Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([C:11]2[C:12]([S:22][CH3:23])=[N:13][N:14]3[C:19](Cl)=[CH:18][C:17]([CH3:21])=[N:16][C:15]=23)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[NH3:24]>CO>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([C:11]2[C:12]([S:22][CH3:23])=[N:13][N:14]3[C:19]([NH2:24])=[CH:18][C:17]([CH3:21])=[N:16][C:15]=23)(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: N
Reactant: CSc1nn2c(Cl)cc(C)nc2c1S(=O)(=O)c1ccc(Br)cc1
Solvent: CO
Product: CSc1nn2c(N)cc(C)nc2c1S(=O)(=O)c1ccc(Br)cc1

Procedure:
In an analogous manner to that described in Example 4, from 3-(4-bromo-benzenesulphonyl)-7-chloro-5-methyl-2-methylsulphanyl-pyrazolo[1,5-a]pyrimidine and NH3 in MeOH there was obtained 3-(4-bromo-benzenesulphonyl)-5-methyl-2-methylsulphanyl-pyrazolo[1,5-a]pyrimidin-7-ylamine as colorless crystals, m.p.>230°.
Reaction SMILES: [CH2:1]([N:8]([CH2:12][Si](C)(C)C)[CH2:9]OC)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:17]1(=[O:22])[CH2:21][CH2:20][CH:19]=[CH:18]1.FC(F)(F)C(O)=O>C(Cl)Cl>[CH2:1]([N:8]1[CH2:9][C@@H:19]2[CH2:20][CH2:21][C:17](=[O:22])[C@@H:18]2[CH2:12]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COCN(Cc1ccccc1)C[Si](C)(C)C
Reactant: O=C1C=CCC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C1CC[C@H]2CN(Cc3ccccc3)C[C@@H]12
Temperature: 0 °C
Reaction time: 4 h
Yield: 84 %

Procedure:
A round bottom flask purged with argon was charged with N-benzyl-1-methoxy-N-(trimethylsilylmethyl)methanamine (31.2 g, 131.4 mmol) and cyclopent-2-ene-1-one (9.0 g, 9.2 mL, 109.5 mmol). The reaction mixture was cooled to 0° C. and a solution of trifluoroacetic acid (1.25 g, 847 μL, 11.0 mmol) in DCM (11 mL) was added to it. The reaction mixture was stirred at 0° C. for 4 h, warmed to room temperature and stirred for 18 h. The reaction was quenched by the addition of saturated sodium bicarbonate and the layers were separated. The aqueous layer was extracted with DCM and the combined organic layers was washed with brine, dried over sodium sulfate and concentrated under reduced pressure. The crude material was purified via silica gel column chromatography using 40 to 80% EtOAc in hexanes to obtain (3aR,6aS)-2-benzyl-1,3,3a,4,5,6a-hexahydrocyclopenta[c]pyrrol-6-one (19.8 g, 84%) as a light yellow oil.
Reaction SMILES: [C:1](CC(O)CCN)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[N+:14]([C:17]1[CH:22]=[CH:21][C:20]([F:23])=[CH:19][C:18]=1[OH:24])([O-:16])=[O:15]>>[F:23][C:20]1[CH:21]=[CH:22][C:17]([N+:14]([O-:16])=[O:15])=[C:18]([CH:19]=1)[O:24][CH:18]([CH2:19][CH3:20])[CH2:17][NH:14][C:1](=[O:2])[O:3][C:4]([CH3:5])([CH3:6])[CH3:7]
Reactant: CC(C)(C)OC(=O)CC(O)CCN
Reactant: O=[N+]([O-])c1ccc(F)cc1O
Product: CCC(CNC(=O)OC(C)(C)C)Oc1cc(F)ccc1[N+](=O)[O-]

Procedure:
Prepared analogously to example I-1 using BOC-4-amino-2-butanol and 2-nitro-5-fluorophenol.
Reaction SMILES: [NH2:1][C:2]1[NH:3][C:4](=[O:25])[C:5]([N+:22]([O-:24])=[O:23])=[C:6]([C:8]([C:20]#[N:21])([CH2:14][C:15]2[O:16][CH:17]=[CH:18][CH:19]=2)C(OCC)=O)[N:7]=1.Cl>[OH-].[Na+]>[NH2:1][C:2]1[NH:3][C:4](=[O:25])[C:5]([N+:22]([O-:24])=[O:23])=[C:6]([CH:8]([CH2:14][C:15]2[O:16][CH:17]=[CH:18][CH:19]=2)[C:20]#[N:21])[N:7]=1
Reactant: CCOC(=O)C(C#N)(Cc1ccco1)c1nc(N)[nH]c(=O)c1[N+](=O)[O-]
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: N#CC(Cc1ccco1)c1nc(N)[nH]c(=O)c1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 0.03 h
Yield: 76.2 %

