Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][OH:7].[H-].[Na+].[Cl:10][C:11]1[CH:16]=[CH:15][CH:14]=[C:13](Cl)[N:12]=1>O1CCCC1>[Cl:10][C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([O:7][CH2:6][C:2]2[S:1][CH:5]=[CH:4][CH:3]=2)[N:12]=1
Reactant: Clc1cccc(Cl)n1
Reactant: OCc1cccs1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Clc1cccc(OCc2cccs2)n1

Procedure:
To a solution containing 2-thiophenemethanol (1.5 g, 0.0135×1.0 mol) and sodium hydride (0.58 g, (ca.60% in mineral oil), 0.0135×1.1 mol) in tetrahydrofuran, 2,6-dichloropyridine (2.0 g, 0.0135 mol) was added and the resultant solution was refluxed for about 2 hours. The reaction solution was partitioned between ethyl acetate and aqueous saturated sodium hydrogen carbonate. The obtained organic layer was washed with aqueous saturated sodium chloride, dried over anhydrous sodium sulfate and thereafter, concentrated and purified on a silica gel column to obtain the end product.
Reaction SMILES: N1C=CC=NC=1.[CH3:7][C:8]1[N:13]([CH3:14])[C:12](=[O:15])[C:11]([O:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[C:10]([CH2:24][OH:25])[N:9]=1.[Na+].[Br-].[OH-:28].[Na+]>CC1(C)N([O])C(C)(C)CCC1.CCCCCCCC[N+](CCCCCCCC)(CCCCCCCC)C.[Cl-].C(Cl)Cl.O>[CH3:7][C:8]1[N:13]([CH3:14])[C:12](=[O:15])[C:11]([O:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[C:10]([C:24]([OH:28])=[O:25])[N:9]=1
Reactant: [OH-]
Reactant: Cc1nc(CO)c(OCc2ccccc2)c(=O)n1C
Agent: CC1(C)CCCC(C)(C)N1[O]
Agent: CCCCCCCC[N+](C)(CCCCCCCC)CCCCCCCC
Agent: [Br-]
Solvent: c1cncnc1
Solvent: O
Solvent: ClCCl
Product: Cc1nc(C(=O)O)c(OCc2ccccc2)c(=O)n1C
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 54.9 %

Procedure:
The above pyrimidine, 32 (9.00 g, 34.6 mmol), TEMPO catalyst (55 mg), Adogen-464 phase transfer catalyst (690 mg) and NaBr (360 mg, 3.50 mmol) were combined in CH2Cl2 (400 mL) and water (10 mL). After cooling to 0° C. the reaction was stirred at 1500 r.p.m. while adding a cooled (10° C.) buffered bleach solution (125 mL commercial bleach+125 mL water+12.5 g NaHCO3) keeping the reaction <4° C. (takes approx. 15 min). After a further 5 min, 2M NaOH solution was added until a solution of pH 10 was obtained. The CH2Cl2 layer was separated and extracted with basic water (pH 10, 100 mL). The combined aqueous solutions were washed with CH2Cl2 (50 mL). The aqueous phase was concentrated to ˜200-250 mL and carefully acidified (conc. HCl) to pH 2, concomitant with precipitation. After standing at 5° C. overnight the white solid was filtered, washed with water and dried under high vacuum to give 5.20 g (54.9%) of 33. Mp: 180-181° C. (+)FABMS: m/z 275. 1H NMR (CDCl3, 300 MHz): δ 2.53 (s, 3H, 2-Me), 3.55 (s, 3H, N-Me), 5.46 (s, 2H, BnCH2), 7.30-7.38 (m, 3H, Ph), 7.49-7.52 (m, 2H, Ph). 13C NMR (DMSO-d6, 100 MHz): δ 22.6, 31.2, 73.3, 128.0, 128.2, 128.3, 136.9, 139.1, 143.0, 155.7, 159.2, 165.7. Anal. Calcd (found) for C14H14N2O4: C, 61.31(61.36); H, 5.14 (5.06); N, 10.21(10.30).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[N:6]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[NH2:7].C(N(CC)CC)C.[Cl:22][C:23]1[CH:31]=[CH:30][C:26]([C:27](Cl)=[O:28])=[CH:25][CH:24]=1>C1COCC1>[Cl:22][C:23]1[CH:31]=[CH:30][C:26]([C:27]([NH:7][N:6]([C:2]2[S:1][CH:5]=[CH:4][CH:3]=2)[C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])=[O:28])=[CH:25][CH:24]=1
Reactant: O=C(Cl)c1ccc(Cl)cc1
Reactant: CC(C)(C)OC(=O)N(N)c1cccs1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N(NC(=O)c1ccc(Cl)cc1)c1cccs1
Temperature: 25 °C
Reaction time: 1 h
Yield: 77087.8 %

