) 3.82 (s, 3H) 2.50 (s, 3H). HRMS calcd. for C13H15N3O2S (M+H)+ 350.0958. found 350.096.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[C:14](=O)[CH3:15])=[CH:4][CH:3]=1.[CH2:17]1[O:26][C:20]2([CH2:25][CH2:24][NH:23][CH2:22][CH2:21]2)[O:19][CH2:18]1.C(O)C.[BH4-].[Na+]>C(OCC)(=O)C.CC(C)[O-].[Ti+4].CC(C)[O-].CC(C)[O-].CC(C)[O-]>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[CH:14]([N:23]2[CH2:24][CH2:25][C:20]3([O:26][CH2:17][CH2:18][O:19]3)[CH2:21][CH2:22]2)[CH3:15])=[CH:4][CH:3]=1
Reactant: CC(=O)c1ccccc1-c1ccc(Cl)cc1
Reactant: C1CC2(CCN1)OCCO2
Agent: [Ti+4]
Agent: CC(C)[O-]
Agent: [BH4-]
Solvent: CCOC(C)=O
Solvent: CCO
Product: CC(c1ccccc1-c1ccc(Cl)cc1)N1CCC2(CC1)OCCO2
Temperature: 75 °C
Reaction time: 18 h
Yield: 95.8 %

Procedure:
To a mixture of 1-(4′-Chloro-biphenyl-2-yl)-ethanone (2.42 g, 10.5 mmol) and 4-piperidone ethylene ketal (1.50 g, 10.5 mmol) and titanium (IV) isopropoxide (5.96 g, 21.0 mmol) is heated up to 75° C. for 3 hours. The reaction is then cooled to room temperature and is added 50 mL of ethanol followed by sodium borohydride (1.19 g, 31.5 mmol) the reaction is then stirred for 18 hours at room temperature and then quench with 50 mL of methanol. The crude reaction is then dissolved in ethyl acetate and then washed with a saturated solution of sodium bicarbonate. The aqueous layer is then extracted 2 times with ethyl acetate. The combined organic layer are then dried on MgSO4 and the solvent is removed under vacuum. The residue is chromatographed on silica gel gel (gradient: heptane/EtOAc; 0 to 60% EtOAc over 15 minutes) to afford 8-[1-(4′-Chloro-biphenyl-2-yl)-ethyl]-1,4-dioxa-8-aza-spiro[4.5]decane (3.6 g, 96%). Found m/z ES+=358.5 (M+H); 1H NMR (400 MHz, CD2Cl2) δ 7.64 (1H, d, J=8.1 Hz), 7.41 (2H, d, J=8.6 Hz), 7.40 (1H, t), 7.30 (2H, J=8.6 Hz), 7.29 (1H, t), 7.18 (1H, d, J=7.6 Hz), 3.90 (4H, s), 3.51 (1H, m), 2.48 (2H, m), 2.36 (2H, m), 1.62 (4H, m), 1.27 (3H, d, J=6.6 Hz).
Reaction SMILES: [CH2:1]([C:3]1[S:7][C:6](=[NH:8])[N:5]([CH2:9][C:10]2[CH:15]=[CH:14][C:13]([I:16])=[CH:12][CH:11]=2)[N:4]=1)[CH3:2].[C:17]12[C:25](=[O:26])[O:24][C:22](=[O:23])[C:18]=1[CH2:19][CH2:20][CH2:21]2>C(Cl)(Cl)Cl.C(OCC)C>[CH2:1]([C:3]1[S:7][C:6](=[N:8][C:25]([C:17]2[CH2:21][CH2:20][CH2:19][C:18]=2[C:22]([OH:24])=[O:23])=[O:26])[N:5]([CH2:9][C:10]2[CH:15]=[CH:14][C:13]([I:16])=[CH:12][CH:11]=2)[N:4]=1)[CH3:2]
Reactant: O=C1OC(=O)C2=C1CCC2
Reactant: CCc1nn(Cc2ccc(I)cc2)c(=N)s1
Solvent: ClC(Cl)Cl
Solvent: CCOCC
Product: CCc1nn(Cc2ccc(I)cc2)c(=NC(=O)C2=C(C(=O)O)CCC2)s1
Temperature: 25 °C
Reaction time: 1 h
Yield: 98.3 %

