Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH3:1].F[C:3]1[N:8]=[CH:7][C:6]([C:9]2[CH:14]=[CH:13][C:12]([N:15]3[C@@H:19]([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)[C:18]([CH3:27])([CH3:26])[O:17][C:16]3=[O:28])=[CH:11][CH:10]=2)=[CH:5][C:4]=1[C:29]1[N:34]=[CH:33][CH:32]=[CH:31][N:30]=1>CS(C)=O>[NH2:1][C:3]1[N:8]=[CH:7][C:6]([C:9]2[CH:14]=[CH:13][C:12]([N:15]3[C@@H:19]([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)[C:18]([CH3:27])([CH3:26])[O:17][C:16]3=[O:28])=[CH:11][CH:10]=2)=[CH:5][C:4]=1[C:29]1[N:34]=[CH:33][CH:32]=[CH:31][N:30]=1
Reactant: N
Reactant: CC1(C)OC(=O)N(c2ccc(-c3cnc(F)c(-c4ncccn4)c3)cc2)[C@H]1c1ccccc1
Solvent: CS(C)=O
Product: CC1(C)OC(=O)N(c2ccc(-c3cnc(N)c(-c4ncccn4)c3)cc2)[C@H]1c1ccccc1
Temperature: 100 °C

Procedure:
A 2-mL glass microwave reaction vessel was charged with ammonia (2 M solution in 2-propanol) (123 μL, 5.68 mmol, commercially available from Sigma-Aldrich, Milwaukee, Wis.) and (S)-3-(4-(6-fluoro-5-(pyrimidin-2-yl)pyridin-3-yl)phenyl)-5,5-dimethyl-4-phenyloxazolidin-2-one (25 mg, 0.057 mmol) in DMSO (568 μL). The reaction mixture was stirred and heated at 100° C. in a heating block overnight. LC-MS indicated clean and complete conversion to the desired product. The material thus obtained was purified by reverse-phase preparative HPLC using 0.1% TFA in ACN/H2O, gradient 15% to 90% over 20 minutes to provide (S)-3-(4-(6-amino-5-(pyrimidin-2-yl)pyridin-3-yl)phenyl)-5,5-dimethyl-4-phenyloxazolidin-2-one as a yellow solid. 1H NMR (500 MHz, DMSO-d6) δ 8.93 (d, J=5.02 Hz, 2H), 8.84 (d, J=2.46 Hz, 1H), 8.42 (d, J=2.56 Hz, 1H), 7.56 (s, 4H), 7.43 (t, J=4.81 Hz, 1H), 7.34-7.41 (m, 2H), 7.25-7.34 (m, 3H), 5.48 (s, 1H), 1.65 (s, 3H), 0.91 (s, 3H). m/z (ESI) 438.2 (M+H)+.
Reaction SMILES: [Li]CCCC.Br[C:7]1[CH:12]=[C:11]([CH:13]([C:18]([CH3:21])([CH3:20])[CH3:19])[O:14][SiH:15]([CH3:17])[CH3:16])[CH:10]=[C:9]([CH:22]([C:27]([CH3:30])([CH3:29])[CH3:28])[O:23][SiH:24]([CH3:26])[CH3:25])[CH:8]=1.[CH3:31][C:32]([CH3:34])=[O:33].[NH4+].[Cl-]>CCCCCC.C1COCC1>[OH:33][C:32]([C:7]1[CH:12]=[C:11]([CH:13]([C:18]([CH3:20])([CH3:19])[CH3:21])[O:14][SiH:15]([CH3:17])[CH3:16])[CH:10]=[C:9]([CH:22]([C:27]([CH3:30])([CH3:28])[CH3:29])[O:23][SiH:24]([CH3:25])[CH3:26])[CH:8]=1)([CH3:34])[CH3:31]
Reactant: C[SiH](C)OC(c1cc(Br)cc(C(O[SiH](C)C)C(C)(C)C)c1)C(C)(C)C
Reactant: CC(C)=O
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCCCCC
Product: C[SiH](C)OC(c1cc(C(O[SiH](C)C)C(C)(C)C)cc(C(C)(C)O)c1)C(C)(C)C
Temperature: -71 °C

Procedure:
10.5 ml of n-BuLi as a 1.6M solution in hexane are added dropwise to 4.32 g of 1-bromo-3,5-bis[(tert-butyl)dimethylsilanyloxymethyl]benzene (G. T. Crisp and P. D. Turner, Tetrahedron, 2000, 56 (42), 8335) in solution in 150 ml of THF cooled to −71° C. After 1 h 30, 4.27 ml of acetone are added dropwise. The mixture is allowed to return to AT and then hydrolysed with a saturated aqueous NH4Cl solution. The aqueous phase is extracted with 100 ml of AcOEt, the combined organic phases are dried over MgSO4 and concentrated under RP, and the residue is purified by flash chromatography on silica (Biotage 65+M) using a gradient from 0 to 20% AcOEt in heptane. 2.48 g of 1-(1-hydroxy-1-methylethyl)-3,5-bis[(tert-butyl)dimethylsilanyloxymethyl]benzene are thus obtained.
Reaction SMILES: Cl.[Br:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[CH2:13][CH2:12][CH2:11][NH:10]2)=[CH:5][CH:4]=1.C=O.[BH-](OC(C)=O)(OC(C)=O)O[C:18](C)=O.[Na+]>CO>[Br:2][C:3]1[CH:4]=[CH:5][C:6]([CH:9]2[CH2:13][CH2:12][CH2:11][N:10]2[CH3:18])=[CH:7][CH:8]=1
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Reactant: Brc1ccc(C2CCCN2)cc1
Agent: C=O
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: CN1CCCC1c1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 111.2 %

