Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH:9]=[O:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C=O.[C:13](O)(=O)CCCCCCCCCCCCCCCCC.C(NCCCC)CCC>O>[CH2:7]([C:8](=[CH2:13])[CH:9]=[O:10])[C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=CCCc1ccccc1
Reactant: CCCCCCCCCCCCCCCCCC(=O)O
Agent: C=O
Solvent: O
Solvent: CCCCNCCCC
Product: C=C(C=O)Cc1ccccc1
Temperature: 90 °C
Reaction time: 0.5 h
Yield: 3762.3 %

Procedure:
A four-necked 500-ml flask equipped with a thermometer and condenser was charged with 134 g (1.0 mol) of 3-phenylpropionaldehyde, 85 g (1.05 mol) of a 37% aqueous formalin solution and 6 g (0.02 mol) of stearic acid, followed by the dropwise addition of 9 g (0.07 mol) of dibutylamine at room temperature under a nitrogen atmosphere over 10 minutes. After the temperature was increased to 90° C., stirring was conducted at the same temperature for 30 minutes. After cooling, 200 ml of water were added to the reaction mixture. The resulting mixture was then extracted with 200 ml of hexane, followed by washing with 200 ml of water. The organic layer was dried and concentrated, whereby 161 g of a crude product were obtained. The crude product was distilled (3.5 mmHg, 80° C.), whereby 110 g (yield: 75%) of 2-benzylacrylaldehyde were obtained.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:12])[CH:5]([C:10]#[N:11])[CH2:6][CH2:7][CH:8]=[CH2:9])[CH3:2].CN(C=O)C.[H-].[Na+].Cl[CH2:21][C:22]1[CH:27]=[C:26]([O:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[CH:25]=[CH:24][C:23]=1[N+:35]([O-:37])=[O:36]>C(OCC)(=O)C>[CH2:1]([O:3][C:4](=[O:12])[C:5]([C:10]#[N:11])([CH2:21][C:22]1[CH:27]=[C:26]([O:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[CH:25]=[CH:24][C:23]=1[N+:35]([O-:37])=[O:36])[CH2:6][CH2:7][CH:8]=[CH2:9])[CH3:2]
Reactant: O=[N+]([O-])c1ccc(Oc2ccccc2)cc1CCl
Reactant: C=CCCC(C#N)C(=O)OCC
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: C=CCCC(C#N)(Cc1cc(Oc2ccccc2)ccc1[N+](=O)[O-])C(=O)OCC
Temperature: 0 °C
Reaction time: 0.08 h

Procedure:
To a round bottom flask equipped with a nitrogen inlet 2-cyano-hex-5-enoic acid ethyl ester (2.0 g, 11.96 mmol) and DMF (40 mL) were added. The reaction mixture was cooled to 0° C. followed by addition of NaH (0.48 g, 12.0 mmol, 60% dispersion in mineral oil). The reaction mixture was allowed to stir at 0° C. for another 5 min, followed by addition of 2-chloromethyl-1-nitro-4-phenoxy-benzene (2.6 g, 9.86 mmol). The reaction turned a dark purple color. After 3 h the reaction was quenched with 1N HCl, and the solvent was evaporated to yield crude mixture. The crude mixture was dissolved in ethyl acetate and washed 3 times with 1N HCl followed by a wash with saturated brine solution. The phases were separated, and the organic phase was dried with sodium sulfate and filtered, and the solvent was removed under reduced pressure to yield a residue. The residue was purified by flash chromatography using heptanes/ethyl acetate as the mobile phase 9:1 to yield a residue.
Reaction SMILES: [NH:1]([C:5]1[S:6][CH:7]=[C:8]([CH2:10][S:11][CH2:12][CH2:13][C:14](=[NH:17])OC)[N:9]=1)[C:2]([NH2:4])=[NH:3].[CH3:18][S:19]([NH2:22])(=[O:21])=[O:20]>CO.C(O)C>[CH3:18][S:19]([NH:22][C:14](=[NH:17])[CH2:13][CH2:12][S:11][CH2:10][C:8]1[N:9]=[C:5]([NH:1][C:2]([NH2:4])=[NH:3])[S:6][CH:7]=1)(=[O:21])=[O:20]
Reactant: COC(=N)CCSCc1csc(NC(=N)N)n1
Reactant: CS(N)(=O)=O
Solvent: CCO
Solvent: CO
Product: CS(=O)(=O)NC(=N)CCSCc1csc(NC(=N)N)n1
Yield: 56.9 %