Procedure:
To a solution of 5-ethyl-2-imino-3-(4-iodobenzyl)-1,3,4-thiadiazoline (17.3 g) in chloroform (200 ml) was added 1-cyclopentene-1,2-dicarboxylic anhydride (7.5 g), and they were stirred at room temperature for one hour. The reaction mixture was washed with 1N hydrochloric acid and dried over anhydrous magnesium sulfate, followed by removal through distillation. The residue so obtained was dispersed in diethyl ether and collected by filtration, whereby 23.8 g of the title compound was obtained.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[N:18]([CH2:19][C:20]([OH:22])=O)[C:13]3=[N:14][CH:15]=[CH:16][CH:17]=[C:12]3[N:11]=2)=[CH:6][CH:5]=1)([O-:3])=[O:2].C(N1C=CN=C1)(N1C=CN=C1)=O.[CH2:35]([NH:38][CH2:39][CH2:40][CH3:41])[CH2:36][CH3:37]>O1CCCC1>[N+:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[N:18]([CH2:19][C:20]([N:38]([CH2:39][CH2:40][CH3:41])[CH2:35][CH2:36][CH3:37])=[O:22])[C:13]3=[N:14][CH:15]=[CH:16][CH:17]=[C:12]3[N:11]=2)=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: O=C(O)Cn1c(-c2ccc([N+](=O)[O-])cc2)nc2cccnc21
Reactant: CCCNCCC
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Product: CCCN(CCC)C(=O)Cn1c(-c2ccc([N+](=O)[O-])cc2)nc2cccnc21
Temperature: 25 °C
Reaction time: 3 h
Yield: 31.9 %

Procedure:
A suspension of crude 2-(4-nitrophenyl)-3H-imidazo[4,5-b]pyridine-3-acetic acid (3.0 g, 0.0101 mole), 1,1'-carbonyldi imidazole (1.63 g, 0.0101 mole) and dry tetrahydrofuran (100 ml) was stirred at room temperature for three hours with nitrogen bubbling through it and then refluxed under nitrogen overnight. The mixture was cooled to room temperature and a solution of dipropylamine (3.06 g, 0.0302 mole) in tetrahydrofuran (5 ml) was added. The suspension was refluxed over the weekend under nitrogen. The solvents were removed under reduced pressure and the solid residue was triturated in water (100 ml) overnight. The solid was collected by filtration, rinsed twice with water, twice with 5% potassium hydroxide solution and then twice more with water. The solid was dissolved in hot isopropyl alcohol, filtered while hot, and cooled to room temperature to precipitate a solid. Water was added and the solid was collected by filtration, rinsed with water and dried under high vacuum at 70° C. to give 1.23 g (32%) of title compound, mp. 205°-208° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[C:13]3[N:14]([CH2:29][C@H:30]4[CH2:35][CH2:34][C@H:33]([CH3:36])[CH2:32][CH2:31]4)[C:15]([N:17]4[CH2:22][CH2:21][O:20][CH2:19][C@H:18]4[C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=4)=[N:16][C:12]=3[CH:11]=[C:10]([C:37]#[N:38])[N:9]=2)[CH:5]=[N:6][CH:7]=1.[Cl-].[Cl-].CC1(C)CCCC(C)(C)[N-]1.[Mg+2].[Li+].[Br:53]N1C(C)(C)C(=O)N(Br)C1=O>C1COCC1>[Br:53][C:11]1[C:12]2[N:16]=[C:15]([N:17]3[CH2:22][CH2:21][O:20][CH2:19][C@H:18]3[C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[N:14]([CH2:29][C@H:30]3[CH2:35][CH2:34][C@H:33]([CH3:36])[CH2:32][CH2:31]3)[C:13]=2[C:8]([C:4]2[CH:5]=[N:6][CH:7]=[C:2]([Cl:1])[CH:3]=2)=[N:9][C:10]=1[C:37]#[N:38]
Reactant: C[C@H]1CC[C@H](Cn2c(N3CCOC[C@H]3c3ccccc3)nc3cc(C#N)nc(-c4cncc(Cl)c4)c32)CC1
Reactant: CC1(C)C(=O)N(Br)C(=O)N1Br
Agent: CC1(C)CCCC(C)(C)[N-]1
Agent: [Cl-]
Agent: [Li+]
Solvent: C1CCOC1
Product: C[C@H]1CC[C@H](Cn2c(N3CCOC[C@H]3c3ccccc3)nc3c(Br)c(C#N)nc(-c4cncc(Cl)c4)c32)CC1
Temperature: -78 °C
Reaction time: 0.75 h