Procedure:
To a solution of tert-butyl 1-(thiophen-2-yl)hydrazinecarboxylate (100 mg, 0.467 mmol) in THF (5 mL) was added triethylamine (64 μL, 0.476 mmol, 1 eq.) and 4-chlorobenzoyl chloride (60 μL, 82 mg, 0.467 mmol, 1 eq.), and the resulting mixture was stirred for 1 hour at room temperature. A sample of the reaction mixture (quenched in water, and extracted with EtOAc) showed the presence of the intermediate crude product tert-butyl 2-(4-chlorobenzoyl)-1-(thiophen-2-yl)-hydrazinecarboxylate, as determined by NMR. The reaction mixture was then poured in water and extracted with EtOAc. The organic layer was dried over MgSO4 and concentrated in vacuo. The crude product (278 mg) was purified by automated column chromatography (EtOAc/heptane) to yield tert-butyl 2-(4-chlorobenzoyl)-1-(thiophen-2-yl)-hydrazinecarboxylate (127 mg, 360 mmol, yield 77%) as a light brown solid with an HPLC purity of greater than 99%. LC-MS (M−1) 351 (C16H17ClN2O3S-1, expected 352.06).
Reaction SMILES: [CH3:1][NH:2][C@H:3]([C:11]([OH:13])=[O:12])[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.Cl.[N:15]([O-:17])=[O:16].[Na+]>O>[N+:15]([N:2]([CH3:1])[C@H:3]([C:11]([OH:13])=[O:12])[CH2:4][C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=1)([O-:17])=[O:16]
Reactant: CN[C@@H](Cc1ccccc1)C(=O)O
Reactant: O=N[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Product: CN([C@@H](Cc1ccccc1)C(=O)O)[N+](=O)[O-]
Temperature: 5 °C

Procedure:
N-Methyl-L-phenylalamne (2.50 g) was suspended in water (25 ml) and cone. HCl (1 ml) was addded, with stirring. The solution was cooled to 5° C. and solid sodium nitrite (1.35 g) was added to the stirred solution. After stirring at 5° C. for 1 h, the reaction mixture was partitioned between dichloromethane and water. The organic solution was washed with brine and dried (MgSO4). After filtration the solvent was evaporated to yield N-nitro-N-methyl-L-phenylalanine as a white solid.
Reaction SMILES: [Br:1][C:2]1[CH:15]=[C:14]2[C:5]([O:6][C:7]3[C:8]([F:24])=[CH:9][C:10]([O:22][CH3:23])=[CH:11][C:12]=3[C:13]2([C:17]2[NH:18][CH:19]=[CH:20][N:21]=2)Cl)=[CH:4][CH:3]=1.[N:25]#[C:26][NH2:27]>O1CCOCC1>[Br:1][C:2]1[CH:15]=[C:14]2[C:5]([O:6][C:7]3[C:8]([F:24])=[CH:9][C:10]([O:22][CH3:23])=[CH:11][C:12]=3[C:13]32[C:17]2=[N:18][CH:19]=[CH:20][N:21]2[C:26]([NH2:27])=[N:25]3)=[CH:4][CH:3]=1
Reactant: COc1cc(F)c2c(c1)C(Cl)(c1ncc[nH]1)c1cc(Br)ccc1O2
Reactant: N#CN
Solvent: C1COCCO1
Product: COc1cc(F)c2c(c1)C1(N=C(N)n3ccnc31)c1cc(Br)ccc1O2
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 100 %

