Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[S:3][C:4]([CH:7]=[O:8])=[CH:5][N:6]=1.[CH3:9][Mg+].[Br-]>C1COCC1.CCOCC>[Br:1][C:2]1[S:3][C:4]([CH:7]([OH:8])[CH3:9])=[CH:5][N:6]=1
Reactant: C[Mg+]
Reactant: O=Cc1cnc(Br)s1
Agent: [Br-]
Solvent: C1CCOC1
Solvent: CCOCC
Product: CC(O)c1cnc(Br)s1
Reaction time: 0.5 h

Procedure:
To a 0° C. solution of 2-bromo-5-formylthiazole (100.6 mg, 0.524 mmol) in THF (5 mL) was added MeMgBr (175 μL of a 3M solution in Et2O, 0.524 mmol). After 30 minutes, additional MeMgBr (50 μL of a 3M solution in Et2O, 0.150 mmol) was added. After 30 more minutes, the reaction was quenched by pouring into saturated NH4Cl (20 mL). The mixture was extracted with EtOAc (50 mL) and the organic layer was washed with water and brine (25 mL each). The organic layer was dried over Na2SO4, filtered, and concentrated. Purification of the residue by flash chromatography (0 to 80% EtOAc/hexanes) afforded 1-(2-bromo-1,3-thiazol-5-yl)ethanol. Rf=0.13 (25% EtOAc/hexanes). LCMS=210.0 (M+1)+. 1H NMR (CDCl3, 500 MHz) δ 7.40 (s, 1H), 5.12 (q, J=6.4 Hz, 1H), 1.59 (d, J=6.4 Hz, 3H).
Reaction SMILES: [CH2:1]([N:3]1[CH2:13][CH:12]2[CH2:14][CH2:15][CH:5]([C:6]3[CH:7]=[CH:8][C:9]([NH2:16])=[CH:10][C:11]=32)[CH2:4]1)[CH3:2].Cl[C:18]1[N:23]=[C:22]([NH:24][C:25]2[CH:34]=[CH:33][CH:32]=[CH:31][C:26]=2[C:27]([NH:29][CH3:30])=[O:28])[C:21]([Cl:35])=[CH:20][N:19]=1.Cl.O1CCOCC1>CC(O)C>[Cl:35][C:21]1[C:22]([NH:24][C:25]2[CH:34]=[CH:33][CH:32]=[CH:31][C:26]=2[C:27]([NH:29][CH3:30])=[O:28])=[N:23][C:18]([NH:16][C:9]2[CH:10]=[C:11]3[C:6](=[CH:7][CH:8]=2)[CH:5]2[CH2:15][CH2:14][CH:12]3[CH2:13][N:3]([CH2:1][CH3:2])[CH2:4]2)=[N:19][CH:20]=1
Reactant: CNC(=O)c1ccccc1Nc1nc(Cl)ncc1Cl
Reactant: CCN1CC2CCC(C1)c1cc(N)ccc12
Agent: Cl
Solvent: CC(C)O
Solvent: C1COCCO1
Product: CCN1CC2CCC(C1)c1cc(Nc3ncc(Cl)c(Nc4ccccc4C(=O)NC)n3)ccc12
Temperature: 130 °C
Yield: 57.7 %