Procedure:
4-(5-Chloropyridin-3-yl)-3-[(trans-4-methylcyclohexyl)methyl]-2-[(3R)-3-phenylmorpholin-4-yl]-3H-imidazo[4,5-c]pyridine-6-carbonitrile (Example 2.1, Step 4; 180 mg, 0.342 mmol) was taken up in THF (3415 μl) and cooled to −78° C. Lithium magnesium 2,2,6,6-tetramethylpiperidin-1-ide dichloride (1M solution in THF/toluene, 683 μl, 0.683 mmol) was added, and the mixture was stirred at −78° C. for 45 minutes. 1,3-dibromo-5,5-dimethylimidazolidine-2,4-dione (244 mg, 0.854 mmol) was then added. The cooling bath was removed, and the solution warmed to room temperature and stirred for 60 minutes. The mixture was then diluted with ethyl acetate and washed with sodium thiosulfate (2×) and brine (1×). The organic layer was dried over magnesium sulfate, filtered, and concentrated. The resulting residue was purified via silica gel chromatography (0-100% ethyl acetate/hexanes) to afford 7-bromo-4-(5-chloropyridin-3-yl)-3-[(trans-4-methylcyclohexyl)methyl]-2-[(3R)-3-phenylmorpholin-4-yl]-3H-imidazo[4,5-c]pyridine-6-carbonitrile as a white solid that was contaminated with unreacted starting material. MS ESI calc'd. for C30H30BrClN6O [M+1]+, [M+3]+605, 607. found 605, 607.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[C:4]([O:9][CH:10]([CH3:12])[CH3:11])[CH:3]=1.[Cl-].[C:14]([O:18][C:19](=[O:22])[CH2:20][Zn+])([CH3:17])([CH3:16])[CH3:15].CCOCC>O1CCOCC1.CC(C)([P](C(C)(C)C)([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)C(C)(C)C)C>[C:14]([O:18][C:19](=[O:22])[CH2:20][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[C:4]([O:9][CH:10]([CH3:12])[CH3:11])[CH:3]=1)([CH3:17])([CH3:16])[CH3:15]
Reactant: CC(C)(C)OC(=O)C[Zn+]
Reactant: CC(C)Oc1cc(Br)ccc1Cl
Agent: CC(C)(C)[P]([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)(C(C)(C)C)C(C)(C)C
Agent: [Cl-]
Solvent: CCOCC
Solvent: C1COCCO1
Product: CC(C)Oc1cc(CC(=O)OC(C)(C)C)ccc1Cl
Temperature: 25 °C
Reaction time: 48 h

Procedure:
To a solution of 4-bromo-1-chloro-2-isopropoxy-benzene (2.48 g, 9.8 mmol, 1.0 eq.) and bis(tri-tert-butylphosphine)palladium(0) (501 mg, 0.98 mmol, 0.1 eq.) in dioxane (84 mL), a 0.5M solution of 2-tert-butoxy-2-oxoethylzinc chloride in Et2O (35.3 mL, 17.6 mmol, 1.8 eq.) was added. The resulting mixture was stirred at r.t. for 2 days. The mixture was filtered over celite and concentrated in vacuo. The residue was purified by flashmaster (column: 100 g, flow: 45 mL/min, 30 fractions of 45 mL, Heptane 100% to Heptane+8% AcOEt) to yield the title compound as a colorless oil.
Reaction SMILES: C[O:2][C:3](=[O:33])[CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][CH:13]([C:15]2[O:19][C:18]([C:20]3[CH:25]=[CH:24][C:23]([C:26]([F:29])([F:28])[F:27])=[CH:22][CH:21]=3)=[N:17][C:16]=2[CH2:30][CH3:31])[CH3:14])=[CH:8][C:7]=1[CH3:32].[OH-].[Na+].C1COCC1>CO>[CH2:30]([C:16]1[N:17]=[C:18]([C:20]2[CH:25]=[CH:24][C:23]([C:26]([F:27])([F:28])[F:29])=[CH:22][CH:21]=2)[O:19][C:15]=1[CH:13]([O:12][C:9]1[CH:10]=[CH:11][C:6]([CH2:5][CH2:4][C:3]([OH:33])=[O:2])=[C:7]([CH3:32])[CH:8]=1)[CH3:14])[CH3:31]
Reactant: CCc1nc(-c2ccc(C(F)(F)F)cc2)oc1C(C)Oc1ccc(CCC(=O)OC)c(C)c1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: CCc1nc(-c2ccc(C(F)(F)F)cc2)oc1C(C)Oc1ccc(CCC(=O)O)c(C)c1