Procedure:
A solution of 2-Amino-α-cyano-α-(2-furanyl-methyl)-1,6-dihydro-5-nitro-6-oxo-4-pyrimidineacetic acid, ethyl ester (5.0 g) in 1N NaOH (200 mL) is stirred at room temperature for 2 h. The reaction mixture is acidified (pH 1) by the dropwise addition of conc HCl and is stirred at room temperature for 2 min. The precipitate is collected by filtration, washed with water, and dried to give 2-Amino-α-(2-Furanylmethyl)-1, 6-dihydro-5-nitro-6-oxo-4-pyrimidineacetonitrile (3.02 g 73%). ##STR22##
Reaction SMILES: [CH3:1][O:2][C:3](=[O:26])[C:4]1[CH:9]=[C:8]([N:10]2[CH:14]=[C:13]([C:15]([F:18])([F:17])[F:16])[N:12]=[CH:11]2)[C:7]([C:19]([F:22])([F:21])[F:20])=[CH:6][C:5]=1[N+:23]([O-])=O>CO.[Pd]>[CH3:1][O:2][C:3](=[O:26])[C:4]1[CH:9]=[C:8]([N:10]2[CH:14]=[C:13]([C:15]([F:16])([F:17])[F:18])[N:12]=[CH:11]2)[C:7]([C:19]([F:20])([F:21])[F:22])=[CH:6][C:5]=1[NH2:23]
Reactant: COC(=O)c1cc(-n2cnc(C(F)(F)F)c2)c(C(F)(F)F)cc1[N+](=O)[O-]
Agent: [Pd]
Solvent: CO
Product: COC(=O)c1cc(-n2cnc(C(F)(F)F)c2)c(C(F)(F)F)cc1N
Yield: 91.5 %

Procedure:
In a similar way a solution of 5-(4-trifluoromethyl-imidazol-1-yl)-2-nitro-4-trifluoromethyl-benzoic acid methyl ester (1.0 g, 2.6 mmol) in 100 ml methanol is hydrogenated over 55 mg of 10% palladium on charcoal to obtain after the usual workup procedure 840 mg (2.38 mmol, 91%) of amorphous 2-amino-5-(4-trifluoromethyl-imidazol-1 -yl)-4-trifluoromethyl-benzoic acid methyl ester, ES-MS: m/z 354 [M+H]+.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2([NH:11][C:12](=[O:22])[O:13][CH:14]3[CH:19]4[CH2:20][CH2:21][N:16]([CH2:17][CH2:18]4)[CH2:15]3)[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[CH3:23][O:24][C:25]1[CH:30]=[CH:29][C:28](B(O)O)=[CH:27][CH:26]=1>CC([O-])=O.CC([O-])=O.[Pd+2]>[N:16]12[CH2:21][CH2:20][CH:19]([CH2:18][CH2:17]1)[CH:14]([O:13][C:12](=[O:22])[NH:11][C:8]1([C:5]3[CH:6]=[CH:7][C:2]([C:28]4[CH:29]=[CH:30][C:25]([O:24][CH3:23])=[CH:26][CH:27]=4)=[CH:3][CH:4]=3)[CH2:10][CH2:9]1)[CH2:15]2
Reactant: O=C(NC1(c2ccc(Br)cc2)CC1)OC1CN2CCC1CC2
Reactant: COc1ccc(B(O)O)cc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Product: COc1ccc(-c2ccc(C3(NC(=O)OC4CN5CCC4CC5)CC3)cc2)cc1
Yield: 0.1 %

