Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][NH:2][C:3]([CH:5]1[C:17]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[C:11]2[C:6]1=[CH:7][CH:8]=[CH:9][CH:10]=2)=[O:4].[C:18](#[N:21])[CH:19]=[CH2:20]>O1CCCC1>[C:18]([CH2:19][CH2:20][C:5]1([C:3](=[O:4])[NH:2][CH3:1])[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:11]=2[C:12]2[C:17]1=[CH:16][CH:15]=[CH:14][CH:13]=2)#[N:21]
Reactant: CNC(=O)C1c2ccccc2-c2ccccc21
Reactant: C=CC#N
Solvent: C1CCOC1
Product: CNC(=O)C1(CCC#N)c2ccccc2-c2ccccc21

Procedure:
A 36.8 g. portion of 9-(N-methylcarbamoyl)fluorene was reacted with 10.6 g. of acrylonitrile in the presence of 10 g. of Triton B in tetrahydrofuran as described in Example 4. The reaction mixture was then concentrated under vacuum to a semi-solid, which was added to ice-water/ethyl acetate. The organic layer was separated, washed with water, and dried over sodium sulfate. The solution was evaporated to dryness to obtain 45.8 g. of crude product, which was crystallized from ethyl acetate/hexane to obtain 30 g. of the desired product, m.p. 185°-187°. Infrared analysis of the product showed a carbonyl band at 1685 cm-1 and a nitrile band at 2270 cm-1.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([N+:8]([O-])=O)[CH:5]=[C:4]([CH3:11])[C:3]=1[N:12]=[C:13]1[NH:17][CH2:16][CH2:15][NH:14]1.[ClH:18]>C(O)C.[Fe]>[ClH:18].[ClH:18].[NH2:8][C:6]1[CH:5]=[C:4]([CH3:11])[C:3]([N:12]=[C:13]2[NH:14][CH2:15][CH2:16][NH:17]2)=[C:2]([CH3:1])[CH:7]=1
Reactant: Cc1cc([N+](=O)[O-])cc(C)c1N=C1NCCN1
Agent: [Fe]
Agent: Cl
Solvent: CCO
Product: Cc1cc(N)cc(C)c1N=C1NCCN1

Procedure:
The 2-(2,6-dimethyl-4-nitrophenylimino)imidazolidine (8.75 g) was reduced with iron and hydrochloric acid in aqueous ethanol according to the process of Example 12. The product was chromatographed on a silica column and eluted with a methanol in methylene chloride gradient. The fractions containing the required compound were evaporated and the residue was treated with ethanolic hydrochloric acid to give 2-(4-amino-2,6-dimethylphenylimino)imidazolidine dihydrochloride. An analytical sample was recrystallised as the mono-hydro-iodine salt, mp 252°-253° C.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]([NH:16][C:17]2[CH:22]=[N:21][CH:20]=[CH:19][N:18]=2)[S:5][C:6]=1[C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([N+:13]([O-])=O)[CH:8]=1>C(OCC)(=O)C.C1COCC1.[Pd]>[NH2:13][C:9]1[CH:8]=[C:7]([C:6]2[S:5][C:4]([NH:16][C:17]3[CH:22]=[N:21][CH:20]=[CH:19][N:18]=3)=[N:3][C:2]=2[CH3:1])[CH:12]=[CH:11][CH:10]=1
Reactant: Cc1nc(Nc2cnccn2)sc1-c1cccc([N+](=O)[O-])c1
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: Cc1nc(Nc2cnccn2)sc1-c1cccc(N)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 36.4 %