Procedure:
10-Ethyl-10-aza-tricyclo[6.3.2.0*2,7*]trideca-2(7),3,5-trien-4-ylamine (29.8 mg, 0.138 mmol) and 2-(2,5-dichloro-pyrimidin-4-ylamino)-N-methyl-benzamide (45 mg, 0.152 mmol, 1.1 eq) were dissolved in IPA (1.5 mL). 4.0 M HCl in dioxane (38 μL, 0.152 mmol, 1.1 eq) was added and the reaction was heated at 130° C. in a microwave for 10 minutes. The reaction was then concentrated under reduced pressure and the residue was taken up in CH2Cl2 (10 mL) and washed with sat. NaHCO3 (10 mL). The organic layer was dried (sodium sulfate), filtered, and concentrated under reduced pressure. Purification by basic alumina chromatography using a gradient of 0-5% MeOH/CH2Cl2 as the eluting solvent to obtain 2-[5-chloro-2-(10-ethyl-10-aza-tricyclo[6.3.2.0*2,7*]trideca-2,4,6-trien-4-ylamino)-pyrimidin-4-ylamino]-N-methyl-benzamide as a yellow solid (38 mg, 58%). m.p. dec. at 106° C.; LCMS (m/e) 477 (M+1); 1H-NMR (CDCl3, 400 MHz) δ 11.02 (s, 1H), 8.67 (d, 1H, J=8.4 Hz), 8.09 (s, 1H), 7.50-7.40 (m, 2H), 7.34 (d, 1H, J=2.3 Hz), 7.30-7.20 (m, 1H), 7.02 (t, 1H, J=7.6 Hz), 7.00 (d, 1H, J=7.9 Hz), 6.87 (s, 1H), 6.19 (bs, 1H), 3.03 (d, 3H, 4.9 Hz), 3.00-2.90 (m, 4H), 2.44 (q, 2H, J=7.1 Hz), 2.21-2.16 (m, 4H), 1.64-1.60 (m, 2H), 1.00 (t, 3H, J=7.1 Hz).
Reaction SMILES: [C:1]1([N:7]=[C:8]=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(N)CC.NC(N)=O.C(CC(O)=O)#N.N[C:25]1[N:30]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[C:29](=[O:37])[N:28]([CH2:38][CH2:39][CH3:40])[C:27](=[O:41])[CH:26]=1>>[CH2:27]([NH:28][C:29]([NH:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)=[O:37])[CH2:26][CH3:25].[CH3:29][NH:30][C:25]1[N:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[C:8](=[O:9])[N:28]([CH2:38][CH2:39][CH3:40])[C:27](=[O:41])[CH:26]=1
Reactant: CCCn1c(=O)cc(N)n(-c2ccccc2)c1=O
Reactant: O=C=Nc1ccccc1
Agent: N#CCC(=O)O
Agent: NC(N)=O
Solvent: CCCN
Product: CCCNC(=O)Nc1ccccc1
Product: CCCn1c(=O)cc(NC)n(-c2ccccc2)c1=O

Procedure:
N-Propyl-N'-phenylurea was prepared preliminarily from phenyl isocyanate and propylamine by the same procedure as in Reference Example 1. The urea compound as the starting material was reacted with cyanoacetic acid to form a uracil ring. Subsequently, 6-amino-1-phenyl-3-propyluracil was treated as in Reference Example 2 so that the substituent amino group at the 6-position was converted to a methylamino group to yield 6-methylamino-1-phenyl-3-propyluracil. Using sodium nitrite a nitroso group was introduced into the 5-position of the uracil ring and then reduced with hydrogen gas to prepare 5-amino-6-methylamino-1-phenyl-3-propyluracil.
Reaction SMILES: [CH3:1][C:2]1([CH3:30])[C:11]2[CH:10]=[CH:9][C:8]([C:12]#[C:13][C:14]3[CH:24]=[CH:23][C:17]([C:18]([O:20][CH2:21][CH3:22])=[O:19])=[CH:16][CH:15]=3)=[CH:7][C:6]=2[C:5]([C:25]2SC=CN=2)=[CH:4][CH2:3]1.FC(F)(F)S([O:36][C:37]1C2C=C(C#CC3C=CC(C(OCC)=O)=CC=3)C=CC=2C(C)(C)[CH2:45][CH:46]=1)(=O)=O>>[CH3:30][C:2]1([CH3:1])[C:11]2[CH:10]=[CH:9][C:8]([C:12]#[C:13][C:14]3[CH:24]=[CH:23][C:17]([C:18]([O:20][CH2:21][CH3:22])=[O:19])=[CH:16][CH:15]=3)=[CH:7][C:6]=2[C:5]([C:25]2[O:36][CH:37]=[CH:46][CH:45]=2)=[CH:4][CH2:3]1
Reactant: CCOC(=O)c1ccc(C#Cc2ccc3c(c2)C(c2nccs2)=CCC3(C)C)cc1
Reactant: CCOC(=O)c1ccc(C#Cc2ccc3c(c2)C(OS(=O)(=O)C(F)(F)F)=CCC3(C)C)cc1
Product: CCOC(=O)c1ccc(C#Cc2ccc3c(c2)C(c2ccco2)=CCC3(C)C)cc1