Procedure:
Using general procedure E, quinuclidin-3-yl 1-(4-bromophenyl)cyclopropylcarbamate (0.485 g, 1.33 mmol), 4-methoxyphenyl boronic acid (0.404 g, 2.66 mmol) and Pd(OAc)2 (0.016 g, 0.071 mmol) gave the title compound as a grey solid (0.337 mg, 65%). 1H NMR (CDCl3) δ 7.48 (dd, J=8.6, 5.5 Hz, 4H), 7.29 (d, J=7.6 Hz, 2H), 6.96 (d, J=8.8 Hz, 2H), 5.58 (d, J=48.7 Hz, 1H), 4.83-4.63 (m, 1H), 3.84 (s, 3H), 3.20 (dd, J=24.0, 15.5 Hz, 1H), 2.97-2.42 (m, 5H), 1.97 (d, J=30.9 Hz, 1H), 1.81 (s, 1H), 1.75-1.33 (m, 3H), 1.28 (d, J=6.8 Hz, 4H) ppm. 13C NMR major rotomer (CDCl3) δ 159.1, 156.0, 141.4, 139.0, 133.4, 128.0, 126.7, 125.9, 114.2, 71.5, 55.7, 55.3, 47.4, 46.5, 35.3, 25.5, 24.6, 19.6, 17.8 ppm. Purity: LCMS >97.1% (214 nm & 254 nm): retention time 0.88 min: (M+1) 393.4.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([OH:9])[CH:5]=[CH:6][C:7]=1[CH3:8].C[O-].[Na+].CO.Br[CH:16]([C:21]1[CH:26]=[CH:25][C:24]([O:27][CH2:28][CH2:29][CH2:30][O:31][C:32]2[CH:37]=[CH:36][C:35]([Cl:38])=[CH:34][CH:33]=2)=[CH:23][CH:22]=1)[C:17]([O:19][CH3:20])=[O:18]>C1C=CC=CC=1>[CH3:20][O:19][C:17](=[O:18])[CH:16]([O:9][C:4]1[CH:5]=[CH:6][C:7]([CH3:8])=[C:2]([CH3:1])[CH:3]=1)[C:21]1[CH:22]=[CH:23][C:24]([O:27][CH2:28][CH2:29][CH2:30][O:31][C:32]2[CH:33]=[CH:34][C:35]([Cl:38])=[CH:36][CH:37]=2)=[CH:25][CH:26]=1
Reactant: Cc1ccc(O)cc1C
Reactant: COC(=O)C(Br)c1ccc(OCCCOc2ccc(Cl)cc2)cc1
Agent: C[O-]
Agent: [Na+]
Solvent: c1ccccc1
Solvent: CO
Product: COC(=O)C(Oc1ccc(C)c(C)c1)c1ccc(OCCCOc2ccc(Cl)cc2)cc1

Procedure:
To a mixture of 3.05 g of 3,4-dimethylphenol, 1.19 g of sodium methoxide, 40 ml of methanol and 10 ml of benzene is added 8.27 g of methyl bromo{p-[3-(p-chlorophenoxy)propoxy]phenyl}acetate. The mixture is refluxed for 24 hours and the solvent removed under reduced pressure. The residue is chromatographed over silica gel with dichloromethane as eluent. The product is obtained as a viscous oil.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([C:8](=[O:10])[CH3:9])=[C:5]([CH3:7])[N:6]=1.C1N=C[N:13]([C:16](N2C=NC=C2)=[O:17])C=1.N>CN(C=O)C.O1CCOCC1>[C:8]([C:4]1[S:3][C:2]([NH:1][C:16]([NH2:13])=[O:17])=[N:6][C:5]=1[CH3:7])(=[O:10])[CH3:9]
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: CC(=O)c1sc(N)nc1C
Agent: N
Solvent: CN(C)C=O
Solvent: C1COCCO1
Product: CC(=O)c1sc(NC(N)=O)nc1C
Temperature: 25 °C
Reaction time: 3 h
Yield: 39.2 %

Procedure:
2-Amino-4-methyl-5-acetylthiazole (3 g, 19.2 mmol) is dissolved in DMF (30 mL). CDI (3.5 g, 21.1 mmol) is added and the mixture is stirred at RT for 3 h. Ammonia 0.5 N in dioxane is added (60 mL, 30 mmol) is added and the mixture is stirred for 2 days in a closed system. The resulting precipitate is recovered by filtration, washed with petroleum ether and dried under vacuo, affording N-(5-acetyl-4-methyl-1,3-thiazol-2-yl)urea as colorless solid (1.5 g, 39%).
Reaction SMILES: [OH:1][C@H:2]1[CH2:7][CH2:6][C@H:5]([C:8]([OH:10])=[O:9])[CH2:4][CH2:3]1.[H-].[Na+].Cl[C:14]1[CH:23]=[N:22][C:21]2[C:16](=[CH:17][C:18]([O:26][CH3:27])=[C:19]([O:24][CH3:25])[CH:20]=2)[N:15]=1>C1COCC1.CN(C=O)C>[CH3:25][O:24][C:19]1[CH:20]=[C:21]2[C:16](=[CH:17][C:18]=1[O:26][CH3:27])[N:15]=[C:14]([O:1][C@H:2]1[CH2:7][CH2:6][C@H:5]([C:8]([OH:10])=[O:9])[CH2:4][CH2:3]1)[CH:23]=[N:22]2
Reactant: COc1cc2ncc(Cl)nc2cc1OC
Reactant: O=C(O)[C@H]1CC[C@H](O)CC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: COc1cc2ncc(O[C@H]3CC[C@H](C(=O)O)CC3)nc2cc1OC