Procedure:
[4-Methyl-5-(3-nitro-phenyl)-thiazol-2-yl]-pyrazin-2-yl-amine (42b) (1.079 g, 3.4 mmol) is dissolved in ethyl acetate/THF (5/1, 240 ml) and stirred at room temperature under an atmosphere of argon. The solution is then treated with 10% Pd/C (1.1 g). The reaction mixture is purged three times with nitrogen and placed under an atmosphere of hydrogen overnight. The mixture is then filtered through celite and the catalyst is washed with THF (200 ml). The solvent is removed in vacuo to leave [5-(3-amino-phenyl)-4-methyl-thiazol-2-yl]-pyrazin-2-yl-amine (0.351 g, 36%). MH+ (ESMS):283.5
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH:18]=[CH:19][CH:20]=1)[CH2:6][O:7][C:8]1[CH:9]=[C:10]([CH:15]=[CH:16][CH:17]=1)[C:11]([O:13][CH3:14])=O)#[N:2].COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:30])=CC=1>C1(C)C(C)=CC=CC=1>[C:1]([C:3]1[CH:4]=[C:5]([CH:18]=[CH:19][CH:20]=1)[CH2:6][O:7][C:8]1[CH:9]=[C:10]([CH:15]=[CH:16][CH:17]=1)[C:11]([O:13][CH3:14])=[S:30])#[N:2]
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: COC(=O)c1cccc(OCc2cccc(C#N)c2)c1
Solvent: Cc1ccccc1C
Product: COC(=S)c1cccc(OCc2cccc(C#N)c2)c1
Yield: 80.5 %

Procedure:
In an analogous manner to that described in Example 1(B). 8.9 g (33.3 mmol) of methyl 3-[(3-cyanobenzyl)oxy]benzoate were heated to reflux for 17 hours with 13.5 g (33.4 mmol) of Lawesson reagent in xylene and thereafter chromatographed on silica gel. Elution with an 8:2 and 7:3 mixture of hexane and methylene chloride yielded 7.6 g (65.8%) of O-methyl 3-[(3-cyanobenzyl)oxy]thiobenzoate as a yellow oil which gradually crystallized upon standing.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]2[CH:18]=[C:17]3[C:12]([C:13]([OH:40])=[C:14]([C:35](OCC)=[O:36])[C:15](=[O:34])[N:16]3[CH2:19][CH2:20][CH2:21][N:22]([CH3:33])[C:23]([O:25][CH2:26][C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)=[O:24])=[N:11][CH:10]=2)=[CH:4][CH:3]=1.[NH2:41][CH2:42][CH2:43][CH2:44][CH2:45][OH:46]>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][C:9]2[CH:18]=[C:17]3[C:12]([C:13]([OH:40])=[C:14]([C:35]([NH:41][CH2:42][CH2:43][CH2:44][CH2:45][OH:46])=[O:36])[C:15](=[O:34])[N:16]3[CH2:19][CH2:20][CH2:21][N:22]([CH3:33])[C:23](=[O:24])[O:25][CH2:26][C:27]3[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=3)=[N:11][CH:10]=2)=[CH:6][CH:7]=1
Reactant: CCOC(=O)c1c(O)c2ncc(Cc3ccc(F)cc3)cc2n(CCCN(C)C(=O)OCc2ccccc2)c1=O
Reactant: NCCCCO
Product: CN(CCCn1c(=O)c(C(=O)NCCCCO)c(O)c2ncc(Cc3ccc(F)cc3)cc21)C(=O)OCc1ccccc1

Procedure:
This compound was prepared from ethyl 7-[(4-fluorophenyl)methyl]-4-hydroxy-1-[3-(methyl{[(phenylmethyl)oxy]carbonyl}amino)propyl]-2-oxo-1,2-dihydro-1,5-naphthyridine-3-carboxylate and 4-amino-1-butanol using conditions similar to Step 5 from Example 497 and obtained as a white solid: ES+ MS: 591 (M+H+).
Reaction SMILES: [CH3:1][C:2]([CH3:5])([O-])[CH3:3].[K+].O=C1C[N:10]([C:12]([O:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[O:13])C1>[Br-].C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C(OCC)C>[CH2:1]=[C:2]1[CH2:5][N:10]([C:12]([O:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[O:13])[CH2:3]1
Reactant: O=C1CN(C(=O)OCc2ccccc2)C1
Reactant: CC(C)(C)[O-]
Agent: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Agent: [K+]
Solvent: CCOCC
Product: C=C1CN(C(=O)OCc2ccccc2)C1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 74.7 %