Procedure:
In 10 ml of methanol were dissolved 1 g of methyl 3-[(2-guanidinothiazol-4-yl)methylthio]propionimidate and 0.38 g of methanesulfonamide and after causing reaction for 48 hours at room temperature, the solvent was distilled off under reduced pressure. Then, the residue formed was dissolved in 3 ml of ethanol and the solution was allowed to cool, thereby white crystals deposited. The crystals were collected by filtration and dried to provide 0.7 g of N-methanesulfonyl-3-[(2-guanidinothiazol-4-yl)methylthio]propionamidine. The product shows the following physicochemical properties:
Reaction SMILES: [CH2:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][N:2]1[C@H:10]([CH2:14][O:15][CH3:16])[C:11]([OH:13])=O.CN1CCOCC1.ClC(OCC(C)C)=O.[CH2:32]([NH2:39])[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1>C1COCC1>[CH2:32]([NH:39][C:11](=[O:13])[C@H:10]([N:2]1[CH2:1][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3]1)[CH2:14][O:15][CH3:16])[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1
Reactant: NCc1ccccc1
Reactant: COC[C@H](C(=O)O)N1Cc2ccccc2C1
Agent: CC(C)COC(=O)Cl
Solvent: CN1CCOCC1
Solvent: C1CCOC1
Product: COC[C@H](C(=O)NCc1ccccc1)N1Cc2ccccc2C1
Reaction time: 0.08 h
Yield: 88 %

Procedure:
To the crude acid (R)-2-(Isoindolin-2-yl)-3-methoxypropanoic acid (FIG. 2, No. 5)(1.25 g, 5 mmol) in dry THF was added N-methylmorpholine (0.66 mL, 6.0 mmol) at −78° C. under an argon atmosphere. After 5 min, isobutyl chloroformate (0.78 mL, 6.0 mmol) was added and stirred for another 5 min. To this reaction mixture benzylamine (0.65 mL, 6.0 mmol) was added at −78° C. after which the reaction mixture was stirred at room temperature for 1 h. After completion of the reaction, the reaction mixture was filtered through a celite pad, washed with ethyl acetate, and dried over anhydrous MgSO4. The solvent was removed in vacuo and the crude product was subjected to silica gel column chromatography (Ethyl acetate/Hexane, 4:6) to yield 1.48 g, 88% yield of (R)—N—Benzyl-2-(isoindolin-2-yl)-3-methoxypropanamide (FIG. 2, No. 6) as a crystalline solid. [Rf=0.26, ethyl acetate/hexane (4:6)]; [α]D25 +81.8 (c 1, CH2Cl2); IR (CH2Cl2) v: 1718, 1685, 1535, and 1387 cm−1; 1H NMR (400 MHz, CDCl3) δ:3.38 (bs, 3H), 3.75 (m, 1H), 4.34 (t, J=9.64 Hz, 1H), 4.46 (m, 2H), 5.0 (m, 1H), 7.1 (bs, 1H), 7.21-7.33 (m, 5H), 7.7 (dd, J=3.2, 5.48 Hz, 2H), 7.83 (dd, J=3.2, 5.48 Hz, 2H); 13C NMR (100 MHz, CDCl3) δ: 29.6, 43.5, 51.7, 58.9, 70.1, 123.5, 127.1, 127.3, 127.4, 128.4, 128.6, 131.8, 134.1, 137.9, 167.3, 167.9; HRMS (ESI-TOF) m/z calcd for C19H18N2O4Na [M+Na+] 361.120. Found 361.116.
Reaction SMILES: [F:1][C:2]([F:6])([F:5])[CH2:3][OH:4].C(N(CC)CC)C.[C:14]1([CH3:24])[CH:19]=[CH:18][C:17]([S:20](Cl)(=[O:22])=[O:21])=[CH:16][CH:15]=1>ClCCl>[CH3:24][C:14]1[CH:19]=[CH:18][C:17]([S:20]([O:4][CH2:3][C:2]([F:6])([F:5])[F:1])(=[O:22])=[O:21])=[CH:16][CH:15]=1
Reactant: OCC(F)(F)F
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)OCC(F)(F)F)cc1
Temperature: 0 °C
Yield: 98.3 %