Procedure:
A mixture of cis/trans-4-hydroxy-cyclohexanecarboxylic acid (144 mg, 1 mmol) and NaH (60%, 160 mg, 4 mmol) in anhydrous THF/DMF(10 mL/2 mL) is refluxed for one hour before addition of 2-chloro-6,7-dimethoxyquinoxaline (225 mg, 1 mmol). The resulting mixture is continued to refluxed for four hours. The reaction mixture is neutralized to pH 5 and extracted with ethyl acetate (2×50 mL). The combined organic solutions are dried over magnesium sulfate and filtered. The residue after concentration is chromatographed on silica gel (ethyl acetate, followed by methanol) to provide the desired product as a white solid (m.p. 90-93° C.). Anal. Calcd. for C17H20N2O5.0.5 H2O: C, 59.89; H, 6.19; N, 8.22; Found: C, 59.91; H, 6.62; N, 7.90.
Reaction SMILES: [CH3:1][O:2][C:3]([N:5]1[C@@H:13]2[C@@H:8]([C@@:9]([OH:23])([C:14]#[C:15][C:16]3[CH:17]=[C:18]([CH3:22])[CH:19]=[CH:20][CH:21]=3)[CH2:10][CH2:11][CH2:12]2)[CH2:7][CH2:6]1)=[O:4].[C:24](O)(=[O:35])[CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH3:34]>>[CH3:1][O:2][C:3]([N:5]1[C@H:13]2[C@H:8]([C@@:9]([C:14]#[C:15][C:16]3[CH:17]=[C:18]([CH3:22])[CH:19]=[CH:20][CH:21]=3)([O:23][C:24](=[O:35])[CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH3:34])[CH2:10][CH2:11][CH2:12]2)[CH2:7][CH2:6]1)=[O:4]
Reactant: CCCCCCCCCCC(=O)O
Reactant: COC(=O)N1CC[C@H]2[C@@H]1CCC[C@]2(O)C#Cc1cccc(C)c1
Product: CCCCCCCCCCC(=O)O[C@@]1(C#Cc2cccc(C)c2)CCC[C@@H]2[C@H]1CCN2C(=O)OC

Procedure:
Synthesis in analogy to the General Method 1 starting from (3aS,4R,7aS)-4-hydroxy-4-m-tolylethynyl-octahydro-indole-1-carboxylic acid methyl ester and undecanoic acid to yield (3aR,4S,7aR)-4-m-tolylethynyl-4-undecanoyloxy-octahydro-indole-1-carboxylic acid methyl ester. MS [M+H]=296 (ester elimination ion); RT=1.77 min; UPLC Method I
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH2:4][CH2:5][C:6](=[O:12])[CH2:7]2.[CH3:13][N:14](C=O)C>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-]#N.[Zn+2].[C-]#N>[O:12]=[C:6]1[CH2:5][CH2:4][C:3]2[CH:2]=[C:11]([C:13]#[N:14])[CH:10]=[CH:9][C:8]=2[CH2:7]1
Reactant: O=C1CCc2c(Br)cccc2C1
Reactant: CN(C)C=O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [C-]#N
Agent: [Zn+2]
Product: N#Cc1ccc2c(c1)CCC(=O)C2

Procedure:
The 5-bromo-2 tetralone (2.0 g, 8.9 mmol), tetrakis(triphenylphosphine)palladium (0.62 g, 0.53 mmol) and zinc cyanide (0.73 g, 6.2 mmol) were added to 4 ml DMF in a 20 ml microwave tube. The mixture was degassed and microwaved at 80° C. for 30 mins. TLC showed no starting material left and the mixture was diluted with ethyl acetate and washed with ammonium hydroxide (2M, ×4 ml). The organic layer was separated and dried over Na2SO4 then filtered. The solvent was evaporated under reduced pressure. The residue was chromatographed through 40 gm Isco Redi-sep column and eluted with 0-30% ethyl acetate-hexane to yield 6-oxo-5,6,7,8-tetrahydronaphthalene-2-carbonitrile.
Reaction SMILES: [CH3:1][N:2]1[C:10]2[CH:9]=[CH:8][CH:7]=[C:6]([C:11](OC3C=CC=CC=3)=[O:12])[C:5]=2[C:4]2([C:31]3[C:22](=[CH:23][C:24]4[O:29][CH2:28][CH2:27][O:26][C:25]=4[CH:30]=3)[O:21][CH2:20]2)[C:3]1=[O:32].Cl.[CH:34]1([NH2:38])[CH2:37][CH2:36][CH2:35]1.C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[CH:34]1([NH:38][C:11]([C:6]2[C:5]3[C:4]4([C:31]5[C:22](=[CH:23][C:24]6[O:29][CH2:28][CH2:27][O:26][C:25]=6[CH:30]=5)[O:21][CH2:20]4)[C:3](=[O:32])[N:2]([CH3:1])[C:10]=3[CH:9]=[CH:8][CH:7]=2)=[O:12])[CH2:37][CH2:36][CH2:35]1
Reactant: CN1C(=O)C2(COc3cc4c(cc32)OCCO4)c2c(C(=O)Oc3ccccc3)cccc21
Reactant: NC1CCC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CN1C(=O)C2(COc3cc4c(cc32)OCCO4)c2c(C(=O)NC3CCC3)cccc21
Temperature: 110 °C
Yield: 15.8 %