Procedure:
A suspension of methyltriphenylphosphonium bromide (23.0 g, 0.0649 mol) and potassium tert-butoxide (7.3 g, 0.0649 mol) in diethyl ether (140 mL) was stirred at room temperature for 20 min, and then heated to 35° C. for 1 h. To this bright yellow reaction mixture was slowly added a dilute solution of phenylmethyl 3-oxoazetidine-1-carboxylate (3.33 g, 0.0162 mol) in diethyl ether (50 mL) The reaction mixture was stirred at 35° C. for 12 hours then filtered through a bed of celite and rinsed with ethyl ether. The filtrate was washed with water and brine, dried over anhydrous magnesium sulfate and concentrated. The residue was purified by flash chromatography (SiO2, 5-10% ethyl acetate in hexanes) to afford phenylmethyl 3-methylideneazetidine-1-carboxylate (2.46 g, 75% yield) as a clear and colorless oil). 1H NMR (400 MHz, CDCl3): 7.27-7.22 (m, 5H), 5.02 (s, 2H), 4.93-4.90 (m, 2H), 4.48-4.47 (m, 4H). MS (EI) for C12H13NO2: 203 (M+).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:7]=[CH:8][C:9]=1[O:10][CH3:11])[NH2:6].[CH3:12][O:13][C:14]1[CH:15]=[C:16]([CH2:22][CH2:23][N:24]2[CH:29]3[CH2:30][CH2:31][CH:25]2[CH2:26][C:27](=O)[CH2:28]3)[CH:17]=[CH:18][C:19]=1[O:20][CH3:21].C([BH3-])#N.[Na+]>CO>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH:6][CH:27]2[CH2:28][CH:29]3[N:24]([CH2:23][CH2:22][C:16]4[CH:17]=[CH:18][C:19]([O:20][CH3:21])=[C:14]([O:13][CH3:12])[CH:15]=4)[CH:25]([CH2:31][CH2:30]3)[CH2:26]2)[CH:7]=[CH:8][C:9]=1[O:10][CH3:11]
Reactant: COc1ccc(CCN2C3CCC2CC(=O)C3)cc1OC
Reactant: COc1ccc(N)cc1OC
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Product: COc1ccc(CCN2C3CCC2CC(Nc2ccc(OC)c(OC)c2)C3)cc1OC
Reaction time: 8 h

Procedure:
To a stirred solution of 4 g (26 mmol) 3,4-dimethoxyaniline and 5 ml 14N methanolic HCl in 200 ml methanol, were added 5.7 g (20 mmol) of 8-[2-(3,4-dimethoxyphenyl)ethyl]-8-azabicyclo[3.2.1]octane-3-one (D1), followed by addition of 1 g (16 mmol) sodium cyanoborohydride. The reaction mixture was stirred overnight, slightly acidified and concentrated to dryness. The crude residue was filtered over a short column of silica gel using 95:5 methylene chloride:methanol. The expected fraction was triturated with ethyl acetate affording 4 g (47%) of the desired compound. mp.: 220° C. 1H NMR shows a mixture of two conformations of the title compound.
Reaction SMILES: [NH:1]([C:5]1[S:6][CH:7]=[C:8]([CH2:10][S:11][CH2:12][CH2:13][NH2:14])[N:9]=1)[C:2]([NH2:4])=[NH:3].Cl[C:16]1[C:21]([C:22]([OH:24])=[O:23])=[CH:20][CH:19]=[CH:18][N:17]=1>O>[NH:1]([C:5]1[S:6][CH:7]=[C:8]([CH2:10][S:11][CH2:12][CH2:13][NH:14][C:16]2[C:21]([C:22]([OH:24])=[O:23])=[CH:20][CH:19]=[CH:18][N:17]=2)[N:9]=1)[C:2]([NH2:4])=[NH:3]
Reactant: N=C(N)Nc1nc(CSCCN)cs1
Reactant: O=C(O)c1cccnc1Cl
Solvent: O
Product: N=C(N)Nc1nc(CSCCNc2ncccc2C(=O)O)cs1
Yield: 17 %

Procedure:
An intimate mixture of 2-(2-guanidino-4-thiazolylmethylthio)ethylamine (2.31 g; 0.010 moles) and 2-chloropyridine-3-carboxylic acid (1.58 g; 0.010 moles) was heated to 140° for 3 hours. After cooling the mixture, it was dissolved in hot water and the solution was filtered hot. On leaving the filtrate to stand, a solid mass deposited. This was filtered off and recrystallised from water to give 2-[2-(2-guanidino-4-thiazolylmethylthio)ethyl]aminopyridine-3-carboxylic acid (0.60 g) as a beige-coloured solid m.p. 141°-5°.
Reaction SMILES: Cl.CO[C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[O:10][C:9](=[O:14])[CH:8]=[C:7]2[NH:15][CH:16]1[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]1.C(Cl)Cl>CO>[NH:19]1[CH2:20][CH2:21][CH:16]([NH:15][C:7]2[C:6]3[C:11](=[CH:12][CH:13]=[CH:4][CH:5]=3)[O:10][C:9](=[O:14])[CH:8]=2)[CH2:17][CH2:18]1
Reactant: COc1ccc2oc(=O)cc(NC3CCNCC3)c2c1
Agent: Cl
Solvent: CO
Solvent: ClCCl
Product: O=c1cc(NC2CCNCC2)c2ccccc2o1
Temperature: 60 °C
Reaction time: 12 h