Procedure:
To 2-(7-bromo-9-chloro-4-fluoro-2-methoxy-9H-xanthen-9-yl)-1H-imidazole (10 g, 24.41 mmol) was added a solution of cyanamide (1.539 g, 36.6 mmol) in dioxane (244 mL). The solution was stirred at RT for 30 minutes. The solution was then heated at reflux for 6 hrs until only a product peak was seen by LCMS. The solution was concentrated under vacuum. The solution was quenched with 500 ml of saturated sodium bicarbonate and 500 ml of water, and sonicated for 30 minutes. The product was then collected by filtration. The solid was then triturated with DCM and dried under vacuum to afford 7′-bromo-4′-fluoro-2′-methoxyspiro[imidazo[1,5-a]imidazole-7,9′-xanthen]-5-amine (10 g, 24.4 mmol) as a light brown solid.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][C@@H:10]([C@H:13]2[CH2:15][O:14]2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:16][S-:17].[Na+]>CN(C=O)C>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][C@@H:10]([C@H:13]([OH:14])[CH2:15][S:17][CH3:16])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: C[S-]
Reactant: CC(C)(C)OC(=O)N1CC[C@@H]([C@H]2CO2)C1
Agent: [Na+]
Solvent: CN(C)C=O
Product: CSC[C@@H](O)[C@@H]1CCN(C(=O)OC(C)(C)C)C1
Temperature: 50 °C
Reaction time: 3 h
Yield: 57 %

Procedure:
(R)-(S)-3-Oxiranylpyrrolidine-1-carboxylic acid t-butyl ester (1.0 g, 4.7 mmol, 1.0 eq.) in DMF (10 mL) was combined with sodium methyl mercaptide (2.5 g, 14.1 mmol, 3.0 eq.), and the resulting mixture was stirred at 50° C. for 3 hours under nitrogen. Upon completion of the reaction, the mixture was concentrated under vacuum, extracted with EtOAc, washed with saturated aqueous NaCl and water, dried, and concentrated. The crude product was purified by preparative HPLC (MeCN:EtOH=4:6) to yield the title compound (700 mg).
Reaction SMILES: [C:1]1([C:7]2[N:8]=[CH:9][C:10]([N:19]([CH2:23][CH2:24][CH2:25][CH2:26][OH:27])[CH:20]([CH3:22])[CH3:21])=[N:11][C:12]=2[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH-].[K+].Br[CH2:31][C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33]>C1C=CC=CC=1.S([O-])(O)(=O)=O.C([N+](CCCC)(CCCC)CCCC)CCC>[C:35]([O:34][C:32](=[O:33])[CH2:31][O:27][CH2:26][CH2:25][CH2:24][CH2:23][N:19]([C:10]1[CH:9]=[N:8][C:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)=[C:12]([C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)[N:11]=1)[CH:20]([CH3:21])[CH3:22])([CH3:38])([CH3:37])[CH3:36]
Reactant: CC(C)N(CCCCO)c1cnc(-c2ccccc2)c(-c2ccccc2)n1
Reactant: CC(C)(C)OC(=O)CBr
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=S(=O)([O-])O
Agent: [K+]
Solvent: c1ccccc1
Product: CC(C)N(CCCCOCC(=O)OC(C)(C)C)c1cnc(-c2ccccc2)c(-c2ccccc2)n1
Yield: 82.9 %