Procedure:
2,2,2-trifluoroethanol 7a (7.2 mL, 100 mmol) was dissolved in 300 mL dichloromethane, followed by addition of triethylamine (28 mL, 200 mmol). The reaction mixture was cooled to 0° C. The reaction mixture was warmed and stirred for 16 hours at room temperature after a solution (100 mL) of p-toluene sulfonyl chloride (TsCl) (30 g, 150 mmol) in dichloromethane was dropwise added. Thereafter, the reaction mixture was extracted with dichloromethane (100 mL×3) after 100 mL water were added. The organic extract was washed with saturated sodium chloride solution (50 mL) and combined, dried over anhydrous magnesium sulfate, and filtered. The filtrate was concentrated under reduced pressure and the resulting residue was purified by silica gel chromatography with elution system D to obtain the title compound 2,2,2-trifluoroethyl 4-methylbenzenesulfonate 7b (25 g, colourless liquid), yield: 98.4%. 1H NMR (400 MHz, CDCl3): δ 7.88-7.76 (m, 2H), 7.44-7.33 (m, 2H), 4.35 (d, 2H), 2.47 (s, 3H).
Reaction SMILES: CC1C=CC(S(O[CH2:12][C@@H:13]2[O:25][C:24]3[C:20]4=[CH:21][O:22][N:23]=[C:19]4[CH:18]=[CH:17][C:16]=3[O:15][CH2:14]2)(=O)=O)=CC=1.[NH:26]1[CH2:31][CH:30]=[C:29]([C:32]2[C:40]3[C:35](=[CH:36][CH:37]=[CH:38][CH:39]=3)[NH:34][CH:33]=2)[CH2:28][CH2:27]1>CS(C)=O>[NH:34]1[C:35]2[C:40](=[CH:39][CH:38]=[CH:37][CH:36]=2)[C:32]([C:29]2[CH2:30][CH2:31][N:26]([CH2:12][CH:13]3[O:25][C:24]4[C:20]5=[CH:21][O:22][N:23]=[C:19]5[CH:18]=[CH:17][C:16]=4[O:15][CH2:14]3)[CH2:27][CH:28]=2)=[CH:33]1
Reactant: Cc1ccc(S(=O)(=O)OC[C@H]2COc3ccc4nocc4c3O2)cc1
Reactant: C1=C(c2c[nH]c3ccccc23)CCNC1
Solvent: CS(C)=O
Product: C1=C(c2c[nH]c3ccccc23)CCN(CC2COc3ccc4nocc4c3O2)C1
Temperature: 77.5 °C

Procedure:
(2R)-2,3-Dihydro[1,4]dioxino[2,3-e][2,1]benzisoxazol-2-ylmethyl 4-methyl-benzenesulfonate (0.60 g, 1.66 mmole) and 3-(1,2,3,6-tetrahydro-4-pyridinyl)-1H-indole (0.98 g, 4.90 mmole) were combined in 30 mL of DMSO under nitrogen. This solution was heated to 75-80° C. under nitrogen for 6 hours. After completion, the reaction was cooled to room temperature and partitioned between 400 mL each of ethyl acetate and saturated aqueous sodium bicarbonate. The organic phase was removed and washed with brine, dried over magnesium sulfate and concentrated in vacuum. The crude residue was column chromatographed on silica gel using methylene chloride to remove impurities and 1% methanol/methylene chloride to elute the product. Upon evaporation of the product fractions, 0.47 g (73%) of the (S)-enantiomer of the title compound was obtained as a white solid, m.p. 110° C.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[CH:4][C:5]2[NH:11][C:10](=[O:12])[C:9]3([CH2:14][CH2:13]3)[CH2:8][N:7]([CH:15]3[CH2:19][CH2:18][CH2:17][CH2:16]3)[C:6]=2[N:20]=1.[CH3:21]I.[H-].[Na+]>CC(N(C)C)=O>[Cl:1][C:2]1[N:3]=[CH:4][C:5]2[N:11]([CH3:21])[C:10](=[O:12])[C:9]3([CH2:14][CH2:13]3)[CH2:8][N:7]([CH:15]3[CH2:19][CH2:18][CH2:17][CH2:16]3)[C:6]=2[N:20]=1
Reactant: O=C1Nc2cnc(Cl)nc2N(C2CCCC2)CC12CC2
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CC(=O)N(C)C
Product: CN1C(=O)C2(CC2)CN(C2CCCC2)c2nc(Cl)ncc21
Temperature: 0 °C
Reaction time: 1 h
Yield: 81 %