Procedure:
To a 4 mL screw cap vial charged with MP-BH3CN resin (Argonaut Technologies, loading 2.32 mmol/g; 0.056 g; 2 eq.) and 6-methoxy-4-(piperidin-4-ylamino)-chromen-2-one hydrochloride (I)(0.020 g, 0.064 mmol) a solution of the corresponding aldehyde (1.5 eq.) in 1.0 mL of 1:1 MeOH:CH2Cl2(1% AcOH) was added. The resulting mixture was agitated at 60° C. for 12 h. Then, additional MP-BH3CN resin (0.028 g; 1 eq.) was added followed by a solution of the aldehyde (0.75 eq.) in 0.5 mL of the same solvent. The resulting mixture was shaken at 60° C. for additional 12 h. The reaction mixture was then filtered and the resin washed with MeOH (1 mL, twice). The filtrate and the washes were combined, evaporated in vacuo and the residual oil was purified by reverse phase HPLC (TFA method).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@@:8]2([OH:16])[CH2:13][CH2:12][NH:11][CH2:10][C:9]2([CH3:15])[CH3:14])=[CH:4][CH:3]=1.[C:17]([O:21][C:22]([NH:24][C@H:25]1[CH2:28][CH2:27][C@H:26]1[C:29](O)=[O:30])=[O:23])([CH3:20])([CH3:19])[CH3:18].C(N(CC)CC)C.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1>C(Cl)Cl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@@:8]2([OH:16])[CH2:13][CH2:12][N:11]([C:29]([C@H:26]3[CH2:27][CH2:28][C@H:25]3[NH:24][C:22](=[O:23])[O:21][C:17]([CH3:19])([CH3:18])[CH3:20])=[O:30])[CH2:10][C:9]2([CH3:14])[CH3:15])=[CH:4][CH:3]=1
Reactant: CC1(C)CNCC[C@]1(O)c1ccc(Cl)cc1
Reactant: CC(C)(C)OC(=O)N[C@H]1CC[C@H]1C(=O)O
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N[C@@H]1CC[C@@H]1C(=O)N1CC[C@](O)(c2ccc(Cl)cc2)C(C)(C)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 96.1 %

Procedure:
A mixture of (S)-4-(4-chlorophenyl)-3,3-dimethylpiperidin-4-ol (91 mg, 0.381 mmol), (±)-(cis)-2-(tert-butoxycarbonylamino)cyclobutanecarboxylic acid (82 mg, 0.381 mmol), and triethylamine (0.186 mL, 1.333 mmol) in methylene chloride (5 mL) was treated with BOP (168 mg, 0.381 mmol), and the mixture was stirred overnight at room temperature. At the conclusion of this period, the solvent was evaporated with a stream of nitrogen, and the resulting residue was taken up in ethyl acetate. The resulting mixture was washed 3× with saturated sodium carbonate, 3× with 1 N HCl, once with water, and once with brine, then the organic phase was concentrated in vacuo to yield the title compound (160 mg, 96% yield) as a colorless glass. The material was used as-is without further purification. MS (ESI+)=437.4 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:16][C:17]2[C:26]3[C:21](=[CH:22][CH:23]=[CH:24][C:25]=3[O:27][CH2:28][CH2:29][NH:30][CH:31]3[CH2:33][CH2:32]3)[N:20]=[CH:19][N:18]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][N:11]=1.[C:34](Cl)(=[O:36])[CH3:35]>>[Cl:1][C:2]1[CH:3]=[C:4]([NH:16][C:17]2[C:26]3[C:21](=[CH:22][CH:23]=[CH:24][C:25]=3[O:27][CH2:28][CH2:29][N:30]([CH:31]3[CH2:33][CH2:32]3)[C:34](=[O:36])[CH3:35])[N:20]=[CH:19][N:18]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][N:11]=1
Reactant: CC(=O)Cl
Reactant: Clc1cc(Nc2ncnc3cccc(OCCNC4CC4)c23)ccc1OCc1ccccn1
Product: CC(=O)N(CCOc1cccc2ncnc(Nc3ccc(OCc4ccccn4)c(Cl)c3)c12)C1CC1
Yield: 38 %

