Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([CH2:6][CH:7]([C:18]2[NH:22][C:21]([C:23]([OH:25])=O)=[C:20]([CH3:26])[CH:19]=2)[C:8]2[CH:13]=[CH:12][C:11]([S:14]([CH3:17])(=[O:16])=[O:15])=[CH:10][CH:9]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.Cl.C[N:29](C)CCCN=C=NCC>CN(C)C=O.C(OCC)(=O)C>[CH:1]1([CH2:6][CH:7]([C:18]2[NH:22][C:21]([C:23]([NH2:29])=[O:25])=[C:20]([CH3:26])[CH:19]=2)[C:8]2[CH:13]=[CH:12][C:11]([S:14]([CH3:17])(=[O:16])=[O:15])=[CH:10][CH:9]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CCN=C=NCCCN(C)C
Reactant: Cc1cc(C(CC2CCCC2)c2ccc(S(C)(=O)=O)cc2)[nH]c1C(=O)O
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: Cc1cc(C(CC2CCCC2)c2ccc(S(C)(=O)=O)cc2)[nH]c1C(N)=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 97.1 %

Procedure:
To a solution (5 mL) of 5-{2-cyclopentyl-1-[4-(methylsulfonyl)phenyl]ethyl}-3-methyl-1H-pyrrole-2-carboxylic acid (160 mg) in N,N-dimethylformamide were added under ice-cooling N-[3-(dimethylamino)propyl]-N′-ethylcarbodiimide hydrochloride (125 mg) and 1-hydroxybenzotriazole-ammonia complex (100 mg). The reaction mixture was slowly warmed to room temperature, and stirred overnight. The reaction mixture was diluted with ethyl acetate, and washed with saturated aqueous sodium hydrogen carbonate. The ethyl acetate layer was washed with saturated brine, dried (MgSO4) and concentrated. The residue was subjected to silica gel column chromatography, and the title compound (155 mg, yield 97%) was obtained as colorless amorphous crystals from a fraction eluted with ethyl acetate-hexane (4:1, volume ratio). MS: 375 (MH+).
Reaction SMILES: [O:1]=[S:2]1(=[O:18])[CH2:6][CH2:5][CH2:4][N:3]1[C:7]1[CH:15]=[CH:14][C:10]([C:11]([OH:13])=O)=[C:9]([O:16][CH3:17])[CH:8]=1.Cl.[CH:20]1([C:23]2[C:24]([N:32]3[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]3)=[N:25][CH:26]=[C:27]([CH:29]3[CH2:31][CH2:30]3)[CH:28]=2)[CH2:22][CH2:21]1>>[CH:20]1([C:23]2[C:24]([N:32]3[CH2:33][CH2:34][N:35]([C:11]([C:10]4[CH:14]=[CH:15][C:7]([N:3]5[CH2:4][CH2:5][CH2:6][S:2]5(=[O:1])=[O:18])=[CH:8][C:9]=4[O:16][CH3:17])=[O:13])[CH2:36][CH2:37]3)=[N:25][CH:26]=[C:27]([CH:29]3[CH2:31][CH2:30]3)[CH:28]=2)[CH2:21][CH2:22]1
Reactant: c1nc(N2CCNCC2)c(C2CC2)cc1C1CC1
Reactant: COc1cc(N2CCCS2(=O)=O)ccc1C(=O)O
Agent: Cl
Product: COc1cc(N2CCCS2(=O)=O)ccc1C(=O)N1CCN(c2ncc(C3CC3)cc2C2CC2)CC1
Yield: 69.9 %