Procedure:
Phenyl 1′-methyl-2′-oxo-1′,2,2′,3-tetrahydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indole]-4′-carboxylate (0.30 g, 0.70 mmol), cyclobutylamine hydrochloride (0.23 g, 2.1 mmol), potassium carbonate (0.39 g, 2.8 mmol) and N,N-dimethylformamide (3.0 mL) were added to a microwave reaction vessel. The reaction was heated at 110° C. for 1 h in a microwave reactor, allowed to cool to ambient temperature, poured into water (25 mL) and extracted with ethyl acetate (3×50 mL). The combined organic extracts were washed with 1 M hydrochloric acid (50 mL) and brine (50 mL), dried over magnesium sulfate, filtered and concentrated in vacuo. The residue was purified by column chromatography and eluted with a 20% to 100% gradient of ethyl acetate in hexanes followed by recrystallization from dichloromethane/diethyl ether to afford N-cyclobutyl-1′-methyl-2′-oxo-1′,2,2′,3-tetrahydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indole]-4′-carboxamide (0.045 g, 17%) as a colorless solid: mp 128-129° C. (dichloromethane/diethyl ether); 1H NMR (300 MHz, CDCl3) δ 7.41-7.33 (m, 1H), 7.26-7.21 (m, 1H), 6.97-6.93 (m, 1H), 6.51 (s, 1H), 6.20 (s, 1H), 5.46 (d, J=6.65 Hz, 1H), 4.96-4.81 (m, 2H), 4.35-4.01 (m, 5H), 3.25 (s, 3H), 2.27-2.09 (m, 2H), 1.70-1.40 (m, 4H); MS (ES+) m/z 407.0 (M+1). N,N,1′-trimethyl-2′-oxo-1′,2,2′,3-tetrahydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indole]-4′-carboxamide (0.12 g, 37%) was isolated as a byproduct from the synthesis of N-cyclobutyl-1′-methyl-2′-oxo-1′,2,2′,3-tetrahydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indole]-4′-carboxamide, obtained as colorless solid: mp 218-221° C. (dichloromethane/diethyl ether); 1H NMR (300 MHz, CDCl3) δ 7.32 (dd, J=7.8, 7.8 Hz, 1H), 6.91-6.84 (m, 2H), 6.44 (s, 1H), 6.22 (s, 1H), 5.05 (d, J=8.8 Hz, 1H), 4.79 (d, J=8.8 Hz, 1H), 4.20-4.04 (m, 4H), 3.28 (s, 3H), 2.79 (s, 3H), 2.19 (s, 3H); MS (ES+) m/z 381.0 (M+1).
Reaction SMILES: [C:1]([NH:8][CH2:9][CH:10]([CH3:14])[C:11]([OH:13])=[O:12])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[CH3:15]CCCC>C1COCC1>[CH3:15][N:8]([C:1]([O:3][C:4]([CH3:6])([CH3:7])[CH3:5])=[O:2])[CH2:9][C@@H:10]([CH3:14])[C:11]([OH:13])=[O:12]
Reactant: CCCCC
Reactant: CC(CNC(=O)OC(C)(C)C)C(=O)O
Solvent: C1CCOC1
Product: C[C@H](CN(C)C(=O)OC(C)(C)C)C(=O)O
Reaction time: 8 h