Procedure:
3-(4-{1-[4-Ethyl-2-(4-trifluoromethyl-phenyl)-oxazol-5-yl]-ethoxy}-2-methyl-phenyl)-propionic acid methyl ester (0.095 g, 0.206 mmole) is treated with a mixture of NaOH(aq) (1 mL)/THF (3 mL)/MeOH (3 mL) at room temperature overnight. The organic solvents are removed on rota-vapor. The residue is diluted with water (10 mL), acidified to pH=2 with 6N HCl(aq). The precipitate is collected through filtration, washed with cold water (30 mL) and dried to provide the titled compound as a white solid. Mass [EI+] 448 (M++H), 446 (M+−H).
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[C:9]([S:11]([CH3:14])(=[O:13])=[O:12])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].N1C=CC=CC=1.Cl[C:22](Cl)([O:24]C(=O)OC(Cl)(Cl)Cl)Cl>C(#N)C.ClCCl>[CH3:14][S:11]([C:9]1[CH:8]=[CH:7][C:3]2[C:4](=[O:6])[O:5][C:22](=[O:24])[NH:1][C:2]=2[CH:10]=1)(=[O:13])=[O:12]
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: CS(=O)(=O)c1ccc(C(=O)O)c(N)c1
Solvent: CC#N
Solvent: c1ccncc1
Solvent: ClCCl
Product: CS(=O)(=O)c1ccc2c(=O)oc(=O)[nH]c2c1
Temperature: 55 °C
Reaction time: 2 h

Procedure:
To a suspension of 2-amino-4-methanesulfonyl-benzoic acid (1.00 g, 4.64 mmol) in acetonitrile (15 mL) at 55° C. were simultaneously added pyridine (0.75 mL, 9.3 mmol) and a solution of triphosgene (0.455 g, 1.53 mmol) in dichloromethane (5 mL). The resulting mixture was stirred at 55° C. for 2 hours and the solvent was removed using a rotary evaporator. The residue was diluted with water (50 mL) and the precipitate was filtered, and air dried to provide 7-methanesulfonyl-1H-benzo[d][1,3]oxazine-2,4-dione. Yield: 0.98 g (82%).
Reaction SMILES: [OH:1][N:2]=[C:3]([C:9](=[O:11])[CH3:10])[C:4]([O:6][CH2:7][CH3:8])=[O:5].C(=O)([O-])[O-].[K+].[K+].Br[CH:19]1[CH2:23][CH2:22][NH:21][C:20]1=[O:24]>CC(C)=O>[NH:21]1[CH2:22][CH2:23][CH:19]([O:1]/[N:2]=[C:3](/[C:9](=[O:11])[CH3:10])\[C:4]([O:6][CH2:7][CH3:8])=[O:5])[C:20]1=[O:24]
Reactant: O=C1NCCC1Br
Reactant: CCOC(=O)C(=NO)C(C)=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCOC(=O)/C(=N\OC1CCNC1=O)C(C)=O
Temperature: 0 °C
Yield: 66.1 %

Procedure:
31.8 g of ethyl 2-hydroxyimino-3-oxo-n-butyrate are dissolved in 150 ml of acetone, and 83 g of anhydrous potassium carbonate are added thereto. 33 g of 3-bromo-2-pyrrolidone are added to the mixture at 20° to 25° C. with stirring, and the mixture is stirred at the same temperature for one hour. One liter of ice-water is added to said mixture, and the aqueous mixture is extracted with ethyl acetate. The extract is dried and concentrated under reduced pressure to remove solvent. The residue is crystallized with diisopropyl ether, and the crystals are collected by filtration. The crystals are recrystallized from ethyl acetate. 32 g of ethyl (Z)-2-[(2-pyrrolidon-3-yl)-oxyimino]-3-oxo-n-butyrate are obtained as colorless needles.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([O:11][C:12]3[N:17]=[CH:16][N:15]=[C:14]([C:18]4[CH:23]=[CH:22][C:21]([C:24]([F:27])([F:26])[F:25])=[CH:20][C:19]=4[NH2:28])[CH:13]=3)[CH:9]=2)[CH:4]=[CH:3][CH:2]=1.[C:29]1([S:35](Cl)(=[O:37])=[O:36])[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1>>[N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([O:11][C:12]3[N:17]=[CH:16][N:15]=[C:14]([C:18]4[CH:23]=[CH:22][C:21]([C:24]([F:25])([F:27])[F:26])=[CH:20][C:19]=4[NH:28][S:35]([C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=4)(=[O:37])=[O:36])[CH:13]=3)[CH:9]=2)[CH:4]=[CH:3][CH:2]=1
Reactant: Nc1cc(C(F)(F)F)ccc1-c1cc(Oc2ccc3cccnc3c2)ncn1
Reactant: O=S(=O)(Cl)c1ccccc1
Product: O=S(=O)(Nc1cc(C(F)(F)F)ccc1-c1cc(Oc2ccc3cccnc3c2)ncn1)c1ccccc1

Procedure:
The title compound was prepared from 2-[6-(quinolin-7-yloxy)-pyrimidin-4-yl]-5-trifluoromethyl-phenylamine, (Example 163) and phenylsulfonyl chloride (Aldrich) analogous to the conditions described in Example 172. Mp: 168-170° C. MS (ESI, pos. ion) m/z: 523.1 (M+1).