Procedure:
Using 4-(1,1-dioxo-1λ6-isothiazolidin-2-yl)-2-methoxybenzoic acid (271 mg) described in Preparation Example 19 and 1-(3,5-dicyclopropylpyridin-2-yl)piperazine hydrochloride (316 mg) described in Preparation Example 87 and by the reaction and treatment in the same manner as in Example 86, the title compound (347 mg) was obtained.
Reaction SMILES: C(=O)([O:7][C:8]1[CH:13]=[CH:12][C:11]([F:14])=[C:10]([C:15]([C:17]2[CH:18]=[C:19]3[C:24](=[CH:25][CH:26]=2)[N:23]=[CH:22][C:21](Cl)=[N:20]3)=[O:16])[C:9]=1[F:28])OC(C)(C)C.[C:30]1(B(O)O)[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1.C([O-])([O-])=O.[Na+].[Na+]>O1CCOCC1.O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[F:28][C:9]1[C:8]([OH:7])=[CH:13][CH:12]=[C:11]([F:14])[C:10]=1[C:15]([C:17]1[CH:18]=[C:19]2[C:24](=[CH:25][CH:26]=1)[N:23]=[CH:22][C:21]([C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)=[N:20]2)=[O:16]
Reactant: CC(C)(C)OC(=O)Oc1ccc(F)c(C(=O)c2ccc3ncc(Cl)nc3c2)c1F
Reactant: OB(O)c1ccccc1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Solvent: O
Product: O=C(c1ccc2ncc(-c3ccccc3)nc2c1)c1c(F)ccc(O)c1F
Temperature: 100 °C

Procedure:
A mixture of tert-butyl (3-(3-chloroquinoxaline-6-carbonyl)-2,4-difluorophenyl) carbonate (60 mg, 0.14 mmol, 1.0 eq.), phenylboronic acid (17 mg, 0.14 mmol, 1.1 eq.), Pd(dppf)2Cl2 (6 mg, 0.007 mmol, 0.05 eq.) and Na2CO3 (30 mg, 0.28 mmol, 2.0 eq.) in dioxane and water (9 mL/1 mL) was heated at 100° C. overnight under N2 protection, then cooled and concentrated. The resulting residue was purified via flash column chromatography (PE/EA=3/1, v/v) to (2,6-difluoro-3-hydroxyphenyl)(3-phenylquinoxalin-6-yl)methanone (15.4 mg, 30%). LRMS (M+H+) m/z calculated 363.1, found 363.0. 1H NMR (CDCl3, 400 MHz) δ 10.38 (s, 1 H), 9.76 (s, 1 H), 8.28-8.40 (m, 5 H), 7.60-7.62 (m, 3 H), 7.18-7.27 (m, 2 H).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][N+:7]([O-])=[C:6]2[NH:11][CH:12]=[CH:13][C:5]=12)([O-])=O>C(O)(=O)C.[Fe]>[NH2:1][C:4]1[CH:9]=[CH:8][N:7]=[C:6]2[NH:11][CH:12]=[CH:13][C:5]=12
Reactant: O=[N+]([O-])c1cc[n+]([O-])c2[nH]ccc12
Agent: [Fe]
Solvent: CC(=O)O
Product: Nc1ccnc2[nH]ccc12

Procedure:
9.35 g (167 mmol) of iron powder are added to a solution of 3.00 g (16.8 mmol) of 4-nitro-1H-pyrrolo[2,3-b]pyridine 7-oxide (from example (XVI) in 225 ml of acetic acid, and the mixture is heated under reflux for 2 hours. The crude mixtures of two such batches are combined and jointly worked up further. The solid is separated off and washed with 50 ml of acetic acid and 100 ml of tetrahydrofuran. Using a rotary evaporator, the filtrate is concentrated to dryness. The residue is diluted with 50 ml of water and the solution is made alkaline using 45% strength sodium hydroxide solution. Dichloromethane is then added, and the mixture is filtered off with suction through kieselguhr. The filtrate is extracted six times with in each case 100 ml of dichloromethane and the organic phase is dried over sodium sulfate and evaporated to dryness using a rotary evaporator. The residue is dried under high vacuum. For further purification, the residue is triturated with tetrahydrofuran and the solid is filtered off with suction. The filtrate is concentrated and the residue is taken up in dichloromethane, dried and concentrated.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:12]([C:14]2[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=2)[NH2:13])[CH:5]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1.[CH:21](OC(=O)C)=[O:22].C(OC(=O)C)(=O)C.C(O)=O>C(Cl)Cl>[F:1][C:2]1[CH:3]=[C:4]([CH:12]([C:14]2[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=2)[NH:13][CH:21]=[O:22])[CH:5]=[C:6]([C:8]([F:10])([F:11])[F:9])[CH:7]=1
Reactant: CC(=O)OC=O
Reactant: NC(c1ccc(F)cc1)c1cc(F)cc(C(F)(F)F)c1
Solvent: CC(=O)OC(C)=O
Solvent: O=CO
Solvent: ClCCl
Product: O=CNC(c1ccc(F)cc1)c1cc(F)cc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 94 %