Procedure:
To a solution of N-Boc-α-(R,S)-methyl-β-alanine (1.33 g, 6.5 mmol) in THF (80 ml)was added pentane washed sodium hydride(1.2 g, 60% in oil dispersion) followed by methyl iodide (2 ml, exess). The reaction mixture was stirred overnight and then poured into an iced solution of citric acid (0.5N). The aqueous THF solution was extracted into ethyl acetate. Then the required acid was back extracted between ethyl acetate, sodium hydrogen carbonate and potassium hydrogen sulphate solutions. The organic extracts were dried (MgSO4) and evaporated to afford the title compound. (1.00 g, 71%), Anal: C10H19NO4.0.3H2O, Calc: C, 53.94; H, 8.87; N, 6.29. Found, C, 54.02; H, 8.56; N, 6.63.
Reaction SMILES: [Cl:1][C:2]1[CH:25]=[CH:24][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12](/[CH:16]=[C:17]4/[C:18](=[O:23])[NH:19][C:20](=[O:22])[S:21]/4)=[CH:13][CH:14]=3)[CH:9]=[N:8]2)=[C:4]([C:26]([F:29])([F:28])[F:27])[CH:3]=1.Br.Br[CH2:32][CH2:33][N:34]1[CH2:38][CH2:37][CH2:36][CH2:35]1>>[Cl:1][C:2]1[CH:25]=[CH:24][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12](/[CH:16]=[C:17]4/[C:18](=[O:23])[N:19]([CH2:32][CH2:33][N:34]5[CH2:38][CH2:37][CH2:36][CH2:35]5)[C:20](=[O:22])[S:21]/4)=[CH:13][CH:14]=3)[CH:9]=[N:8]2)=[C:4]([C:26]([F:27])([F:29])[F:28])[CH:3]=1
Reactant: O=C1NC(=O)/C(=C/c2ccc3c(cnn3Cc3ccc(Cl)cc3C(F)(F)F)c2)S1
Reactant: BrCCN1CCCC1
Agent: Br
Product: O=C1S/C(=C\c2ccc3c(cnn3Cc3ccc(Cl)cc3C(F)(F)F)c2)C(=O)N1CCN1CCCC1

Procedure:
(5Z)-5-({1-[4-Chloro-2-(trifluoromethyl)benzyl]-1H-indazol-5-yl}methylidene)-3-(2-pyrrolidin-1-ylethyl)-1,3-thiazolidine-2,4-dione was prepared from [(5Z)-5-({1-[4-chloro-2-(trifluoromethyl)benzyl]-1H-indazol-5-yl}methylidene)-2,4-dioxo-1,3-thiazolidine (from Example 1) and 1-(2-bromoethyl)pyrrolidine hydrobromide following General Procedure H.
Reaction SMILES: [NH2:1][C:2]1[NH:6][N:5]=[C:4]([CH3:7])[C:3]=1[C:8]1[S:9][C:10]2[CH:16]=[C:15]([S:17](Cl)(=[O:19])=[O:18])[CH:14]=[CH:13][C:11]=2[N:12]=1.[NH2:21][CH2:22][C:23]1[CH:28]=[CH:27][C:26]([NH2:29])=[CH:25][CH:24]=1.CN1CCOCC1>CO>[NH2:29][C:26]1[CH:27]=[CH:28][C:23]([CH2:22][NH:21][S:17]([C:15]2[CH:14]=[CH:13][C:11]3[N:12]=[C:8]([C:3]4[C:4]([CH3:7])=[N:5][NH:6][C:2]=4[NH2:1])[S:9][C:10]=3[CH:16]=2)(=[O:19])=[O:18])=[CH:24][CH:25]=1
Reactant: NCc1ccc(N)cc1
Reactant: Cc1n[nH]c(N)c1-c1nc2ccc(S(=O)(=O)Cl)cc2s1
Solvent: CO
Solvent: CN1CCOCC1
Product: Cc1n[nH]c(N)c1-c1nc2ccc(S(=O)(=O)NCc3ccc(N)cc3)cc2s1
Yield: 12.1 %