Procedure:
Employing the same general procedure as for the preparation of ethyl 4-[(7,8-dihydro-8,8-dimethyl-5-(2-thiazolyl)naphth-3-yl)ethynyl]benzoate (Compound 67), 250.0 mg (0.52 mmol) of ethyl 4-[(5-trifluoromethylsulfonyloxy-7,8-dihydro-8,8-dimethylnaphth-3-yl)ethynyl]benzoate (Compound 66) was converted into the title compound (colorless solid) using 142.4 mg (1.045 mmol) of zinc chloride, 24.1 mg (0.02 mmol) of tetrakis(triphenylphosphine)palladium(0) and 2-lithiofuran (prepared by the addition of 53.4 mg (0.52 ml, 0.78 mmol) of n-butyllithium (1.5M solution in hexane) to a cold solution (-78° C.) of 53.4 mg (0.784 mmol) of furan in 1.0 mL of THF).
Reaction SMILES: Br[CH2:2][CH2:3][N:4]1[CH:8]=[C:7]([C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH:6]=[C:5]1[C:14]([O:16][CH2:17][CH3:18])=[O:15].[N-:19]=[N+:20]=[N-:21].[Na+]>CN(C=O)C.O.CCOC(C)=O>[N:19]([CH2:2][CH2:3][N:4]1[CH:8]=[C:7]([C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH:6]=[C:5]1[C:14]([O:16][CH2:17][CH3:18])=[O:15])=[N+:20]=[N-:21]
Reactant: CCOC(=O)c1cc(C(=O)OCC)n(CCBr)c1
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCOC(=O)c1cc(C(=O)OCC)n(CCN=[N+]=[N-])c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 56.8 %

Procedure:
To a solution of diethyl 1-(2-bromoethyl)-1H-pyrrole-2,4-dicarboxylate (0.8 g) in DMF (10 mL) was added sodium azide (0.2 g, 3.07 mmol). The resulting mixture was stirred at rt overnight then diluted with water (10 mL) and EtOAc (100 mL). After separation, the aqueous layer was extracted with EtOAc (2×50 mL). The combined organic layers were washed with brine, dried (MgSO4) and concentrated. Purification via flash chromatography (petroleum ether:EtOAc, 20:1 to 15:1) afforded diethyl 1-(2-azidoethyl)-1H-pyrrole-2,4-dicarboxylate (0.4 g, 57%). 1H NMR (CDCl3, 300 MHz) δ7.49 (d, J=1.8 Hz, 1 H), 7.43 (d, J=1.8 Hz, 1 H), 4.88 (t, J=5.5 Hz, 2 H), 4.32 (q, J=7.2 Hz, 4 H), 3.70 (t, J=6.4 Hz, 2 H), 1.38 (m, 6 H).
Reaction SMILES: [Br:1][C:2]1[N:7]=[C:6]([CH3:8])[C:5]([CH:9]=O)=[CH:4][CH:3]=1.[N:11]1([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]1.ClCCl.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>O>[Br:1][C:2]1[N:7]=[C:6]([CH3:8])[C:5]([CH2:9][N:14]2[CH2:13][CH2:12][N:11]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:16][CH2:15]2)=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: Cc1nc(Br)ccc1C=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Product: Cc1nc(Br)ccc1CN1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 81.4 %

Procedure:
A 100 mL round-bottom flask was charged with 6-bromo-2-methylpyridine-3-carbaldehyde (2.50 g, 12.6 mmol, 1.00 equiv), tert-butyl piperazine-1-carboxylate (2.34 g, 12.6 mmol, 1.00 equiv), and dichloromethane (50 mL). The resulting solution was stirred for 30 min at room temperature. Sodium triacetoxyborohydride (8.00 g, 37.8 mmol, 3.00 equiv) was added. The resulting solution was stirred overnight at room temperature and then diluted with water (30 mL). The resulting mixture was extracted with dichloromethane (3×20 mL) and the organic layers were combined, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was chromatographed on a silica gel column with ethyl acetate/petroleum ether (22/78) to provide 3.80 g (82% yield) of tert-butyl 4-[(6-bromo-2-methylpyridin-3-yl)methyl]piperazine-1-carboxylate as a white solid. LCMS (ESI, m/z): 370 [M+H]+.
Reaction SMILES: [C:1](O)(=O)[CH2:2][C:3]([OH:5])=[O:4].[C:8]1([N:14]([C:21]2[CH:28]=[CH:27][C:24](C=O)=[CH:23][CH:22]=2)[C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.N1CCCCC1.Cl>N1C=CC=CC=1>[C:21]1([N:14]([C:8]2[CH:9]=[CH:10][C:11]([CH:1]=[CH:2][C:3]([OH:5])=[O:4])=[CH:12][CH:13]=2)[C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH:22]=[CH:23][CH:24]=[CH:27][CH:28]=1
Reactant: O=Cc1ccc(N(c2ccccc2)c2ccccc2)cc1
Reactant: O=C(O)CC(=O)O
Agent: Cl
Solvent: c1ccncc1
Solvent: C1CCNCC1
Product: O=C(O)C=Cc1ccc(N(c2ccccc2)c2ccccc2)cc1
Temperature: 140 °C
Reaction time: 2.5 h
Yield: 53.7 %