Procedure:
To a stirred solution of 2′-chloro-9′-cyclopentyl-8′,9′-dihydrospiro[cyclopropane-1,7′-pyrimido[4,5-b][1,4]diazepin]-6′(5′H)-one (Intermediate 131; 15 g, 51.24 mmol) in DMA (1 L) under nitrogen was added methyl iodide 3.51 mL, 56.36 mL). The mixture was cooled in ice/water to 4° C. Sodium hydride (60% mineral oil dispersion; 2.26 g, 56.36 mmol) was added in one portion. A small exotherm to 6° C. was observed. The reaction mixture was stirred on an ice/water bath for 1 hour, the cooling bath was removed and the reaction stirred at room temperature overnight. Solvent was evaporated in vacuo and the residue treated with water. This afforded a solid, which was filtered off and washed with water to give an off white solid, which was crystallised from IPA (100 mL) with hot filtration through fluted paper to remove a small amount insoluble matter. The crystallised material was filtered, washed with chilled IPA, and dried by dessication under high vacuum at room temperature over the weekend to give the title compound as a white crystalline solid (12.78_g, 81%)
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[C:9]1[C:20](=[O:21])[N:19]([CH3:22])[C:12]2[N:13]=[C:14](SC)[N:15]=[CH:16][C:11]=2[CH:10]=1.[CH2:23]([NH2:30])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>CN(C)C=O>[CH2:23]([NH:30][C:14]1[N:15]=[CH:16][C:11]2[CH:10]=[C:9]([C:3]3[C:2]([Cl:1])=[CH:7][CH:6]=[CH:5][C:4]=3[Cl:8])[C:20](=[O:21])[N:19]([CH3:22])[C:12]=2[N:13]=1)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: NCc1ccccc1
Reactant: CSc1ncc2cc(-c3c(Cl)cccc3Cl)c(=O)n(C)c2n1
Solvent: CN(C)C=O
Product: Cn1c(=O)c(-c2c(Cl)cccc2Cl)cc2cnc(NCc3ccccc3)nc21
Temperature: 120 °C
Reaction time: 0.08 h
Yield: 47.6 %

Procedure:
A mixture of 0.165 g (0.47 mmol) of 6-(2,6-dichlorophenyl)-8-methyl-2-methylsulfanyl-8H-pyrido-[2,3-d]pyrimidin-7-one, 0.50 g (4.70 mmol) of benzylamine and 0.5 mL of dimethylformamide was heated with stirring in a 120° C. oil bath. After 5 minutes, solution was complete. After 5 hours, the excess amine and dimethylformamide were evaporated at reduced pressure, and the residue was triturated with a solution of 1 mL of acetone and 2 mL of petroleum ether. The tacky solid was filtered and recrystallized from ethyl acetate/petroleum ether to give 0.092 g of pure product; mp 217-219° C.
Reaction SMILES: Br.[Br:2][C:3]1[C:4]([CH3:12])=[N:5][C:6]([CH3:11])=[C:7]([Br:10])[C:8]=1O.O=P(Cl)(Cl)[Cl:15].CN(C)C1C=CC=CC=1>CCOCC>[Br:2][C:3]1[C:4]([CH3:12])=[N:5][C:6]([CH3:11])=[C:7]([Br:10])[C:8]=1[Cl:15]
Reactant: Cc1nc(C)c(Br)c(O)c1Br
Reactant: O=P(Cl)(Cl)Cl
Agent: Br
Solvent: CN(C)c1ccccc1
Solvent: CCOCC
Product: Cc1nc(C)c(Br)c(Cl)c1Br
Temperature: 130 °C
Reaction time: 2 h
Yield: 63.1 %