Procedure:
To a solution of (3-fluoro-5-(trifluoromethyl)phenyl)(4-fluorophenyl)methanamine (315 mg, 1.1 mmol) in CH2Cl2 (2 mL) at 0° C. was added acetic formic anhydride (314 uL, formed by heating a 2:1 v/v ratio of acetic anhydride and formic acid at 60° C. for 2 h). The reaction mixture was allowed to warm to room temperature and stirred for 0.5 h. The reaction mixture was concentrated under reduced pressure and the residue was purified on a 40 g column of silica gel, eluting with 0 to 100% EtOAc/hexane, to give N-((3-fluoro-5-(trifluoromethyl)phenyl)(4-fluorophenyl)methyl)formamide (327 mg, 94% yield) as a clear, viscous oil. LCMS: RT=1.37 min [M+H] 316.1 (2 min Phenomenex Luna C18 column, 4.6×30 mm eluting with 10-90% acetonitrile/H2O over 2 minutes containing 0.1% TFA; 5 mL/min, monitoring at 220 nm); NMR: 400 MHz 1H (CDCl3) δ ppm 6.13 (bs, 1H), 6.34 (d, J=7.47 Hz, 1H), 7.05-7.20 (m, 5H), 7.27-7.34 (m, 2H), 8.35 (s, 1H). To a solution of N-((3-fluoro-5-(trifluoromethyl)phenyl)(4-fluorophenyl)methyl)formamide (327 mg, 1.04 mmol) in THF (5 mL) at 0° C. was added Et3N (0.79 mL, 5.7 mmol) followed by phosphorous oxychloride (0.125, 1.35 mmol). The reaction mixture was allowed to warm to room temperature and stirred for 16 h. The reaction mixture was diluted with ice-water (25 mL) and extracted with Et2O (3×20 mL). The combined organic layers were washed with sat. NaCl (20 mL), dried over anhydrous Na2SO4, the filtered through basic alumina. The filtrate was concentrated to give 1-fluoro-3-((4-fluorophenyl)(isocyano)methyl)-5-(trifluoromethyl)benzene (268 mg, 93% yield) as a pale brown oil. LCMS: RT=1.71 min [M−NC] 271.0 (2 min Phenomenex Luna C18 column, 4.6×30 mm eluting with 10-90% acetonitrile/H2O over 2 minutes containing 0.1% TFA; 5 mL/min, monitoring at 220 nm); IR νmax cm−1 neat: 2139 (N═C); NMR: 500 MHz 1H (CDCl3) δ ppm 5.94 (s, 1H), 7.12 (t, J=8.52 Hz, 2H), 7.25-7.29 (m, 1H), 7.30-7.35 (m, 3H), 7.41 (s, 1H).
Reaction SMILES: [CH3:1][C:2]1([CH3:9])[CH2:7][CH2:6][C:5](=[O:8])[CH2:4][CH2:3]1.F[B-](F)(F)F.[CH2:15]([O:17][CH+:18][O:19][CH2:20][CH3:21])[CH3:16].C(N(CC)C(C)C)(C)C>>[CH2:15]([O:17][CH:18]([O:19][CH2:20][CH3:21])[CH:4]1[CH2:3][C:2]([CH3:9])([CH3:1])[CH2:7][CH2:6][C:5]1=[O:8])[CH3:16]
Reactant: CCO[CH+]OCC
Reactant: CC1(C)CCC(=O)CC1
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(OCC)C1CC(C)(C)CCC1=O