Procedure:
22.84 g of 4-[N-(5,6-diphenylpyrazin-2-yl)-N-isopropylamino]-1-butanol was dissolved in 160 ml of benzene and 10.73 g of tetra-n-butylammonium hydrogen sulfate and 160 ml of an aqueous 40% potassium hydroxide solution were added. While stirring vigorously under ice cooling, 10.73 g of tert-butyl bromoacetate was added dropwise so as to control the inner temperature within a range from 5 to 10° C. After stirring for 45 minutes, an ice bath was removed and the mixture was stirred at room temperature for one hour. The reaction solution was diluted with water and then extracted with diethyl ether. The extract was washed with water and dried over anhydrous magnesium sulfate, and then the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography to obtain 21.70 g of the desired compound as a pale yellow oily substance.
Reaction SMILES: C(NC(C)C)(C)C.[Li]CCCC.[C:13]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])(=[O:15])[CH3:14].[CH3:21][O:22][C:23]1[CH:24]=[C:25]([OH:33])[C:26](=[CH:31][CH:32]=1)[C:27](OC)=[O:28]>>[OH:33][C:25]1[CH:24]=[C:23]([O:22][CH3:21])[CH:32]=[CH:31][C:26]=1[C:27](=[O:28])[CH2:14][C:13]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15]
Reactant: COC(=O)c1ccc(OC)cc1O
Reactant: CC(=O)OC(C)(C)C
Agent: [Li]CCCC
Solvent: CC(C)NC(C)C
Product: COc1ccc(C(=O)CC(=O)OC(C)(C)C)c(O)c1

Procedure:
Prepared according to above procedure using diisopropylamine (8.0 mL, 58 mmol), nBuLi (34 mL, 1.6 M), tert-butyl acetate (4.7 mL, 35 mmol), methyl 4-methoxysalicylate (1.83 g, 10 mmol) yielding 2.04 g (76%) as white needles. mp=40-42° C.; IR (film) 2978.7; 2936.4; 1731.9; 1633.5; 1357.0; 1129.3 cm−1; 1H NMR (500 MHz, CDCl3) δ 12.42 (s, 1H); 7.57 (d, J=9.0 Hz, 1H); 6.45 (d, J=9.0, 1H); 6.44 (s, 1H); 3.85 (s, 3H); 3.84 (s, 2H); 1.46 (s, 9H); 13C NMR (125 MHz, CDCl3) δ 197.1, 166.7, 166.6, 165.9, 132.3, 113.5, 108.3, 101.2, 82.5, 55.9, 47.2, 28.2; LRMS (electrospray): Mass calculated for C14H18O5, [M]+, 266.12. Found [M+23]+, 289.5.
Reaction SMILES: [F:1][C:2]([P:8](C(F)(F)C(F)(F)F)[C:9]([F:15])([F:14])[C:10]([F:13])([F:12])[F:11])([F:7])[C:3]([F:6])([F:5])[F:4].[OH-].[K+].P(Cl)(Cl)(Cl)(Cl)[Cl:26]>COCCOC.O>[P:8]([Cl:26])([C:9]([C:10]([F:13])([F:12])[F:11])([F:15])[F:14])[C:2]([C:3]([F:6])([F:5])[F:4])([F:7])[F:1]
Reactant: FC(F)(F)C(F)(F)P(C(F)(F)C(F)(F)F)C(F)(F)C(F)(F)F
Reactant: ClP(Cl)(Cl)(Cl)Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: COCCOC
Product: FC(F)(F)C(F)(F)P(Cl)C(F)(F)C(F)(F)F
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A solution of 1.16 g (3.0 mmol) of tris(pentafluoroethyl)phosphine, (C2F5)3P, in 1,2-dimethoxyethane is treated with an excess (6 mmol) of a 1.5 M solution of KOH in water. The mixture is stirred at room temperature for 30 min, and the solvent is removed in vacuo. The residue is taken up in 1,2-dimethoxyethane, and an excess of PCl5 (6 mmol) is added, giving bis(pentafluoroethyl)phosphinous acid chloride, (C2F5)2PCl, identified as described above.
Reaction SMILES: OC1C=C(CNC=C2C3C(=CC=C(I)C=3)C(=O)NC2=O)C=CC=1C1C=CC=CC=1.[C:30]([C:34]1[CH:35]=[C:36]2[C:41](=[CH:42][CH:43]=1)[C:40](=[O:44])[NH:39][C:38](=[O:45])[C:37]2=[CH:46]OC)([CH3:33])([CH3:32])[CH3:31].[NH2:49][CH2:50][C:51]1[C:52]([F:63])=[CH:53][C:54]([C:58]2[CH:62]=[CH:61][O:60][CH:59]=2)=[C:55]([OH:57])[CH:56]=1>>[C:30]([C:34]1[CH:35]=[C:36]2[C:41](=[CH:42][CH:43]=1)[C:40](=[O:44])[NH:39][C:38](=[O:45])[C:37]2=[CH:46][NH:49][CH2:50][C:51]1[CH:56]=[C:55]([OH:57])[C:54]([C:58]2[CH:62]=[CH:61][O:60][CH:59]=2)=[CH:53][C:52]=1[F:63])([CH3:33])([CH3:32])[CH3:31]
Reactant: COC=C1C(=O)NC(=O)c2ccc(C(C)(C)C)cc21
Reactant: NCc1cc(O)c(-c2ccoc2)cc1F
Agent: O=C1NC(=O)c2ccc(I)cc2C1=CNCc1ccc(-c2ccccc2)c(O)c1
Product: CC(C)(C)c1ccc2c(c1)C(=CNCc1cc(O)c(-c3ccoc3)cc1F)C(=O)NC2=O
Yield: 60 %