Procedure:
All glassware was dried in a drying oven heated to 140° C. Malonic acid was dried on a high vacuum line over P2O5 and then stored in a nitrogen purged glovebox. Pyridine (Aldrich, anhydrous, 99.8%) and piperidine were used as received and stored in the glovebox. In a 100 mL round bottom flask equipped with a stir bar, condenser and nitrogen inlet-outlet was dissolved malonic acid (2.3 g, 22.0 mmol) in 20 mL pyridine. 4-(N,N-Diphenylamino)benzaldehyde (5.0 g, 18.3 mmol) was added and addition of 20 mL pyridine was necessary to obtain a solution. Piperidine (0.18 mL, 1.8 mmol) was added and the solution was heated to reflux. After heating for 25 hours, malonic acid (0.60 g, 5.8 mmol) was added and heating was resumed for an additional 2.5 h after which time no further reaction was observed. The reaction mixture was allowed to cool to room temperature and then poured into a stirring mixture of 12 N HCl in ice water (1:5). The mixture was filtered and the solids rinsed three times with 20 mL water. The solids were collected and the crude product was purified by recrystallization from 5:3 hexanes:EtOAc at 4° C. The mother liquor was concentrated and recrystallized in a similar fashion from 7:3 hexanes:ethyl acetate. The combined crops give 3.1 g of a light brown powder. The yield was 55%.
Reaction SMILES: [N:1]1[N:2]([C:6]2[N:11]=[CH:10][C:9]([NH2:12])=[CH:8][CH:7]=2)[N:3]=[CH:4][CH:5]=1.Cl[C:14]([O:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[O:15]>CC#N.CCOC(C)=O>[C:17]1([O:16][C:14](=[O:15])[NH:12][C:9]2[CH:10]=[N:11][C:6]([N:2]3[N:3]=[CH:4][CH:5]=[N:1]3)=[CH:7][CH:8]=2)[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: Nc1ccc(-n2nccn2)nc1
Reactant: O=C(Cl)Oc1ccccc1
Solvent: CCOC(C)=O
Solvent: CC#N
Product: O=C(Nc1ccc(-n2nccn2)nc1)Oc1ccccc1
Reaction time: 16 h
Yield: 92.7 %

Procedure:
To a solution consisting of 6-[1,2,3]triazol-2-yl-pyridin-3-ylamine (1.00 g, 6.21 mmol) in CH3CN (10 mL) was added phenyl chloroformate (0.389 mL, 3.10 mmol) dropwise at rt. After 16 h, the reaction mixture was diluted with EtOAc (30 mL) and washed with saturated aq. NaCl. The organic layer was separated, dried (Na2SO4), and concentrated. The crude residue was purified (FCC) to give the title compound as a white solid (0.808 g, 93%). MS (ESI+): calcd. for C14H11N5O2, 281.09. m/z found, 282.1 (M+H)+.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]2([C:21]3[C:12](=[CH:13][C:14]4OC[CH2:17][O:16][C:15]=4[CH:20]=3)[O:11][CH2:10]2)[C:2]1=[O:22].N1C2C(=CC=CC=2)[C@@]2(C3C(=CC4OCCOC=4C=3)[O:33][CH2:32]2)C1=O.Cl[CH2:46][C:47]1[O:51][N:50]=[C:49]([C:52]2[CH:53]=[N:54][CH:55]=[CH:56][CH:57]=2)[CH:48]=1.BrCCCCC>>[N:54]1[CH:55]=[CH:56][CH:57]=[C:52]([C:49]2[CH:48]=[C:47]([CH2:46][N:1]3[C:9]4[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=4)[C:3]4([C:21]5[C:12](=[CH:13][C:14]6[CH2:32][O:33][CH2:17][O:16][C:15]=6[CH:20]=5)[O:11][CH2:10]4)[C:2]3=[O:22])[O:51][N:50]=2)[CH:53]=1
Reactant: ClCc1cc(-c2cccnc2)no1
Reactant: O=C1Nc2ccccc2C12COc1cc3c(cc12)OCCO3
Reactant: O=C1Nc2ccccc2[C@]12COc1cc3c(cc12)OCCO3
Solvent: CCCCCBr
Product: O=C1N(Cc2cc(-c3cccnc3)no2)c2ccccc2C12COc1cc3c(cc12)OCOC3