Procedure:
the title compound (15 mg) was prepared from crude 2-(5-amino-3-methyl-1H-pyrazol-4-yl)-benzothiazole-6-sulfonyl chloride (100 mg, 0.30 mmol), 4-aminomethylphenylamine (69 μL, 0.60 mmol) and PS-NMM (0.320 g, 0.60 mmol) in 5 mL of methanol. MS (m/z, ES+): 415.4 (M+1, 100%). Yield=12%.
Reaction SMILES: [CH:1]1([N:7]2[C:12]([OH:13])=[C:11]([C:14]([NH:16][CH2:17][C:18]([O:20]CC)=[O:19])=[O:15])[C:10](=[O:23])[NH:9][C:8]2=[O:24])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(=O)([O-])[O-].[K+].[K+].[F:31][C:32]([F:46])([F:45])[C:33]1[CH:40]=[C:39]([C:41]([F:44])([F:43])[F:42])[CH:38]=[CH:37][C:34]=1[CH2:35]Br.Cl>CC(N(C)C)=O>[F:31][C:32]([F:45])([F:46])[C:33]1[CH:40]=[C:39]([C:41]([F:42])([F:43])[F:44])[CH:38]=[CH:37][C:34]=1[CH2:35][N:9]1[C:10](=[O:23])[C:11]([C:14]([NH:16][CH2:17][C:18]([OH:20])=[O:19])=[O:15])=[C:12]([OH:13])[N:7]([CH:1]2[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]2)[C:8]1=[O:24]
Reactant: FC(F)(F)c1ccc(CBr)c(C(F)(F)F)c1
Reactant: CCOC(=O)CNC(=O)c1c(O)n(C2CCCCC2)c(=O)[nH]c1=O
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Product: O=C(O)CNC(=O)c1c(O)n(C2CCCCC2)c(=O)n(Cc2ccc(C(F)(F)F)cc2C(F)(F)F)c1=O
Reaction time: 8 h
Yield: 33.5 %

Procedure:
A mixture of ethyl N-[(1-cyclohexyl-6-hydroxy-2,4-dioxo-1,2,3,4-tetrahydro-5-pyrimidinyl)carbonyl]glycinate (340 mg, 1.0 mmoles), pulv. potassium carbonate (750 mg, 5.35 mmoles) and 2,4-bis(trifluoromethyl)benzyl bromide (375 uL, 2.0 mmoles) in dimethylacetamide (6 mL) was vigorously stirred at 100° C. for 3 hours. The mixture was poured into 1 molar hydrochloric acid and extracted with ethyl acetate (×2). The combined organic solutions were washed with 1 molar hydrochloric acid and evaporated. The residue was purified by flash chromatography (10-50% ethyl acetate in hexane), the required fractions evaporated, dissolved in ethanol (5 mL) and 1 molar sodium hydroxide solution (3.0 mL) added. The mixture was stirred overnight, acidified and extracted with ethyl acetate (×2), the combined extracts washed with 1 molar hydrochloric acid, dried and evaporated. Recrystallization from acetic acid-water gave the title compound (180 mg, 34%). 1H NMR (400 MHz, DMSO-d6) δ ppm 13.11 (br. s., 1 H), 8.06 (s, 1 H), 7.98 (d, J=8.59 Hz, 1 H), 7.53 (d, J=8.34 Hz, 1 H), 5.23 (s, 2 H), 4.64 (t, J=12.00 Hz, 1 H), 4.13 (d, J=5.56 Hz, 2 H), 2.24 (q, 2 H), 1.78 (d, J=12.63 Hz, 2 H), 1.52-1.73 (m, 3 H), 1.28 (q, J=13.05 Hz, 2 H), 1.10 (q, 1 H).
Reaction SMILES: [CH:1]1([NH2:4])[CH2:3][CH2:2]1.[C:5]([C:7]1[CH:8]=[CH:9][C:10]([OH:17])=[C:11]([CH:16]=1)[C:12](OC)=[O:13])#[N:6]>CS(C)=O.O>[CH:1]1([NH:4][C:12](=[O:13])[C:11]2[CH:16]=[C:7]([C:5]#[N:6])[CH:8]=[CH:9][C:10]=2[OH:17])[CH2:3][CH2:2]1
Reactant: NC1CC1
Reactant: COC(=O)c1cc(C#N)ccc1O
Solvent: O
Solvent: CS(C)=O
Product: N#Cc1ccc(O)c(C(=O)NC2CC2)c1
Temperature: 80 °C

Procedure:
Cyclopropyl amine (14.3 g) and Na (100 mg) were added to a solution of methyl 5-cyano-2-hydroxybenzoate (10.0 g; from step (b) above) in DMSO (40 mL). The reaction mixture was heated at 80° C. in a sealed steel vessel overnight, diluted with H2O, acidified and extracted with EtOAc giving the sub-title compound (11.0 g), after concentration of the organic layer.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:12](=[CH:13][CH:14]=1)[NH:11][C:10]1[CH:9]([NH2:15])[CH2:8][CH2:7][CH2:6][C:5]2=1.Cl[C:17]1[N:22]=[CH:21][C:20]([C:23]([F:26])([F:25])[F:24])=[CH:19][N:18]=1>>[Br:1][C:2]1[CH:3]=[C:4]2[C:12](=[CH:13][CH:14]=1)[NH:11][C:10]1[CH:9]([NH:15][C:17]3[N:22]=[CH:21][C:20]([C:23]([F:26])([F:25])[F:24])=[CH:19][N:18]=3)[CH2:8][CH2:7][CH2:6][C:5]2=1
Reactant: FC(F)(F)c1cnc(Cl)nc1
Reactant: NC1CCCc2c1[nH]c1ccc(Br)cc21
Product: FC(F)(F)c1cnc(NC2CCCc3c2[nH]c2ccc(Br)cc32)nc1