Procedure:
The procedure described in Example 5 was repeated using N-[3-chloro-4-(pyridin-2-ylmethoxy)phenyl]-5-[2-(cyclopropylamino)ethoxy]quinazolin-4-amine and acetyl chloride to give the title compound in 38% yield; NMR spectrum (DMSO-d6) 0.76-0.82 (m, 4H), 2.06 (s, 3H), 2.76-2.83 (m, 1H), 3.87 (t, 2H), 4.42 (t, 2H), 5.31 (s, 2H), 7.19 (d, 1H), 7.26 (d, 1H), 7.32-7.40 (m, 2H), 7.56-7.61 (m, 2H), 7.70-7.75 (m, 1H), 7.86-7.92 (m, 1H), 7.94-7.96 (m, 1H), 8.45 (s, 1H), 8.60 (d, 1H), 9.76 (s, 1H); Mass spectrum MH+ 504.
Reaction SMILES: C(NC(C)C)(C)C.[Li]CCCC.[CH:13]1[CH:14]=[C:15]([N:21]2[CH2:26][CH2:25][N:24]([CH2:27][CH2:28][CH2:29][CH2:30][O:31][C:32]3[CH:33]=[CH:34][C:35]4[CH2:42][CH2:41][C:39](=[O:40])[NH:38][C:36]=4[CH:37]=3)[CH2:23][CH2:22]2)[C:16]([Cl:20])=[C:17]([Cl:19])[CH:18]=1.[CH3:43][O:44][C:45](Cl)=[O:46]>>[Cl:20][C:16]1[C:17]([Cl:19])=[CH:18][CH:13]=[CH:14][C:15]=1[N:21]1[CH2:26][CH2:25][N:24]([CH2:27][CH2:28][CH2:29][CH2:30][O:31][C:32]2[CH:37]=[C:36]3[C:35]([CH2:42][CH2:41][C:39](=[O:40])[N:38]3[C:45]([O:44][CH3:43])=[O:46])=[CH:34][CH:33]=2)[CH2:23][CH2:22]1
Reactant: O=C1CCc2ccc(OCCCCN3CCN(c4cccc(Cl)c4Cl)CC3)cc2N1
Reactant: COC(=O)Cl
Agent: [Li]CCCC
Solvent: CC(C)NC(C)C
Product: COC(=O)N1C(=O)CCc2ccc(OCCCCN3CCN(c4cccc(Cl)c4Cl)CC3)cc21
Temperature: -78 °C
Reaction time: 0.33 h