Procedure:
Following the procedure as described in EXAMPLE 7.3 and making non-critical variations using 2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one to replace (S)-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one, and 5-(chloromethyl)-3-(pyridin-3-yl)isoxazole to replace 1-bromopentane, 1′-[(3-pyridin-3-ylisoxazol-5-yl)methyl]-2,3-dihydrospiro[furo[2,3-g][1,3]benzodioxine-8,3′-indol]-2′(1′H)-one was obtained (40%) as a colorless solid: 1H NMR (300 MHz, CDCl3) 8.96 (s, 1H), 8.65 (d, J=4.7 Hz, 1H), 8.07 (d, J=8.4 Hz, 1H), 7.39-6.98 (m, 5H), 6.58 (s, 1H), 6.47 (s, 1H), 6.20 (s, 1H), 5.10 (ABq, 2H), 4.76 (ABq, 2H), 4.20-4.03 (m, 4H); 13C NMR (75 MHz, CDCl3) δ 177.2, 167.7, 160.3, 155.2, 151.2, 147.9, 144.7, 141.0, 138.3, 134.0, 131.9, 129.1, 124.7, 124.1, 124.1, 123.7, 120.5, 111.5, 108.8, 100.9, 99.4, 79.9, 64.5, 63.8, 57.9, 35.8; MS (ES+) m/z 453.9 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:23]=[CH:22][CH:21]=[C:20]([Cl:24])[C:3]=1[CH2:4][O:5][C:6]1[CH:7]=[CH:8][C:9]2[N:13]=[C:12]([NH:14][C:15](=[O:18])OC)[NH:11][C:10]=2[CH:19]=1.[N:25]1([CH2:31][CH2:32][NH2:33])[CH2:30][CH2:29][O:28][CH2:27][CH2:26]1>CN1CCCC1=O.C(OCC)C>[Cl:1][C:2]1[CH:23]=[CH:22][CH:21]=[C:20]([Cl:24])[C:3]=1[CH2:4][O:5][C:6]1[CH:7]=[CH:8][C:9]2[N:13]=[C:12]([NH:14][C:15]([NH:33][CH2:32][CH2:31][N:25]3[CH2:30][CH2:29][O:28][CH2:27][CH2:26]3)=[O:18])[NH:11][C:10]=2[CH:19]=1
Reactant: NCCN1CCOCC1
Reactant: COC(=O)Nc1nc2ccc(OCc3c(Cl)cccc3Cl)cc2[nH]1
Solvent: CCOCC
Solvent: CN1CCCC1=O
Product: O=C(NCCN1CCOCC1)Nc1nc2ccc(OCc3c(Cl)cccc3Cl)cc2[nH]1
Reaction time: 0.42 h
Yield: 76 %