Procedure:
Following the same procedure for the preparation of 4-{[(2-Hydroxy-biphenyl-4-ylmethyl)-amino]-methylene}-6-iodo-4H-isoquinoline-1,3-dione, the title compound is prepared from 6-tert-Butyl-4-methoxymethylene-4H-isoquinoline-1,3-dione (11 mg, 0.042 mmol) and 5-Aminomethyl-4-fluoro-2-furan-3-yl-phenol (12 mg, 0.058 mmol) in 60% yield: MS (ESI): 433.2 (M−1)−1.
Reaction SMILES: [NH2:1][N:2]1[C:7](=[O:8])[C:6]([C:9]2[NH:14][C:13]3[CH:15]=[CH:16][CH:17]=[CH:18][C:12]=3[S:11](=[O:20])(=[O:19])[N:10]=2)=[C:5]([OH:21])[C:4]2[S:22][CH:23]=[CH:24][C:3]1=2.[C:25]1(=O)[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]1>CN(C)C(=O)C>[C:25]1(=[N:1][N:2]2[C:7](=[O:8])[C:6]([C:9]3[NH:14][C:13]4[CH:15]=[CH:16][CH:17]=[CH:18][C:12]=4[S:11](=[O:20])(=[O:19])[N:10]=3)=[C:5]([OH:21])[C:4]3[S:22][CH:23]=[CH:24][C:3]2=3)[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]1
Reactant: Nn1c(=O)c(C2=NS(=O)(=O)c3ccccc3N2)c(O)c2sccc21
Reactant: O=C1CCCCC1
Solvent: CC(=O)N(C)C
Product: O=c1c(C2=NS(=O)(=O)c3ccccc3N2)c(O)c2sccc2n1N=C1CCCCC1
Temperature: 25 °C

Procedure:
The product of Example 268D (0.054 g, 0.15 mmol) was reacted with cyclohexanone (0.44 g, 4.5 mmol) in N,N-dimethylacetamide (1mL) in a sealed tube at 135° C. for 45 minutes in a microwave reactor. The reaction was cooled to 25° C. and concentrated under vacuum. The resulting residue was triturated with diethyl ether (3 mL) and filtered to give the title compound.
Reaction SMILES: [C:1]([C:3]([C:6]1[CH:7]=[C:8]([CH:27]=[CH:28][CH:29]=1)[CH2:9][N:10]1[C:18]2[C:13](=[CH:14][C:15]([C:19]([O:21]CC=C)=[O:20])=[CH:16][CH:17]=2)[C:12]([CH3:25])=[C:11]1[CH3:26])([CH3:5])[CH3:4])#[N:2].N1CCOCC1>C1COCC1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:1]([C:3]([C:6]1[CH:7]=[C:8]([CH:27]=[CH:28][CH:29]=1)[CH2:9][N:10]1[C:18]2[C:13](=[CH:14][C:15]([C:19]([OH:21])=[O:20])=[CH:16][CH:17]=2)[C:12]([CH3:25])=[C:11]1[CH3:26])([CH3:5])[CH3:4])#[N:2]
Reactant: C=CCOC(=O)c1ccc2c(c1)c(C)c(C)n2Cc1cccc(C(C)(C)C#N)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: C1COCCN1
Product: Cc1c(C)n(Cc2cccc(C(C)(C)C#N)c2)c2ccc(C(=O)O)cc12
Temperature: 25 °C
Reaction time: 1 h