Procedure:
reacting 4,4-dimethylcyclohexanone, diethoxycarbenium fluoroborate and N,N-diisopropylethylamine at about −60° C. to −90° C. to provide (2-(diethoxymethyl)-4,4-dimethylcyclohexanone and isolating or not isolating the 2-(diethoxymethyl)-4,4-dimethylcyclohexanone;
Reaction SMILES: [CH3:1][C:2]1[CH:30]=[C:29]([CH3:31])[CH:28]=[CH:27][C:3]=1[C:4]([C:6]1[N:10]([CH3:11])[C:9]([CH:12]([C:17]2[CH:22]=[CH:21][C:20]([N+:23]([O-:25])=[O:24])=[CH:19][C:18]=2[F:26])[C:13]([O:15][CH3:16])=[O:14])=[CH:8][CH:7]=1)=[O:5].[CH2:32](O)[CH:33]=C>CC(C)[O-].CC(C)[O-].CC(C)[O-].CC(C)[O-].[Ti+4]>[CH3:1][C:2]1[CH:30]=[C:29]([CH3:31])[CH:28]=[CH:27][C:3]=1[C:4]([C:6]1[N:10]([CH3:11])[C:9]([CH:12]([C:17]2[CH:22]=[CH:21][C:20]([N+:23]([O-:25])=[O:24])=[CH:19][C:18]=2[F:26])[C:13]([O:15][CH2:16][CH:32]=[CH2:33])=[O:14])=[CH:8][CH:7]=1)=[O:5]
Reactant: COC(=O)C(c1ccc([N+](=O)[O-])cc1F)c1ccc(C(=O)c2ccc(C)cc2C)n1C
Reactant: C=CCO
Agent: [Ti+4]
Agent: CC(C)[O-]
Product: C=CCOC(=O)C(c1ccc([N+](=O)[O-])cc1F)c1ccc(C(=O)c2ccc(C)cc2C)n1C
Temperature: 25 °C
Reaction time: 36 h
Yield: 97 %

Procedure:
To a solution of methyl 2-[5- (2,4-dimethylbenzoyl)-1-methylpyrrol-2-yl)-2-(2-fluoro-4-nitrophenyl)acetate (3.51 g, 8.27 mmol) [prepared as described in Example 6, Step(c)] in 75 ml allyl alcohol was added titanium tetraisopropoxide (0.244 ml, 0.827 mmol), and the reaction mixture was heated to reflux. After 36 h, the reaction mixture was cooled to room temperature, and partitioned between ether and water. The organic layer was separated, dried over magnesium sulfate, and concentrated to dryness to give allyl 2-[5-(2,4-dimethylbenzoyl)-1-methylpyrrol-2-yl)-2-(2-fluoro-4-nitrophenyl)-acetate (3.60 g, 97%) as a pale yellow oil. ##STR36##
Reaction SMILES: CN(C=O)C.[CH3:6][O:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]([C:61]2[CH:66]=[CH:65][C:64]([O:67][CH3:68])=[CH:63][CH:62]=2)([C:55]2[CH:60]=[CH:59][CH:58]=[CH:57][CH:56]=2)[NH:15][S:16]([C:19]2[S:20][C:21]3[CH:27]=[C:26]([O:28][CH2:29][C:30]4[N:31]=[N:32][N:33]([CH2:35][C:36]([NH:38][C@H:39]([CH2:45][S:46][CH2:47][C:48]5[CH:53]=[CH:52][CH:51]=[C:50]([OH:54])[CH:49]=5)[C:40]([O:42][CH2:43][CH3:44])=[O:41])=[O:37])[CH:34]=4)[CH:25]=[CH:24][C:22]=3[N:23]=2)(=[O:18])=[O:17])=[CH:10][CH:9]=1.C([O-])([O-])=O.[K+].[K+].Br[CH2:76][C:77]#[CH:78]>O>[CH3:6][O:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]([C:61]2[CH:66]=[CH:65][C:64]([O:67][CH3:68])=[CH:63][CH:62]=2)([C:55]2[CH:60]=[CH:59][CH:58]=[CH:57][CH:56]=2)[NH:15][S:16]([C:19]2[S:20][C:21]3[CH:27]=[C:26]([O:28][CH2:29][C:30]4[N:31]=[N:32][N:33]([CH2:35][C:36]([NH:38][C@H:39]([CH2:45][S:46][CH2:47][C:48]5[CH:53]=[CH:52][CH:51]=[C:50]([O:54][CH2:78][C:77]#[CH:76])[CH:49]=5)[C:40]([O:42][CH2:43][CH3:44])=[O:41])=[O:37])[CH:34]=4)[CH:25]=[CH:24][C:22]=3[N:23]=2)(=[O:18])=[O:17])=[CH:10][CH:9]=1
Reactant: C#CCBr
Reactant: CCOC(=O)[C@@H](CSCc1cccc(O)c1)NC(=O)Cn1cc(COc2ccc3nc(S(=O)(=O)NC(c4ccccc4)(c4ccc(OC)cc4)c4ccc(OC)cc4)sc3c2)nn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: C#CCOc1cccc(CSC[C@@H](NC(=O)Cn2cc(COc3ccc4nc(S(=O)(=O)NC(c5ccccc5)(c5ccc(OC)cc5)c5ccc(OC)cc5)sc4c3)nn2)C(=O)OCC)c1
Temperature: 60 °C
Reaction time: 12 h