Procedure:
put a solution of 250 mg of methyl {6-[(2,6-dichlorobenzyl)oxy]-1H-benzimidazol-2-yl}carbamate and 178 mg of 2-morpholin-4-ylethanamine in 3 cm3 of 1-methylpyrrolidin-2-one in a microwave reactor. After the reactor has been sealed, it is put in the microwave cavity for 25 minutes at 125° C. The reaction mixture is then evaporated to dryness under reduced pressure (0.2 kPa) with a bath temperature of 85° C. The residue is taken up in 30 cm3 of water, then extracted three times with 180 cm3 of ethyl acetate. The combined organic phases are washed three times with 30 cm3 of water, dried over magnesium sulphate, filtered and evaporated under reduced pressure (2 kPa). After purification of the residue by silica-column flash chromatography [eluent: dichloromethane/methanol (90/10 by volume)], the product obtained is solidified in 20 cm3 of diethyl oxide, filtered, washed three times with 3 cm3 of diethyl oxide and dried under reduced pressure in the presence of potassium hydroxide. We obtain 241 mg of 1-{6-[(2,6-dichlorobenzyl)oxy]-1H-benzimidazol-2-yl}-3-(2-morpholin-4-ylethyl)urea in the form of a pink powder, which has the following characteristics:
Reaction SMILES: C(O[C:4]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[CH:5][C:6]1[CH2:10][CH2:9][CH2:8][N:7]=1)C.F[B-](F)(F)F.[NH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>>[C:11]1([C:4](=[N:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH:5]=[C:6]2[CH2:10][CH2:9][CH2:8][NH:7]2)[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1
Reactant: CCOC(=CC1=NCCC1)c1ccccc1
Reactant: Nc1ccccc1
Agent: F[B-](F)(F)F
Product: C(=C1CCCN1)C(=Nc1ccccc1)c1ccccc1

Procedure:
By heating the solution of 9.1 g (0.03 mole) of 2-(2-ethoxy-2-phenyl-ethenyl)-1-pyrroline-tetrafluoroborate in 25 ml of aniline for one hour at 80° and processing analogously to Example 1, there is obtained crude 2-[2-phenyl-2-(phenyl-imino)-ethylidene]-pyrrolidine. An addition of 2.8 g of methanesulphonic acid is made to a solution of the crude base in ethyl acetate and the resulting crystals are filtered off. The product thus obtained is 2-[phenyl-2-(phenylimino)-ethylidene]-pyrrolidine-(1:1)-methanesulphonate, m.p. 193°-194° (decomposition).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[N:9]=[C:10]=[O:11].Cl.Cl.Cl.[NH2:15][CH2:16][CH2:17][CH2:18][N:19]1[CH2:24][CH2:23][N:22]([CH2:25][C:26]2[CH:31]=[CH:30][C:29]([Cl:32])=[CH:28][CH:27]=2)[CH2:21][CH2:20]1.C(N(CC)CC)C>C(Cl)Cl>[ClH:1].[ClH:32].[Cl:32][C:29]1[CH:30]=[CH:31][C:26]([CH2:25][N:22]2[CH2:21][CH2:20][N:19]([CH2:18][CH2:17][CH2:16][NH:15][C:10]([NH:9][C:3]3[C:2]([Cl:1])=[CH:7][CH:6]=[CH:5][C:4]=3[Cl:8])=[O:11])[CH2:24][CH2:23]2)=[CH:27][CH:28]=1
Reactant: O=C=Nc1c(Cl)cccc1Cl
Reactant: NCCCN1CCN(Cc2ccc(Cl)cc2)CC1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(NCCCN1CCN(Cc2ccc(Cl)cc2)CC1)Nc1c(Cl)cccc1Cl
Yield: 104 %