Procedure:
The mixture of allyl 1-(3-(2-cyanopropan-2-yl)benzyl)-2,3-dimethyl-1H-indole-5-carboxylate (0.688 g, 1.78 mmol) and morpholine (1.6 mL, 17.8 mmol) in THF (5 mL) was degassed and then Pd(PPh3)4 (0.21 g, 0.18 mmol) was added. The mixture was stirred at room temperature for 1 h. The solvent was removed and the residue was dissolved in Methanol and acidified to pH4. The solvent was removed and the residue was purified by silica gel to obtain the title compound. ESI-MS (m/z): 347 [M+H]+.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=O)=[CH:4][CH:3]=1.[S:10]1[CH2:14][C:13](=[O:15])[NH:12][C:11]1=[O:16].CO.O>C(O)(=O)C>[CH:4]1[C:5](/[CH:6]=[C:14]2\[C:13]([NH:12][C:11]([S:10]\2)=[O:16])=[O:15])=[CH:8][CH:9]=[C:2]([OH:1])[CH:3]=1
Reactant: O=Cc1ccc(O)cc1
Reactant: O=C1CSC(=O)N1
Solvent: O
Solvent: CC(=O)O
Solvent: CO
Product: O=C1NC(=O)/C(=C\c2ccc(O)cc2)S1

Procedure:
A mixture of 4-hydroxy benzaldehyde, 53 (3 g, 24.6 mmol), 2,4-thiazolidinedione, 54 (2.9 g, 24.8 mmol), pipieridine (2.5 mL) and methanol (100 mL) was refluxed for 18 h. The reaction mixture was poured into water and acidified with acetic acid to give 55, which was recrystallised from methanol. Yield 4.7 g (86%); mp 296-298° C.; MS (FAB) 222 (M++1); IR (KBr) 3404, 3123, 1723, 1678; 1H NMR (200 MHz, DMSO-d6) δ 7.70 (s, 1H), 7.46 (d, J=8.6 Hz, 2H), 6.93 (d, J=8.6 Hz, 2H).
Reaction SMILES: [CH3:1][C:2]1[S:6][C:5]([C:7]([OH:9])=O)=[CH:4][CH:3]=1.[Br:10][C:11]1[CH:17]=[CH:16][C:14]([NH2:15])=[C:13](O)[CH:12]=1>>[Br:10][C:11]1[CH:17]=[CH:16][C:14]2[N:15]=[C:7]([C:5]3[S:6][C:2]([CH3:1])=[CH:3][CH:4]=3)[O:9][C:13]=2[CH:12]=1
Reactant: Nc1ccc(Br)cc1O
Reactant: Cc1ccc(C(=O)O)s1
Product: Cc1ccc(-c2nc3ccc(Br)cc3o2)s1