Procedure:
To a 10 mL round bottomed flask equipped with a magnetic stir bar, rubber septum and argon inlet containing DMF (0.5 mL) was placed 134 (49 mg, 0.054 mmol). To this solution K2CO3 (22 mg, 0.162 mmol) and 3-bromoprop-1-yne (0.01 mL, 0.0702 mmol) were added and the reaction was allowed to stir at 60° C. for 12 h. The reaction was then poured into water (50 mL) and extracted into EtOAc (3×20 mL). The combined organic extracts were washed with water (20 mL), brine (20 mL), dried over MgSO4 and concentrated in vacuo used for next step without further purification.
Reaction SMILES: Cl.[NH:2]=[C:3]1[CH2:7][CH2:6][CH2:5][NH:4]1.Br[CH2:9][C:10]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=O.C(=O)([O-])[O-].[Na+].[Na+].O>CN(C)C=O>[C:12]1([C:10]2[N:2]=[C:3]3[CH2:7][CH2:6][CH2:5][N:4]3[CH:9]=2)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: O=C(CBr)c1ccccc1
Reactant: N=C1CCCN1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: c1ccc(-c2cn3c(n2)CCC3)cc1
Temperature: 80 °C
Yield: 90 %

Procedure:
Combine 2-iminopyrrolidine hydrochloride (6.98 g, 57.8 mmol) (Callahan, et al., J. Med. Chem. 45, 999-1001 (2002)), 2-bromoacetophenone (3.8 g, 19.3 mmol), and sodium carbonate (8.2 g, 77.2 mmol) in dry dimethylformamide (25 mL). Heat at 80° C. for 18 hours. Cool to room temperature, add water (60 mL), and extract with ethyl acetate (3×100 mL). Concentrate the combined organic layers under reduced pressure. Dilute the residue with diethyl ether (100 mL), wash with cold water (3×80 mL), and concentrate under reduced pressure to provide the desired compound as a white solid (3.2 g, 89%).
Reaction SMILES: [CH2:1]([CH:3]([CH2:12][CH:13]=[CH2:14])[CH:4]([OH:11])[CH2:5][C:6]([O:8]CC)=[O:7])[CH3:2]>[OH-].[K+].CO>[CH2:1]([CH:3]([CH2:12][CH:13]=[CH2:14])[CH:4]([OH:11])[CH2:5][C:6]([OH:8])=[O:7])[CH3:2]
Reactant: C=CCC(CC)C(O)CC(=O)OCC
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: C=CCC(CC)C(O)CC(=O)O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Ethyl 4-ethyl-3-hydroxyhept-6-enoate (3.64 g, 18.2 mmol) was dissolved in a 2 N solution of potassium hydroxide in methanol (120 mL), and the solution was stirred overnight at room temperature. From the reaction solution, the solvent was distilled off under reduced pressure. To the residue, a 1 N aqueous sodium hydroxide solution (200 mL) was then added, followed by extraction with diethyl ether. The aqueous layer was made acidic by the addition of concentrated hydrochloric acid under ice cooling, followed by extraction with diethyl ether again. The organic layer was washed with saturated saline and dried over anhydrous magnesium sulfate. Then, the solvent was distilled off under reduced pressure to obtain the compound of interest as a pale yellow oil substance (3.14 g, <100%, mixture of diastereomers).
Reaction SMILES: [N:1]1([CH2:11][CH2:12][C:13]([OH:15])=O)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][CH2:2]1.F[B-](F)(F)F.C1(=O)N(OC(N(C)C)=[N+](C)C)C(=O)CC1.C(N(CC)C(C)C)(C)C.[CH3:45][N:46]([CH3:50])[CH2:47][CH2:48][NH2:49]>CN(C=O)C.[Cl-].[Na+].O>[N:1]1([CH2:11][CH2:12][C:13]([NH:49][CH2:48][CH2:47][N:46]([CH3:50])[CH3:45])=[O:15])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][CH2:2]1
Reactant: CN(C)CCN
Reactant: O=C(O)CCN1CCCc2ccccc21
Agent: CN(C)C(ON1C(=O)CCC1=O)=[N+](C)C
Agent: F[B-](F)(F)F
Agent: [Cl-]
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CN(C)CCNC(=O)CCN1CCCc2ccccc21
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 54.8 %