Procedure:
To a solution of diisopropylamine (0.99 mL, 7.02 mmol) in 2-methyltetrahydrfuran (33 mL) at −5° C. was added n-BuLi (2.67 mL, 2.5 M in hexanes, 6.69 mmol) slowly. After 20 minutes, the reaction was cooled to −78° C. and aripiprazole (1.50 g, 3.34 mmol) was added. After a further 10 minutes, methylchloroformate (0.65 mL, 8.36 mmol) was added. The reaction was held at −78° C. for 2 hours before allowing to warm to room temperature. After 2 hours the reaction was quenched with saturated aqueous ammonium chloride solution (30 mL) and extracted with ethyl acetate (2×30 mL). The organics were combined, washed with saturated aqueous sodium hydrogen carbonate solution (30 mL), brine (30 mL), dried over MgSO4 and concentrated. The crude product was purified by column chromatography on silica eluting with 1:1 ethyl acetate to dichloromethane to 10% methanol in 1:1 ethyl acetate to dichloromethane to give the product. The product was triturated in heptane to remove aliphatic impurities and then filtered to afford Compound-74 (0.824 g) as a colorless solid.
Reaction SMILES: [OH:1][CH2:2][CH:3]([NH:16][C:17](=[O:23])[O:18][C:19]([CH3:22])([CH3:21])[CH3:20])[CH2:4][NH:5][C:6](=[O:15])[O:7][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.[CH3:24][S:25](Cl)(=[O:27])=[O:26]>C(Cl)Cl>[CH3:24][S:25]([O:1][CH2:2][CH:3]([NH:16][C:17]([O:18][C:19]([CH3:20])([CH3:22])[CH3:21])=[O:23])[CH2:4][NH:5][C:6]([O:7][CH2:8][C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1)=[O:15])(=[O:27])=[O:26]
Reactant: CC(C)(C)OC(=O)NC(CO)CNC(=O)OCc1ccccc1
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NC(CNC(=O)OCc1ccccc1)COS(C)(=O)=O
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To a mixture of benzyl tert-butyl (3-hydroxypropane-1,2-diyl)biscarbamate (60.0 g, 185 mmol) in DCM (1000 mL) was added methanesulfonylchloride (23 g, 200 mmol) at 0° C. The reaction mixture was allowed to warm to room temperature. After 12 hours, the reaction mixture was concentrated under reduced pressure and purified directly by chromatography on silica gel to give 3-{[(benzyloxy)carbonyl]amino}-2-[(tert-butoxycarbonyl)amino]propyl methanesulfonate. MS ESI calc'd. for C17H27N2O7S [M+H]+ 403. found 403. 1H NMR (400 MHz, CD3OD) δ 7.34-7.32 (m, 5), 5.17-5.07 (m, 2H), 4.18-4.16 (m, 2H), 4.09-3.91 (m, 1H), 3.29-3.28 (m, 2H), 3.05 (s, 3H), 1.42 (s, 9H).
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:6]=[CH:7][C:8]([O:14][CH2:15][C:16]([F:19])([F:18])[F:17])=[C:9]([CH:13]=1)[C:10]([OH:12])=O)(=[O:4])=[O:3].Cl.[CH2:21]([S:25]([C:28]1[S:32][C:31]([N:33]2[CH2:38][CH2:37][NH:36][CH2:35][CH2:34]2)=[N:30][CH:29]=1)(=[O:27])=[O:26])[CH2:22][CH2:23][CH3:24]>>[CH2:21]([S:25]([C:28]1[S:32][C:31]([N:33]2[CH2:38][CH2:37][N:36]([C:10]([C:9]3[CH:13]=[C:5]([S:2]([CH3:1])(=[O:3])=[O:4])[CH:6]=[CH:7][C:8]=3[O:14][CH2:15][C:16]([F:19])([F:18])[F:17])=[O:12])[CH2:35][CH2:34]2)=[N:30][CH:29]=1)(=[O:27])=[O:26])[CH2:22][CH2:23][CH3:24]
Reactant: CCCCS(=O)(=O)c1cnc(N2CCNCC2)s1
Reactant: CS(=O)(=O)c1ccc(OCC(F)(F)F)c(C(=O)O)c1
Agent: Cl
Product: CCCCS(=O)(=O)c1cnc(N2CCN(C(=O)c3cc(S(C)(=O)=O)ccc3OCC(F)(F)F)CC2)s1
Yield: 63 %

Procedure:
Prepared in analogy to example 1 (b) from 5-methanesulfonyl-2-(2,2,2-trifluoro-ethoxy)-benzoic acid (Example A3) and 1-[5-(butane-1-sulfonyl)-thiazol-2-yl]-piperazine hydrochloride (Example 38(c)). The crude material was purified by chromatography (SiO2, ethyl acetate/heptane) followed by trituration in ether to yield the title compound as a white crystalline solid (yield 63%). MS (m/e): 570.4 (M+H+, 15%), 587.3 (M+NH4+, 100%).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[OH:10])([O-:3])=[O:2].C([O-])([O-])=O.[K+].[K+].Br[CH:18]1[CH2:23][CH2:22][O:21][C:19]1=[O:20].O>CN(C=O)C>[N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[O:10][CH:18]1[CH2:23][CH2:22][O:21][C:19]1=[O:20])([O-:3])=[O:2]
Reactant: O=[N+]([O-])c1ccccc1O
Reactant: O=C1OCCC1Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: O=C1OCCC1Oc1ccccc1[N+](=O)[O-]
Temperature: 0 °C
Reaction time: 0.75 h