Procedure:
A 500-mL RB-flask was charged with solid 3,5-dibromo-2,6-dimethylpyridin-4-ol, hydrobromide (94 g, 260 mmol) and POCl3 (150 ml, 1609 mmol) was added. To this white slurry was added N,N-dimethylaniline (39.5 ml, 312 mmol) and the reaction mixture was heated to 130° C. (oil bath temp). After stirring for 2 h, the reaction mixture was cooled, concentrated and the brown residue taken up in toluene (100 mL) and concentrated to remove any unreacted POCl3. Then, the residue was treated with ice (250 g) for 30 min and carefully neutralized with powder Na2CO3, extracted with CH2Cl2 (3×250 mL). The combined organic layers dried (MgSO4/C), filtered, concentrated to give slurry which was dissolved in ether (500 mL), filtered through a plug of silica gel. The silica gel pad was washed with 1:1 Ether/Hex (1.5-lit). The filtrate was concentrated to give white slurry which was triturated with hexanes (200 mL) and left in the freezer (−10° C., 2 h). The liquid was decanted and solids were rinsed with cold hexanes (4×50 mL) and dried overnight under high vacuum (required to remove dimethylaniline) to afford 3,5-dibromo-4-chloro-2,6-dimethylpyridine (49.2 g, 164 mmol, 63.3% yield) as pale greenish-yellow solid. The decanted solvent was concentrated and purified by flash chromatography using 1-lit each hexanes, 0.5, 1, 2 and 5% EtOAc/Hex to afford additional 3,5-dibromo-4-chloro-2,6-dimethylpyridine (18.763 g, 62.7 mmol, 24.13% yield) as greenish-yellow solid. 1H NMR (500 MHz, CDCl3) δ 2.59 (s, 6H). LCMS (M+H)=300.0.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C@H:9]([CH2:21][CH:22]=O)[CH2:10][N:11]([CH3:20])[C:12](=[O:19])[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:5]=[CH:6][C:7]=1[Cl:8].[N:24]1([CH:31]2[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]2)[CH2:29][CH2:28][CH2:27][CH2:26][C:25]1=[O:30].C(O)(=O)C.C([BH3-])#N.[Na+]>CO.C(=O)(O)[O-].[Na+]>[Cl:1][C:2]1[CH:3]=[C:4]([C@H:9]([CH2:21][CH2:22][N:34]2[CH2:33][CH2:32][CH:31]([N:24]3[CH2:29][CH2:28][CH2:27][CH2:26][C:25]3=[O:30])[CH2:36][CH2:35]2)[CH2:10][N:11]([CH3:20])[C:12](=[O:19])[C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: O=C1CCCCN1C1CCNCC1
Reactant: CN(C[C@@H](CC=O)c1ccc(Cl)c(Cl)c1)C(=O)c1ccccc1
Agent: O=C([O-])O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: CN(C[C@@H](CCN1CCC(N2CCCCC2=O)CC1)c1ccc(Cl)c(Cl)c1)C(=O)c1ccccc1
Reaction time: 0.17 h
Yield: 98.6 %

Procedure:
(S)—N-[2-(3,4-Dichlorophenyl)-4-oxobutyl]-N-methylbenzamide (0.78 g) in methanol (3 mL) was added to a solution of [1,4′]bipiperidinyl-2-one (0.34 g) and acetic acid (0.15 mL) in methanol (8 mL). After 10 minutes, sodium cyanoborohydride (0.17 g) in methanol (4 mL) was added in a single portion. After being stirred overnight, the reaction mixture was diluted with saturated aqueous sodium bicarbonate, stirred for 30 minutes, and extracted with dichloromethane (4×50 mL). The organic extracts were dried, evaporated, and purified by chromatography, with dichloromethane:methanol (gradient 95:5, 90:10) as eluent to give the title compound (0.95 g). MS: m/z=516(M+). The product was dissolved in methanol (2 mL) and citric acid was added. The solution was concentrated and the residue was triturated with ether. The product was obtained as a white foam (1.2 g).
Reaction SMILES: [Cl:1][C:2]1[CH:17]=[C:16]([NH:18][CH:19]([CH3:21])[CH3:20])[C:5]([C:6]([NH:8][CH:9]([CH2:14][OH:15])[C:10]([O:12][CH3:13])=[O:11])=O)=[CH:4][N:3]=1.CCN(S(F)(F)F)CC.C([O-])([O-])=O.[K+].[K+]>C(Cl)Cl>[Cl:1][C:2]1[N:3]=[CH:4][C:5]([C:6]2[O:15][CH2:14][CH:9]([C:10]([O:12][CH3:13])=[O:11])[N:8]=2)=[C:16]([NH:18][CH:19]([CH3:21])[CH3:20])[CH:17]=1
Reactant: COC(=O)C(CO)NC(=O)c1cnc(Cl)cc1NC(C)C
Agent: CCN(CC)S(F)(F)F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Product: COC(=O)C1COC(c2cnc(Cl)cc2NC(C)C)=N1
Reaction time: 4 h