Procedure:
To a solution of Compound 7 (1.0 g, 4.9 mmol) in DMF (20 mL), 2-succinimido-1,1,3,3-tetramethyluronium tetrafluoroborate (1.8 g, 5.8 mmol) and N,N-diisopropyl ethylamine (1.8 mL, 10.2 mmol) were added. Combined mixture was stirred at room temperature for 30 mins and then a solution of N,N-dimethylethylenediamine (0.64 g, 7.3 mmol) in DMF (2 mL) was added. After stirring the mixture for additional 1 hour, it was poured in brine (100 mL) and extracted with ethyl acetate (2×75 mL). The combined organic layers were washed with brine (3×100 mL) and dried over MgSO4. The solvent was removed under reduced pressure to provide Compound 8 as brown viscous liquid (0.74 g, 55%). This product was used without further purification. The structure of Compound 8 is given below:
Reaction SMILES: O=[C:2]1[CH2:5][N:4]([C:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7])[CH2:3]1.[CH3:13][C:14]([S:17]([NH2:19])=[O:18])([CH3:16])[CH3:15]>C1COCC1.C(O[Ti](OCC)(OCC)OCC)C>[C:14]([S:17]([N:19]=[C:2]1[CH2:5][N:4]([C:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7])[CH2:3]1)=[O:18])([CH3:16])([CH3:15])[CH3:13]
Reactant: CC(C)(C)S(N)=O
Reactant: CC(C)(C)OC(=O)N1CC(=O)C1
Agent: CCO[Ti](OCC)(OCC)OCC
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CC(=NS(=O)C(C)(C)C)C1
Temperature: 70 °C
Reaction time: 8 h
Yield: 23.4 %

Procedure:
A mixture of tert-butyl 3-oxoazetidine-1-carboxylate (4 g, 23.37 mmol), 2-methylpropane-2-sulfinamide (3.12 g, 25.7 mmol) and tetraethoxytitanium (10.66 g, 46.7 mmol) in THF (40 ml) in a 20 ml sealed tube was stirred at 70° C. overnight. The reaction mixture was cooled to room temperature, quenched with water and filtered through a bed of Celite. The solid material was washed with ethyl acetate. The organic layer was separated, dried over Na2SO4, filtered and concentrated to obtain a crude mixture. The crude product was then purified by column chromatography (20% EtOAc in Hexane) to afford tert-butyl 3-(tert-butylsulfinylimino)azetidine-1-carboxylate Yield: 1.5 g (24%). 1H NMR (400 MHz, CDCl3): δ 5.15-4.94 (m, 1H), 4.75 (m, 1H), 4.68 (s, 2H), 1.45 (s, 9H), 1.27 (s, 9H).
Reaction SMILES: C(OC([NH:11][C:12]([CH2:31][N:32]1[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]1)([CH2:18][CH2:19][CH2:20][CH2:21][B:22]1[O:26]C(C)(C)C(C)(C)[O:23]1)[C:13]([O:15]CC)=[O:14])=O)C1C=CC=CC=1.[ClH:38]>>[ClH:38].[ClH:38].[NH2:11][C:12]([CH2:31][N:32]1[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]1)([CH2:18][CH2:19][CH2:20][CH2:21][B:22]([OH:26])[OH:23])[C:13]([OH:15])=[O:14]
Reactant: CCOC(=O)C(CCCCB1OC(C)(C)C(C)(C)O1)(CN1CCCCC1)NC(=O)OCc1ccccc1
Agent: Cl
Product: NC(CCCCB(O)O)(CN1CCCCC1)C(=O)O
Temperature: 25 °C