Procedure:
A mixture of 2-nitrophenol (20 g, 0.14 mol) and K2CO3 (25.2 g, 0.18 mol) in 280 mL DMF was cooled to 0 ° C. 2-Bromobutyrolactone was added dropwise, the reaction was stirred for 45 min at 0° C., then stirred at room temperature for 3 hours (h). The mixture was poured into 2 L water containing approx. 200 g salt, and the solution was washed with 6×100 mL of 1:1 diethyl ether/ethyl acetate. The combined organics were washed with 2×100 mL sat'd aq. K2CO3, 5×100 mL water and 100 mL brine, dried (Na2SO4), and filtered. Solvent was removed in vacuo to yield the title compound as an off-white solid (21.88 g, 0.1 mol). 1H (CDCl3): 7.84 (d, 1H, J=7.9), 7.57 (t, 1H, J=7.5), 7.49 (d, 1H, J=7.9), 7.16 (t, 1H, J=7.5), 5.03 (t, 1H, J=7.4), 4.58 (m, 1H), 4.42 (m, 1H), 2.8-2.6 (m, 2H).
Reaction SMILES: [OH:1][CH2:2][C:3]1[C:4]([C:12]2[CH:19]=[CH:18][C:15]([C:16]#[N:17])=[CH:14][CH:13]=2)=[N:5][S:6][C:7]=1[C:8]([F:11])([F:10])[F:9].[CH3:20][C:21]1[C:26]([CH3:27])=[C:25](O)[CH:24]=[CH:23][C:22]=1[CH2:29][CH2:30][C:31]([O:33]CC)=[O:32]>>[C:16]([C:15]1[CH:18]=[CH:19][C:12]([C:4]2[C:3]([CH2:2][O:1][C:25]3[CH:24]=[CH:23][C:22]([CH2:29][CH2:30][C:31]([OH:33])=[O:32])=[C:21]([CH3:20])[C:26]=3[CH3:27])=[C:7]([C:8]([F:11])([F:9])[F:10])[S:6][N:5]=2)=[CH:13][CH:14]=1)#[N:17]
Reactant: N#Cc1ccc(-c2nsc(C(F)(F)F)c2CO)cc1
Reactant: CCOC(=O)CCc1ccc(O)c(C)c1C
Product: Cc1c(CCC(=O)O)ccc(OCc2c(-c3ccc(C#N)cc3)nsc2C(F)(F)F)c1C

Procedure:
The title compound was prepared according to the procedure described in Example 1 starting from 4-[4-(hydroxymethyl)-5-(trifluoromethyl)-1,2-thiazol-3-yl]benzonitrile, following Steps 4-6 and coupling with ethyl 3-(2,3-dimethyl-4-hydroxyphenyl)-propanoate. Upon hydrolysis, compound 264 was afforded as an off-white solid. 1H NMR (400 MHz, CDCl3) δ: 7.85 (d, J=8.4 Hz, 2H), 7.73 (d, J=8.4 Hz, 2H), 6.99 (d, J=8.6 Hz, 1H), 6.67 (d, J=8.6 Hz, 1H), 5.01 (s, 2H), 2.96 (t, J=7.8 Hz, 2H), 2.62 (t, J=7.8 Hz, 2H), 2.24 (s, 3H), 2.00 (s, 3H). 19F NMR (400 MHz, CDCl3) δ: −55.39. Mass spectrum (ESI, m/z): Calcd. for C23H19F3N2O3S, 459.0 (M−H). found 459.0.
Reaction SMILES: [Cl:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[C:6](Cl)[C:5]([CH3:12])=[C:4]([CH3:13])[N:3]=1.Cl.[NH2:15][CH2:16][C:17]1([OH:23])[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1.C(N(CC)CC)C>CN(C)C=O>[Cl:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[C:6]([NH:15][CH2:16][C:17]2([OH:23])[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]2)[C:5]([CH3:12])=[C:4]([CH3:13])[N:3]=1
Reactant: Cc1nc(Cl)c([N+](=O)[O-])c(Cl)c1C
Reactant: NCC1(O)CCCCC1
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: Cc1nc(Cl)c([N+](=O)[O-])c(NCC2(O)CCCCC2)c1C
Temperature: 0 °C