Procedure:
To a stirred solution of methyl 2-(6-chloro-4-(isopropylamino)nicotinamido)-3-hydroxypropanoate (36) (100 mg, 0.317 mmol) in DCM (15 mL), DAST (0.317 mmol) was added at −78° C. and stirred for 4 h. K2CO3 (0.633 mmol) was added to the reaction mixture and stirred for 3 h. The reaction mixture was diluted with DCM and washed with water (twice) followed by brine solution. The organic layer was collected, dried over Na2SO4, filtered and concentrated. The crude material obtained was purified by flash chromatography using silica gel and EtOAC: pet ether as eluent to afford the title compound, methyl 2-(6-chloro-4-(isopropylamino)pyridin-3-yl)-4,5-dihydrooxazole-4-carboxylate. 1H NMR: 400 MHz, DMSO-d6: δ 1.20-1.21 (m, 6H), 3.73 (s, 3H), 3.84-3.89 (m, 1H), 4.51-4.59 (m, 2H), 5.07-5.12 (m, 1H), 6.83 (s, 1H), 8.36 (s, 1H), 8.80 (d, J=7.60 Hz, 1H).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][C:3]=1[CH3:9].[CH2:10]([O:12][C:13]1[CH:19]=[CH:18][C:16]([NH2:17])=[CH:15][CH:14]=1)[CH3:11].CC([O-])(C)C.[Na+].O(CCCC)CCCC>>[CH2:10]([O:12][C:13]1[CH:19]=[CH:18][C:16]([NH:17][C:2]2[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][C:3]=2[CH3:9])=[CH:15][CH:14]=1)[CH3:11]
Reactant: CCOc1ccc(N)cc1
Reactant: Cc1ccc(C)c(Cl)c1
Agent: CC(C)(C)[O-]
Agent: [Na+]
Solvent: CCCCOCCCC
Product: CCOc1ccc(Nc2cc(C)ccc2C)cc1
Temperature: 110 °C
Yield: 97.4 %

Procedure:
Following general procedure E, a mixture of 2-chloro-p-xylene (134 μL, 1.0 mmol), 4-ethoxyaniline (154 μL, 1.2 mmol), NaOt-Bu (115 mg, 1.2 mmol), 10 (0.08 mg, 0.01 mol %), 1 (0.05 mg, 0.01 mol %), and Bu2O (1 mL) was heated to 110° C. for 1 h. The crude product was purified via the Biotage SP4 (silica-packed 25+M; 0-30% EtOAc/hexanes) to provide the title compound as a white solid (235 mg, 98%), mp 56-58° C. 1H NMR (300 MHz, CDCl3) δ: 7.10 (m, 3H), 6.95 (m, 3H), 6.72 (d, J=7.5 Hz, 1H), 5.26 (s, 1H), 4.09 (q, J=7.0 Hz, 2H), 2.33 (s, 3H), 2.29 (s, 3H), 1.51 (t, J=7.0 Hz, 3H) ppm. 13C NMR (75 MHz, CDCl3) δ: 154.7, 143.5, 136.8, 136.5, 130.9, 122.5, 121.0, 116.1, 116.1, 115.6, 64.1, 21.6, 17.7, 15.3 ppm. IR (neat, cm−1): 3402, 2978, 2923, 1511, 1478, 1292, 1238, 1117, 1049, 798. Anal. Calcd. for C16H19NO: C, 79.63; H, 7.94. Found: C, 79.70; H, 8.01.
Reaction SMILES: [CH3:1]C(C)([O-])C.[K+].[NH:7]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH:9]=[CH:8]1.C(OC)(=O)C(OC)=O>CN(C=O)C>[CH3:1][N:7]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH:9]=[CH:8]1
Reactant: c1ccc2[nH]ccc2c1
Reactant: CC(C)(C)[O-]
Agent: COC(=O)C(=O)OC
Agent: [K+]
Solvent: CN(C)C=O
Product: Cn1ccc2ccccc21
Temperature: 25 °C
Yield: 44 %