Procedure:
The procedure described in Example 29 was followed, using 2,6-dichlorophenyl isocyanate (1.88 g; 10 mmole), 1-(3-aminopropyl)-4-(4-chlorobenzyl)piperazine trihydrochloride (3.77 g; 10 mmole), methylene chloride (50 ml) and triethylamine (4.3 ml; 31 mmole). Recrystallization from methanol provided the title compound (2.75 g; 52% yield) as colorless crystals, m.p. 246°-248° C.
Reaction SMILES: [CH3:1][Mg]I.C(OCC)(=O)/[CH:5]=[CH:6]/[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.O.[Cl-].[NH4+].CC[O:22][CH2:23][CH3:24]>>[C:7]1([CH:6]=[CH:5][C:23]([CH3:24])([OH:22])[CH3:1])[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: C[Mg]I
Reactant: CCOC(=O)/C=C/c1ccccc1
Reactant: CCOCC
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Product: CC(C)(O)C=Cc1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a cooled (−10 to −5° C.) 165 mL of 3 M solution of methyl magnesium iodide in ether was added dropwise a solution of ethyl trans-cinnamate (25.0 g) in 200 mL of anhydrous ether. The reaction was warmed to room temperature and stirred overnight. The mixture was then heated up to 33° C. under reflux for two hours and cooled to 0° C. A white solid was formed during cooling and water (105 mL) was gradually added to dissolve the white precipitate followed by an additional 245 mL of saturated aqueous ammonium chloride solution. The mixture was then stirred until the solids were completely dissolved and extracted with 100 mL of ether three times. The combined extract was washed with 100 mL of water, dried over anhydrous sodium sulfate and filtered. The solvent was evaporated to give 22.1 g of the desired 4-phenyl-2-methyl-3-buten-2-ol as an oil which was used in the next step without further purification. 1H NMR (CDCl3, 300 MHz), δ(ppm) 7.41 (m, 5H), 6.58 (d, 1H), 6.34 (d, 1H), 1.41 (broad s, 6H).
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([C:16]2[CH:17]=[C:18]([C:23]3[CH:28]=[CH:27][C:26]([C:29]([O:31][CH2:32][CH3:33])=[O:30])=[CH:25][CH:24]=3)[CH:19]=[CH:20][C:21]=2O)[CH:8]=[CH:9][C:10]=1[N:11]([CH2:14][CH3:15])[CH2:12][CH3:13])([CH3:4])([CH3:3])[CH3:2].C(=O)([O-])[O-:35].[Cs+].[Cs+].Br[CH2:41][CH2:42][CH2:43][CH2:44][O:45][Si:46]([C:49]([CH3:52])([CH3:51])[CH3:50])([CH3:48])[CH3:47]>CN(C)C=O>[C:1]([C:5]1[CH:6]=[C:7]([C:16]2[CH:17]=[C:18]([C:23]3[CH:24]=[CH:25][C:26]([O:35][CH2:41][CH2:42][CH2:43][CH2:44][O:45][Si:46]([C:49]([CH3:52])([CH3:51])[CH3:50])([CH3:48])[CH3:47])([C:29]([O:31][CH2:32][CH3:33])=[O:30])[CH2:27][CH:28]=3)[CH:19]=[CH:20][CH:21]=2)[CH:8]=[CH:9][C:10]=1[N:11]([CH2:14][CH3:15])[CH2:12][CH3:13])([CH3:2])([CH3:4])[CH3:3]
Reactant: CC(C)(C)[Si](C)(C)OCCCCBr
Reactant: CCOC(=O)c1ccc(-c2ccc(O)c(-c3ccc(N(CC)CC)c(C(C)(C)C)c3)c2)cc1
Reactant: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CCOC(=O)C1(OCCCCO[Si](C)(C)C(C)(C)C)C=CC(c2cccc(-c3ccc(N(CC)CC)c(C(C)(C)C)c3)c2)=CC1
Temperature: 25 °C

Procedure:
1 g of ethyl 3″-tert-butyl-4″-diethylamino-4′-hydroxy[1,1′;3′,1″]terphenyl-4-carboxylate obtained in Example 1d (2.2 mmol) are dissolved in 20 mL of dimethylformamide under a nitrogen atmosphere. 880 mg (2.7 mmol) of caesium carbonate are added. The reaction medium stirred at room temperature turns yellow. 0.64 mL of 1-bromo-4-(tert-butyldimethylsilanyloxy)butane (2.4 mmol) is then added and the reaction medium is heated at 80° C. for 18 hours. The reaction medium is then cooled to room temperature and then filtered. The solvents are evaporated off and the residue obtained is purified by chromatography on silica gel (eluent: 70/30 heptane/ethyl acetate).
Reaction SMILES: [OH-].[Na+].[Cl:3][O-].[Na+].[OH:6][C:7]1[N:15]=[CH:14][CH:13]=[CH:12][C:8]=1[C:9]([OH:11])=[O:10].Cl>>[Cl:3][C:13]1[CH:12]=[C:8]([C:9]([OH:11])=[O:10])[C:7]([OH:6])=[N:15][CH:14]=1
Reactant: O=C(O)c1cccnc1O
Reactant: [O-]Cl
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: O=C(O)c1cc(Cl)cnc1O
Reaction time: 8 h
Yield: 81.8 %