Procedure:
A 500 mL round bottom flask was charged with 2,4-dichloro-5,6-dimethyl-3-nitropyridine (6.00 g, 27.1 mmol), 1-aminomethyl-1-cyclohexanol hydrochloride (4.94 g, 29.8 mmol), and N,N-dimethylformamide (200 mL). The solution was cooled to 0° C. and triethylamine (8.31 mL, 59.6 mmol) was added dropwise. The solution was heated to 35° C. for 3 d. The volatiles were removed under reduced pressure and the resulting oil was partitioned between dichloromethane (300 mL) and water (50 mL). The organic layer was washed with water (50 mL) and brine (30 mL), dried over MgSO4, filtered, concentrated under reduced pressure, and dried under vacuum to yield 1-{[(2-chloro-5,6-dimethyl-3-nitropyridin-4-yl)amino]methyl}cyclohexanol that was used without further manipulation in the next step.
Reaction SMILES: FC(F)(F)C(O)=O.C(OC([NH:15][C@@H:16]([CH3:43])[CH2:17][N:18]([C:20]1[N:21]([CH2:39][C:40]#[C:41][CH3:42])[C:22]2[C:27](=[O:28])[N:26]([CH2:29][C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=3[C:36]#[N:37])[N:25]=[CH:24][C:23]=2[N:38]=1)[CH3:19])=O)(C)(C)C.C(=O)([O-])[O-].[Na+].[Na+]>ClCCl>[NH2:15][C@@H:16]([CH3:43])[CH2:17][N:18]([C:20]1[N:21]([CH2:39][C:40]#[C:41][CH3:42])[C:22]2[C:27](=[O:28])[N:26]([CH2:29][C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=3[C:36]#[N:37])[N:25]=[CH:24][C:23]=2[N:38]=1)[CH3:19]
Reactant: CC#CCn1c(N(C)C[C@H](C)NC(=O)OC(C)(C)C)nc2cnn(Cc3ccccc3C#N)c(=O)c21
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC#CCn1c(N(C)C[C@H](C)N)nc2cnn(Cc3ccccc3C#N)c(=O)c21
Temperature: 25 °C
Reaction time: 4 h

Procedure:
1.4 ml trifluoroacetic acid are added dropwise to a solution of 250 mg (S)-2-[N-(2-tert-butyloxycarbonylamino-propyl)-N-methyl-amino]-3-(2-butyn-1-yl)-5-(2-cyanophenylmethyl)-3,5-dihydro-imidazo[4,5-d]pyridazin-4-one in 5 ml dichloromethane. The solution is stirred for 4 h at ambient temperature, then diluted with dichloromethane and made alkaline with saturated aqueous sodium carbonate solution. The organic phase is separated off, washed with water, dried over magnesium sulphate and evaporated down. The residue is stirred with tert-butylmethylether and after separation of the ether dried in vacuo at 40-50° C.
Reaction SMILES: [C:1]([C:3]1[CH:14]=[CH:13][C:6]2[O:7][C:8]3([C:11](=[O:12])[C:5]=2[CH:4]=1)[CH2:10][CH2:9]3)#[N:2].[OH:15]O.[OH-].[Na+].Cl>C(O)C>[C:1]([C:3]1[CH:14]=[CH:13][C:6]2[O:7][C:8]3([C:11](=[O:12])[C:5]=2[CH:4]=1)[CH2:10][CH2:9]3)(=[O:15])[NH2:2]
Reactant: OO
Reactant: N#Cc1ccc2c(c1)C(=O)C1(CC1)O2
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: NC(=O)c1ccc2c(c1)C(=O)C1(CC1)O2
Temperature: 60 °C
Reaction time: 2 h

Procedure:
To a solution of 5-cyanospiro[benzo[b]furan-2(3H), 1'-cyclopropane]-3-one (185 mg.) in ethanol (10 ml.) were added dropwise 5.5 ml. of 7% aqueous solution of hydrogen peroxide and 3.7 ml. of ethanol, then, to the mixture, was added 2 N aqueous solution of sodium hydroxide to adjust pH 10 and the solution was stirred at 60° C. for 2 hours. After cooling, the reaction mixture was neutralized with diluted hydrochloric acid and diluted with ice-water. The preciptating crystals were collected by filtration, washed with water and recrystallized from ethanol to give colorless needles of 5-carbamoylspiro[benzo[b]furan-2(3H), 1'-cyclopropane]-3-one (106 mg.). m.p. 243°-244° C.