Procedure:
A solution of ethyl 2-(benzyloxycarbonylamino)-2-(piperidin-1-ylmethyl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)hexanoate (0.26 g, 0.51 mmol) in 6 N HCl (20 mL) was heated to a gentle reflux for 48 h. After cooling to room temperature, the solution was washed with dichloromethane (5×15 mL) and concentrated (aqueous layer). The resulting residue was dissolved in water (3 mL) and passed through cation exchange resin Dowex 50-200 eluted with 2 N ammonia (4 g resin was loaded on a column, washed successively with water, 1 N HCl, water to neutral pH, 2 N ammonia solution and water to neutral pH). Fractions containing product were concentrated, diluted with minimal water, acidified with 6 N HCl, frozen and lyophilized to give 2-amino-6-borono-2-(piperidin-1-ylmethyl)hexanoic acid dihydrochloride. (60 mg, 43%). 1H NMR (D2O) δ 3.64-3.53 (m, 1H), 3.34 (d, J=13.9 Hz, 1H), 3.05-3.03 (m, 2H), 2.93-2.91 (m, 3H), 1.76-1.67 (m, 5H), 1.53-1.46 (m, 3H), 1.31-1.30 (m, 3H), 1.09-1.07 (m, 1H), 0.70 (t, J=7.3 Hz, 2H). MS found for C12H25BN2O4 m/z[254(M−18+1)].
Reaction SMILES: [C:1](N1C=CN=C1)([N:3]1C=CN=C1)=O.[C:13]([C:15]1[N:19]([C:20]([CH3:23])([CH3:22])[CH3:21])[N:18]=[CH:17][C:16]=1[C:24]([OH:26])=O)#[N:14].CN>CN(C=O)C>[C:13]([C:15]1[N:19]([C:20]([CH3:21])([CH3:22])[CH3:23])[N:18]=[CH:17][C:16]=1[C:24]([NH:3][CH3:1])=[O:26])#[N:14]
Reactant: CC(C)(C)n1ncc(C(=O)O)c1C#N
Reactant: O=C(n1ccnc1)n1ccnc1
Agent: CN
Solvent: CN(C)C=O
Product: CNC(=O)c1cnn(C(C)(C)C)c1C#N
Temperature: 25 °C
Yield: 45.3 %

Procedure:
Carbonyldiimidazole (2.5 grams, 0.015 mole) was added to a solution of 5-cyano-1-tert-butyl-1H-pyrazole-4-carboxylic acid (2.0 grams, 50.01 mole) in DMF. The solution was stirred at room temperature for twenty minutes. Aqueous methylamine (1.5 ml, 0.015 mole) was added and the reaction mixture was stirred at room temperature for 16 hours, then poured into ice-water. The product precipitated and was collected, dried, and recrystallized from ethanol, yielding 1.4 grams of 5-cyano-1-tert-butyl-N-methyl-1H-pyrazole-4-carboxamide, m.p., 164°-166° C.
Reaction SMILES: CC1C=CC(S(O[CH2:12][C:13]2([OH:27])[C:23]3[C:24]4[N:15]([C:16](=[O:26])[CH:17]=[N:18][C:19]=4[CH:20]=[CH:21][C:22]=3[F:25])[CH2:14]2)(=O)=O)=CC=1.[O:28]1[C:37]2[CH:36]=[C:35]([CH2:38][N:39]([CH:47]3[CH2:52][CH2:51][NH:50][CH2:49][CH2:48]3)[C:40](=[O:46])[O:41][C:42]([CH3:45])([CH3:44])[CH3:43])[N:34]=[CH:33][C:32]=2[O:31][CH2:30][CH2:29]1.C(=O)([O-])[O-].[Na+].[Na+]>C(O)C>[O:28]1[C:37]2[CH:36]=[C:35]([CH2:38][N:39]([CH:47]3[CH2:52][CH2:51][N:50]([CH2:12][C:13]4([OH:27])[C:23]5[C:24]6[N:15]([C:16](=[O:26])[CH:17]=[N:18][C:19]=6[CH:20]=[CH:21][C:22]=5[F:25])[CH2:14]4)[CH2:49][CH2:48]3)[C:40](=[O:46])[O:41][C:42]([CH3:45])([CH3:44])[CH3:43])[N:34]=[CH:33][C:32]=2[O:31][CH2:30][CH2:29]1
Reactant: CC(C)(C)OC(=O)N(Cc1cc2c(cn1)OCCO2)C1CCNCC1
Reactant: Cc1ccc(S(=O)(=O)OCC2(O)Cn3c(=O)cnc4ccc(F)c2c43)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Product: CC(C)(C)OC(=O)N(Cc1cc2c(cn1)OCCO2)C1CCN(CC2(O)Cn3c(=O)cnc4ccc(F)c2c43)CC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 52 %