Procedure:
Potassium tert-butoxide was added to a solution of the indole product of Example 61 (354 mg, 1.12 mmol) and dimethyl oxalate (145 mg, 1.23 mmol) in DMF (3 mL) and heated to reflux for 1 h. The mixture was cooled to room temperature and quenched with water (5 mL). After extraction (2×) with CH2Cl2, the organic layer was dried over MgSO4/Na2SO4, filtered, and concentrated in vacuo. Purification by column chromatography (SiO2, 20 g, hexanes to 10% EtOAc/hexanes) provide the N-methyl indole product (163 mg, 44%) as a yellow powder: mp 120-124° C.; 1H NMR (500 MHz, CDCl3) δ7.27-7.24 (m, 1H), 7.08 (d, J=8.5 Hz, 1H), 7.04 (d, J=3.1 Hz, 1H), 7.01 (d, J=10.4 Hz, 1H), 6.96 (d, J=8.2 Hz, 1H), 6.71 (d, J=8.5 Hz, 1H), 6.42 (d, J=3.1 Hz, 1H), 4.29 (t, J=5.8 Hz, 1H), 3.96 (d, J=15.2 Hz, 1H), 3.85 (d, J=15.2 Hz, 1H), 3.76 (s, 3H), 2.99 (dd, J=11.3, 5.2 Hz, 1H), 2.68 (dd, J=11.4, 6.5 Hz, 1H), 2.47 (s, 3H); IR (KBr) 3438, 2943, 2779, 1579, 1488, 1422, 1358, 1266, 1064 cm−1; ESI MS m/z=329 [C19H18ClFN2+H]+.
Reaction SMILES: I[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([NH:11][S:12]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[S:21]([CH3:24])(=[O:23])=[O:22])(=[O:14])=[O:13])[CH:9]=2)[N:4](C(OC(C)(C)C)=O)[N:3]=1.[CH3:32][N:33]([CH3:43])[C:34]1[CH:39]=[CH:38][C:37](B(O)O)=[CH:36][CH:35]=1.C(=O)([O-])O.[Na+]>CN(C)C=O>[CH3:32][N:33]([CH3:43])[C:34]1[CH:39]=[CH:38][C:37]([C:2]2[C:10]3[C:5](=[CH:6][CH:7]=[C:8]([NH:11][S:12]([C:15]4[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=4[S:21]([CH3:24])(=[O:23])=[O:22])(=[O:13])=[O:14])[CH:9]=3)[NH:4][N:3]=2)=[CH:36][CH:35]=1
Reactant: CC(C)(C)OC(=O)n1nc(I)c2cc(NS(=O)(=O)c3ccccc3S(C)(=O)=O)ccc21
Reactant: CN(C)c1ccc(B(O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Product: CN(C)c1ccc(-c2n[nH]c3ccc(NS(=O)(=O)c4ccccc4S(C)(=O)=O)cc23)cc1
Yield: 24.5 %