Procedure:
Preparation is carried out analogously to 4.1.a from 5-methylthiophene-2-carboxylic acid and 4-bromo-2-hydroxy-aniline.
Reaction SMILES: [CH3:1][O:2][C:3]([CH:5]([CH2:11][CH:12]=[CH2:13])[CH2:6][CH2:7][CH2:8][C:9]#[N:10])=[O:4].Br[C:15]1[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=1.C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C>C(#N)C.C(N(CC)CC)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH3:1][O:2][C:3]([CH:5]([CH2:11][CH:12]=[CH:13][C:15]1[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=1)[CH2:6][CH2:7][CH2:8][C:9]#[N:10])=[O:4]
Reactant: C=CCC(CCCC#N)C(=O)OC
Reactant: Brc1cccnc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CC#N
Solvent: CCN(CC)CC
Product: COC(=O)C(CC=Cc1cccnc1)CCCC#N
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A mixture of 23.5 g of 5-methoxycarbonyl-oct-7-enenitrile, 20.07 g of 3-bromopyridine and 0.79 g of tri-o-tolylphosphine in 200 ml of 2:1 acetonitrile/triethylamine is stirred at room temperature under nitrogen for 0.5 h. Palladium acetate (0.27 g) is added and the mixture is stirred under reflux for 40 h. An additional 0.13 g of palladium acetate is added and the reaction mixture is further heated under reflux for 20 h. The reaction mixture is evaporated to dryness and the residue is taken up in ethyl acetate. The ethyl acetate solution is washed with water, and then with 3N hydrochloric acid. The acid extract is washed with ethyl acetate, made basic to pH 8-9 with aqueous ammonia and reextracted with ethyl acetate. The ethyl acetate extract is dried and evaporated to dryness to yield 5-methoxycarbonyl-8-(3-pyridyl)-oct-7-enenitrile.
Reaction SMILES: [F:1][CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:14]=[C:13]2[C:9]([CH2:10][C:11]3([CH2:20][CH2:19][C:18](=[O:21])[CH2:17][CH2:16]3)[C:12]2=[O:15])=[CH:8][CH:7]=1.CO.[B-][N+](C)(C)C.O.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>O1CCCC1.O>[F:1][CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:14]=[C:13]2[C:9]([CH2:10][C:11]3([CH2:16][CH2:17][CH:18]([OH:21])[CH2:19][CH2:20]3)[C:12]2=[O:15])=[CH:8][CH:7]=1
Reactant: O=C1CCC2(CC1)Cc1ccc(OCCCF)cc1C2=O
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [B-][N+](C)(C)C
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: O=C1c2cc(OCCCF)ccc2CC12CCC(O)CC2
Reaction time: 8 h

Procedure:
6′-(3-Fluoropropoxy)spiro[cyclohexane-1,2′-indene]-1′,4(3′H)-dione (Intermediate 63, 3.14 g, 10.8 mmol) were dissolved in tetrahydrofuran (50 mL) and MeOH (4.38 mL, 108 mmol). Borane-trimethylamine complex (1.74 g, 23.8 mmol) was added and the resulting mixture was stirred overnight. Citric acid monohydrate (31.8 g, 151 mmol) was added all at once and was followed by dropwise addition of water (3.90 mL, 216 mmol). The mixture was stirred for 3 h before being diluted with water and extracted with EtOAc (×2). The combined organic phases was dried over MgSO4 and concentrated in vacuo. The product was purified using silica gel flash chromatography using a gradient of MeOH (0-10%) in DCM to give 1.94 (61% yield) of the title compound which was used in the next step without further purification: MS (ES+) m/z 307 [M+H]+.
Reaction SMILES: [CH:1]([C:4]1[CH:5]=[CH:6][C:7]2[C:12]([NH:13][C:14]3[CH:15]=[C:16]([CH:20]=[CH:21][C:22]=3[S:23][C:24]3[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[CH:26][CH:25]=3)[C:17](Cl)=[O:18])=[N:11][CH:10]=[N:9][C:8]=2[N:32]=1)([CH3:3])[CH3:2].[NH2:33][C:34]1[C:35]([CH3:40])=[CH:36][CH:37]=[CH:38][CH:39]=1.NC1C=C(O)C(C)=CC=1>>[CH:1]([C:4]1[CH:5]=[CH:6][C:7]2[C:12]([NH:13][C:14]3[CH:15]=[C:16]([CH:20]=[CH:21][C:22]=3[S:23][C:24]3[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[CH:26][CH:25]=3)[C:17]([NH:33][C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=3[CH3:40])=[O:18])=[N:11][CH:10]=[N:9][C:8]=2[N:32]=1)([CH3:3])[CH3:2]
Reactant: Cc1ccccc1N
Reactant: COc1ccc(Sc2ccc(C(=O)Cl)cc2Nc2ncnc3nc(C(C)C)ccc23)cc1
Agent: Cc1ccc(N)cc1O
Product: COc1ccc(Sc2ccc(C(=O)Nc3ccccc3C)cc2Nc2ncnc3nc(C(C)C)ccc23)cc1