Procedure:
6-Bromo-N-[5-(trifluoromethyl)pyrimidin-2-yl]-2,3,4,9-tetrahydro-1H-carbazol-1-amine was prepared from 6-bromo-2,3,4,9-tetrahydro-1H-carbazol-1-amine (75 mg, 0.28 mmol) and 2-chloro-5-(trifluoromethyl)-pyrimidine (0.5 mL) in a similar manner as described in Example 22 to give 5 mg (4%) of a yellow solid. 1H-NMR (DMSO-d6) taken at 80° C.: δ 10.94-10.88 (m, 1H), 8.69-8.62 (m, 1H), 8.30-8.24 (m, 1H), 7.55 (s, 1H), 7.21 (d, 1H), 7.13-7.10 (m, 1H), 7.02 (d, 1H), 5.40-5.27 (m, 1H), 2.62-2.58 (m, 2H), 2.08-1.96 (m, 2H), 1.87-1.76 (m, 2H); MS m/z (M−1) 409, 411.
Reaction SMILES: [CH2:1]([O:8][CH2:9][C@@H:10]1[O:15][CH2:14][C@@:13]([NH:25][C:26]([NH:28][C:29](=[O:36])[C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)=[S:27])([C:16]2[CH:21]=[C:20]([Br:22])[C:19]([F:23])=[CH:18][C:17]=2[F:24])[C@H:12]([CH2:37]O)[CH2:11]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.N1C=CC=CC=1.FC(F)(F)S(OS(C(F)(F)F)(=O)=O)(=O)=O>ClCCl>[CH2:1]([O:8][CH2:9][C@@H:10]1[O:15][CH2:14][C:13]2([C:16]3[CH:21]=[C:20]([Br:22])[C:19]([F:23])=[CH:18][C:17]=3[F:24])[N:25]=[C:26]([NH:28][C:29](=[O:36])[C:30]3[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=3)[S:27][CH2:37][CH:12]2[CH2:11]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(NC(=S)N[C@@]1(c2cc(Br)c(F)cc2F)CO[C@@H](COCc2ccccc2)C[C@H]1CO)c1ccccc1
Agent: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Solvent: ClCCl
Solvent: c1ccncc1
Product: O=C(NC1=NC2(c3cc(Br)c(F)cc3F)CO[C@@H](COCc3ccccc3)CC2CS1)c1ccccc1
Temperature: 0 °C
Reaction time: 3.5 h

Procedure:
A solution of C8 (0.964 g, 1.59 mmol) and pyridine (0.487 ml, 6.05 mmol) in dichloromethane (27.0 mL) was cooled to −50° C. internal temperature. Trifluoromethanesulfonic anhydride (0.535 mL, 3.18 mmol) was added drop-wise to the solution and the mixture was gradually warmed to 0° C. and allowed to stir at that temperature for 3.5 hours. The reaction mixture was partitioned between dichloromethane (250 mL) and water (250 mL). The organic layer was removed and washed with water (2×300 mL) and brine (1×250 mL), then dried over magnesium sulfate, filtered and concentrated in vacuo Silica gel chromatography (Gradient 0% to 50% ethyl acetate in heptane) provided the product as a white solid. Yield: 822 mg, 1.40 mmol, 88%. LCMS m/z 589.6 [M+H+], Br isotopic pattern. 1H NMR (400 MHz, CD3OD), characteristic peaks: δ 8.05-8.16 (m, 2H), 7.62 (t, J=7.9 Hz, 1H), 7.61-7.67 (m, 1H), 7.42-7.49 (m, 2H), 7.28-7.33 (m, 2H), 7.16-7.25 (m, 3H), 4.58 (d, J=11.7 Hz, 1H), 4.52 (d, J=11.7 Hz, 1H), 4.07 (dd, J=11.9, 1.6 Hz, 1H), 3.89 (br d, J=11.9 Hz, 2H), 3.54-3.62 (m, 2H), 3.11-3.18 (m, 1H), 2.96 (dd, J=13.2, 4.2 Hz, 1H), 2.74 (dd, J=13.2, 2.8 Hz, 1H), 1.88-1.98 (m, 1H), 1.69 (d, J=11.7 Hz, 1H).