Procedure:
To an agitated solution of 216.0 g of sodium hydroxide pellets in 2.25 liters of 5% (1.51 moles) sodium hypochlorite solution was added 150.1 g (1.08 mole) of 2-hydroxynicotinic acid. Temperature of the reaction mixture was 20° C. Four hours later 750 ml of 5% (0.50 mole) of sodium hypochlorite solution was added and stirring was continued overnight. The reaction mixture was mixed with 12N hydrochloric acid in an agitated vessel in such a manner that the receiving solution was always strongly acid and temperature was kept below 20° C. with an ice bath. The amount of 12N acid used was 600 ml. The mixture was readily filtered on a sintered glass suction funnel. The crystalline filter cake was washed with 800 ml of water followed by 800 ml of 1:1 isopropyl ether/isopropyl alcohol. Crystals were powdery when dry. The weight of dry crystals was 153.2 g (81.8% yield). Analysis by 1HNMR showed the dried product contained no starting material and contained about 5% of 3,5-dichloro-2-hydroxypyridine. See Example 3 for method of computing impurity.
Reaction SMILES: [CH2:1]=[C:2]1[O:6][C:4](=[O:5])[CH2:3]1.C(N[CH2:10][CH2:11][OH:12])C.[C:13](#[N:15])[CH3:14]>>[CH2:13]([N:15]([CH:11]([OH:12])[CH3:10])[C:4](=[O:5])[CH2:3][C:2](=[O:6])[CH3:1])[CH3:14]
Reactant: C=C1CC(=O)O1
Reactant: CC#N
Reactant: CCNCCO
Product: CCN(C(=O)CC(C)=O)C(C)O
Temperature: -2.5 °C
Reaction time: 4 h

Procedure:
Acetonitrile (692.5 g) and diketene (46.5 g) were introduced into a 5,000 mL four-necked flask, and the mixture was cooled so that the temperature in the flask was lowered to −5 to 0° C. Diketene and 2-(ethylamino)ethanol were simultaneously added dropwise for 4 hours at a rate of 220 g/h and 233.5 g/h, respectively. During the addition, cooling was suitably conducted to maintain the temperature in the flask at −5 to 0° C. Thereafter, 30 g of 2-(ethylamino)ethanol was added dropwise at a rate of 233.5 g/h. The resultant was heated to room temperature and aged for 12 hours. Then, while the mixture in the flask was heated to a temperature of 40 to 50° C., acetonitrile was removed under reduced pressure, and the resulting mixture was finally kept at a pressure of about 0.001 for 4 hours, to thereby produce about 1,850 g of 2-(N-ethyl-N-(2-acetylacetyl)aminoethanol.
Reaction SMILES: [CH3:1][C:2]([NH:10][C:11]([C:13]1[S:40][C:16]2[N:17](C(OCC)=O)[N:18]=[C:19]([NH:20][C:21](=[O:34])[C:22]3[CH:27]=[CH:26][C:25]([N:28]4[CH2:33][CH2:32][O:31][CH2:30][CH2:29]4)=[CH:24][CH:23]=3)[C:15]=2[CH:14]=1)=[O:12])([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)[CH3:3]>CO.C(N(CC)CC)C>[CH3:3][C:2]([NH:10][C:11]([C:13]1[S:40][C:16]2[NH:17][N:18]=[C:19]([NH:20][C:21](=[O:34])[C:22]3[CH:27]=[CH:26][C:25]([N:28]4[CH2:33][CH2:32][O:31][CH2:30][CH2:29]4)=[CH:24][CH:23]=3)[C:15]=2[CH:14]=1)=[O:12])([C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1)[CH3:1]
Reactant: CCOC(=O)n1nc(NC(=O)c2ccc(N3CCOCC3)cc2)c2cc(C(=O)NC(C)(C)c3ccccc3)sc21
Solvent: CO
Solvent: CCN(CC)CC
Product: CC(C)(NC(=O)c1cc2c(NC(=O)c3ccc(N4CCOCC4)cc3)n[nH]c2s1)c1ccccc1
Temperature: 70 °C
Reaction time: 5 h
Yield: 86.7 %

Procedure:
A suspension of ethyl 5-{[(1-methyl-1-phenylethyl)amino]carbonyl}-3-[(4-morpholin-4-ylbenzoyl)amino]-1H-thieno[2,3-c]pyrazole-1-carboxylate (3.71 g, 6.6 mmol) in methanol (MeOH, 70 mL) and triethylamine (TEA, 7 mL) was stirred at 70° C. for 5 hours. After evaporation of the solvent under reduced pressure, the residue was taken up with DCM and washed with water. The organic layer was separated, dried over sodium sulfate and evaporated. Purification by chromatography (DCM/MeOH 47:3) gave 2.8 g of the title compound.