Procedure:
To a mixture of (7-fluoro-6-hydroxy-3-oxo-5,6-dihydro-3H-pyrrolo[1,2,3-de]quinoxalin-6-yl)methyl 4-methylbenzenesulfonate (0.093 g, 0.24 mmol) in ethanol (3 mL) was added 1,1-dimethylethyl (2,3-dihydro[1,4]dioxino[2,3-c]pyridin-7-ylmethyl)4-piperidinylcarbamate (for a synthesis see WO 2004058144 Example 99(h)) (78.5 mg, 0.22 mmol), then sodium carbonate (71.5 mg, 0.68 mmol). The reaction mixture was stirred at room temperature for 16 hours and evaporated to dryness. The residue was placed directly onto the top of a 20 g silica gel column and chromatographed eluting with a 0-100% ethyl acetate in petrol gradient, then with a 0-50% methanol in ethyl acetate gradient to afford the product (70 mg, 52%).
Reaction SMILES: Cl[C:2]1[C:3]2[C:10]([C:11]3[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=3)=[C:9]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[O:8][C:4]=2[N:5]=[CH:6][N:7]=1.[NH2:25][C:26]1[CH:27]=[C:28]([OH:32])[CH:29]=[CH:30][CH:31]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[CH3:18][O:17][C:14]1[CH:15]=[CH:16][C:11]([C:10]2[C:3]3[C:2]([O:32][C:28]4[CH:27]=[C:26]([CH:31]=[CH:30][CH:29]=4)[NH2:25])=[N:7][CH:6]=[N:5][C:4]=3[O:8][C:9]=2[C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)=[CH:12][CH:13]=1
Reactant: COc1ccc(-c2c(-c3ccccc3)oc3ncnc(Cl)c23)cc1
Reactant: Nc1cccc(O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1ccc(-c2c(-c3ccccc3)oc3ncnc(Oc4cccc(N)c4)c23)cc1

Procedure:
Stir 1000 mg (2.97 mmol) of 4-chloro-5-(4-methoxyphenyl)-6-phenylfuro[2,3-d]pyrimidine, 1296 mg (11.9 mmol) of 3-aminophenol and 615.6 mg (4.45 mmol) of potassium carbonate in 10 ml of DMF at 80° C. for 8 h. After cooling, concentrate under reduced pressure and take up the residue in water. Filter off the precipitated solid, wash the filter residue repeatedly with water and dry the solid at 50° C. under high vacuum. 1195 mg (98.3% of theory) of the target compound are obtained as a brownish solid.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([N:8]2[CH2:12][CH2:11][CH:10]([CH2:13][N:14]3[CH2:18][CH2:17][CH2:16][CH:15]3[CH3:19])[CH2:9]2)[CH:5]=[CH:4][C:3]=1[NH2:20].[N:21]1([C:26]2[CH:34]=[CH:33][C:29]([C:30](O)=[O:31])=[CH:28][CH:27]=2)[CH:25]=[CH:24][N:23]=[CH:22]1>>[N:21]1([C:26]2[CH:27]=[CH:28][C:29]([C:30]([NH:20][C:3]3[CH:4]=[CH:5][C:6]([N:8]4[CH2:12][CH2:11][CH:10]([CH2:13][N:14]5[CH2:18][CH2:17][CH2:16][CH:15]5[CH3:19])[CH2:9]4)=[CH:7][C:2]=3[CH3:1])=[O:31])=[CH:33][CH:34]=2)[CH:25]=[CH:24][N:23]=[CH:22]1
Reactant: O=C(O)c1ccc(-n2ccnc2)cc1
Reactant: Cc1cc(N2CCC(CN3CCCC3C)C2)ccc1N
Product: Cc1cc(N2CCC(CN3CCCC3C)C2)ccc1NC(=O)c1ccc(-n2ccnc2)cc1

Procedure:
The title compound was prepared in a manner substantially the same as Example 1 by coupling 2-methyl-4-[3-(2-methyl-pyrrolidin-1-ylmethyl)-pyrrolidin-1-yl]-phenylamine with 4-imidazol-1-yl-benzoic acid. MS: 444.3 (M+H).