Procedure:
The product from Example 137B was reacted with o-toluidine according to the procedure from Example 137C substituting o-toluidine for 5-amino-o-cresol to provide the title compound as an off white solid after silica gel chromatography (74 mg, 92%). 1H NMR (300 MHz, DMSO-D6) δ ppm: 1.34 (d, J=6.99 Hz, 6H), 2.34 (s, 3H), 3.18-3.29 (m, 1H), 3.78 (s, 3H), 6.91 (d, J=7.35 Hz, 1H), 7.00 (d, J=8.09 Hz, 2H), 7.22 (t, J=7.72 Hz, 1H), 7.40 (d, J=8.46 Hz, 2H), 7.50-7.72 (m, 4H), 7.81 (d, J=8.09 Hz, 1H), 8.00 (s, 1H), 8.59 (s, 1H), 8.87 (d, J=8.46 Hz, 1H), 10.13 (s, 1H), 10.21 (s, 1H); MS (APCI) m/z 536 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[N:3]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[CH3:15])[C:4](=[O:8])[N:5]([CH3:7])[N:6]=1.[Br:16]N1C(=O)CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(Cl)(Cl)(Cl)Cl>[Br:16][CH2:15][C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=1[N:3]1[C:2]([Cl:1])=[N:6][N:5]([CH3:7])[C:4]1=[O:8]
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1ccccc1-n1c(Cl)nn(C)c1=O
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: Cn1nc(Cl)n(-c2ccccc2CBr)c1=O

Procedure:
Preparation of ##STR16## a) 8.95 g of 5-chloro-2-methyl-4-(o-tolyl)-2,4-dihydro[1,2,4]triazol-3-one (prepared according to WO 95/14009) and 7.83 g of N-bromosuccinimide are placed in 50 ml of carbon tetrachloride, and a catalytic amount of dibenzoyl peroxide is added. The suspension is then stirred under reflux with illumination (a 500 W photographic lamp) for 11/2 hours. The suspension is concentrated by evaporation and the residue is chromatographed directly on silica gel using hexane/ethyl acetate (6:4). Recrystallization from toluene/heptane (1:1) gives 4-(2-bromomethylphenyl)-5-chloro-2-methyl-2,4-dihydro[1,2,4]triazol-3-one as white crystals of m.p. 131.5-133° C.
Reaction SMILES: C(O[C:6]([N:8]1[C@:12]2([CH2:16][CH2:15][N:14]([C@H:17]([C:19]([O:21][CH3:22])=[O:20])[CH3:18])[C:13]2=[O:23])[CH2:11][CH2:10][CH2:9]1)=O)(C)(C)C.O1CCOCC1.Cl.C(N(C(C)C)CC)(C)C.BrC[CH:42]=[CH:43][CH2:44][OH:45]>[I-].C([N+](CCCC)(CCCC)CCCC)CCC>[CH3:22][O:21][C:19](=[O:20])[CH:17]([N:14]1[CH2:15][CH2:16][C:12]2([N:8]([CH2:6][CH:42]=[CH:43][CH2:44][OH:45])[CH2:9][CH2:10][CH2:11]2)[C:13]1=[O:23])[CH3:18]
Reactant: OCC=CCBr
Reactant: COC(=O)[C@H](C)N1CC[C@@]2(CCCN2C(=O)OC(C)(C)C)C1=O
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: Cl
Agent: [I-]
Solvent: C1COCCO1
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)C(C)N1CCC2(CCCN2CC=CCO)C1=O

Procedure:
82 mg (0.25 mmol) (S,S)-7-(1-methoxycarbonyl-ethyl)-6-oxo-1,7-diaza-spiro[4.4]nonane-1-carboxylic acid tert-butyl ester are stirred at room temperature for three hours in 1 mL of a 4N HCl dioxane solution, evaporated, then taken up in toluene and evaporated again (twice). The residue is taken up in 2 mL dichloromethane and stirred at room temperature for 65 hours in the presence of 74 mg (0.2 mmol) tetrabutylammonium iodide, 0.035 mL (0.2 mmol) diisopropylethylamine and 30 mg (0.2 mmol) 4-bromo-but-2-en-1-ol. The reaction mixture is extracted with EtOAc and saturated aqueous sodium bicarbonate, the combined organic phases washed with brine, evaporated to dryness and the residue column chromatographed (silica gel, EtOAc/EtOH 9:1) to yield the desired product as a thick liquid.