Procedure:
N-[3-(4-Dimethylaminophenyl)-1H-indazol-5-yl]-2-methylsulfonylbenzenesulfonamide can be obtained as described in Example 59 from 1 g of tert-butyl 3-iodo-5-(2-methylsulfonylbenzenesulfonylamino)indazole-1-carboxylate, 570 mg of 4-dimethylaminophenylboronic acid, 40 ml of dimethylformamide, 3.2 ml of a saturated aqueous solution of sodium hydrogencarbonate and 50 mg of tetrakis(triphenylphosphine)palladium[0]. 200 mg of N-[3-(4-dimethylaminophenyl)-1H-indazol-5-yl]-2-methylsulfonylbenzenesulfonamide are thus obtained in the form of a yellow solid melting above 260° C. (analysis C22H22N4O4S2 % calculated C, 56.15; H, 4.71; N, 11.91; O, 13.60; S, 13.63. % found C, 55.74; H, 4.81; N, 12.03; S, 13.34).
Reaction SMILES: [CH:1]1([C:4]2[CH:5]=[CH:6][C:7]([O:13][CH2:14][CH3:15])=[C:8]([CH:12]=2)[C:9](Cl)=O)[CH2:3][CH2:2]1.BrC1C=CC(O)=C(C=1)C(O)=O.ICC.C1(B(O)O)CC1.[Cl-].[Cl:37][C:38]1[CH:43]=[CH:42][C:41]([C:44]2([CH3:70])[C:48]([C:50]3[CH:55]=[CH:54][C:53]([Cl:56])=[CH:52][CH:51]=3)([CH3:49])[NH:47]C(C3C=CC(C(C)(C)C)=CC=3OCC)=[N:45]2)=[CH:40][CH:39]=1>>[Cl:37][C:38]1[CH:43]=[CH:42][C:41]([C:44]2([CH3:70])[C:48]([C:50]3[CH:51]=[CH:52][C:53]([Cl:56])=[CH:54][CH:55]=3)([CH3:49])[NH:47][C:9]([C:8]3[CH:12]=[C:4]([CH:1]4[CH2:3][CH2:2]4)[CH:5]=[CH:6][C:7]=3[O:13][CH2:14][CH3:15])=[N:45]2)=[CH:40][CH:39]=1
Reactant: CCOc1cc(C(C)(C)C)ccc1C1=NC(C)(c2ccc(Cl)cc2)C(C)(c2ccc(Cl)cc2)N1
Reactant: CCOc1ccc(C2CC2)cc1C(=O)Cl
Agent: O=C(O)c1cc(Br)ccc1O
Agent: OB(O)C1CC1
Agent: [Cl-]
Solvent: CCI
Product: CCOc1ccc(C2CC2)cc1C1=NC(C)(c2ccc(Cl)cc2)C(C)(c2ccc(Cl)cc2)N1

Procedure:
rac-(4S*,5R*)-4,5-Bis-(4-chloro-phenyl)-2-(5-cyclopropyl-2-ethoxy-phenyl)-4,5-dimethyl-4,5-dihydro-1H-imidazole was prepared from 5-cyclopropyl-2-ethoxy-benzoyl chloride (prepared from 5-bromo-2-hydroxy-benzoic acid by alkylation with iodoethane, Suzuki coupling with cyclopropyl boronic acid, then saponification and conversion to the chloride) and meso-2,3-bis-(4-chlorophenyl)-2,3-butanediamine (example 1) in an analogous manner as described in example 2 (method 1).
Reaction SMILES: [Br:1][C:2]1[N:7]2[N:8]=[CH:9][N:10]=[C:6]2[C:5](Br)=[N:4][CH:3]=1.[CH2:12]1[N:17]([C:18]2[CH:23]=[CH:22][C:21]([NH2:24])=[CH:20][CH:19]=2)[CH2:16][CH2:15][O:14][CH2:13]1.C(N(C(C)C)C(C)C)C>CC(O)C>[Br:1][C:2]1[N:7]2[N:8]=[CH:9][N:10]=[C:6]2[C:5]([NH:24][C:21]2[CH:20]=[CH:19][C:18]([N:17]3[CH2:12][CH2:13][O:14][CH2:15][CH2:16]3)=[CH:23][CH:22]=2)=[N:4][CH:3]=1
Reactant: Nc1ccc(N2CCOCC2)cc1
Reactant: Brc1ncc(Br)n2ncnc12
Solvent: CC(C)O
Solvent: CCN(C(C)C)C(C)C
Product: Brc1cnc(Nc2ccc(N3CCOCC3)cc2)c2ncnn12
Yield: 93.8 %

Procedure:
A mixture of 5,8-dibromo-[1,2,4]triazolo[1,5-a]pyrazine (123 mg, 443 μmol), 4-(4-morpholino)aniline (118 mg. 0.664 mmol) and N-ethyldiisopropylamine (116 mL, 0.664 mmol) is heated at reflux in 2-propanol (3 mL) for 4.5 hours. The reaction mixture is evaporated to dryness and the residue partitioned between dichloromethane and citric acid (10%). The organic phase is washed once with water and brine, dried over MgSO4, filtered and evaporated to furnish the title compound (156 mg, 94%) as a yellow solid. 1H-NMR (400 MHz, d6-DMSO) δ (ppm) 3.11 (m, 4H), 3.78 (m, 4H), 6.97 (d, 2H), 7.82 (d, 2H), 7.87 (s, 1H), 8.71 (s, 1H), 9.93 (br s, 1H). LCMS, Rt 3.32 min (96.8%) m/z (APCI) 375 (M+H)+.