Procedure:
To a suspension of 2-(4-bromophenyl)pyrrolidine hydrogen chloride (200 mg, 0.76 mmol) in anhydrous MeOH (5 mL) was added formaldehyde (114 mg, 3.80 mmol) under N2. The mixture was stirred at room temperature for 2 h under N2. After 2 h, NaBH(OAc)3 (242 mg, 1.14 mmol) was added and the mixture was stirred at room temperature under N2 overnight. Additional formaldehyde (2 mL) and NaBH(OAc)3 (242 mg, 1.14 mmol) were then added and the mixture was stirred at room temperature for 5 hrs. The reaction was concentrated and water was added (20 mL) with dichloromethane (8 mL). The layers were separated and the water was extracted with dichloromethane (8 mL×3). The organic layers were combined, washed with brine, dried over sodium sulfate, and concentrated to afford the title compound (0.203 g, quantitative yield) which was used without further purification. 1H NMR (400 MHz, DMSO-d6) δ 7.51 (d, 2H), 7.28 (d, 2H), 3.15-3.10 (t, 1H), 3.04-3.00 (t, 1H), 2.22-2.18 (q, 1H), 2.13-2.09 (m, 1H), 2.05 (s, 3H), 1.80-1.65 (m, 2H), 1.53-1.50 (m, 1H).
Reaction SMILES: [CH3:1][Mg]Br.[CH:4]([N:17]1[CH2:20][C:19](=[O:21])[CH2:18]1)([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1>C1COCC1>[CH:4]([N:17]1[CH2:20][C:19]([CH3:1])([OH:21])[CH2:18]1)([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=1
Reactant: O=C1CN(C(c2ccccc2)c2ccccc2)C1
Reactant: C[Mg]Br
Solvent: C1CCOC1
Product: CC1(O)CN(C(c2ccccc2)c2ccccc2)C1
Temperature: 0 °C
Yield: 81.2 %

Procedure:
To a solution of methylmagnesium bromide (263 mL, 790 mmol) in anhydrous THF (800 mL) was added a solution of 1-benzhydrylazetidin-3-one (75 g, 316 mmol) in THF (300 mL) rapidly with vigorous stirring at 0° C. The reaction mixture was stirred for 10 min, then allowed to warm to 25° C. and stirred for 2 h. The reaction mixture was quenched by the addition of saturated aqueous ammonium chloride (1 L), diluted with water (1 L) and extracted with EtOAc (3×1 L). The combined organic phase was washed with brine (0.5 L), dried over anhydrous Na2SO4 and filtered. The filtrate was evaporated in vacuo and the residue was purified by column chromatography on silica gel (eluting with 10-20% EtOAc in petroleum ether) to give 1-benzhydryl-3-methylazetidin-3-ol (65 g, 81%) as a white solid. 1H NMR (CDCl3, 400 MHz): δ 7.42 (m, 4H), 7.31 (m, 4H), 7.22 (m, 2H), 4.36 (s, 1H), 3.20 (m, 2H), 2.99 (m, 2H), 1.53 (s, 3H).
Reaction SMILES: [C:1]1([S:7]([N:10]2[C:14]3=[N:15][CH:16]=[C:17]([N+:20]([O-:22])=[O:21])[C:18](Cl)=[C:13]3[CH:12]=[CH:11]2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(N(C(C)C)CC)(C)C.[CH2:32]([O:39][C:40]([N:42]1[CH2:47][CH2:46][CH2:45][C:44]([NH2:49])([CH3:48])[CH2:43]1)=[O:41])[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1>C(O)CCC>[CH2:32]([O:39][C:40]([N:42]1[CH2:47][CH2:46][CH2:45][C:44]([NH:49][C:18]2[C:17]([N+:20]([O-:22])=[O:21])=[CH:16][N:15]=[C:14]3[N:10]([S:7]([C:1]4[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=4)(=[O:9])=[O:8])[CH:11]=[CH:12][C:13]=23)([CH3:48])[CH2:43]1)=[O:41])[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1
Reactant: O=[N+]([O-])c1cnc2c(ccn2S(=O)(=O)c2ccccc2)c1Cl
Reactant: CC1(N)CCCN(C(=O)OCc2ccccc2)C1
Solvent: CCCCO
Solvent: CCN(C(C)C)C(C)C
Product: CC1(Nc2c([N+](=O)[O-])cnc3c2ccn3S(=O)(=O)c2ccccc2)CCCN(C(=O)OCc2ccccc2)C1
Yield: 42.8 %

Procedure:
To a solution of 1-Benzenesulfonyl-4-chloro-5-nitro-1H-pyrrolo[2,3-b]pyridine (580 mg, 1.7 mmol) in n-butanol (20 mL) were added diisopropylethylamine (DIPEA) (1.4 mL, 8.4 mmol) and 3-Amino-3-methyl-piperidine-1-carboxylic acid benzyl ester (420 mg, 1.7 mmol). The mixture was heated to reflux overnight, and LCMS showed 1-Benzenesulfonyl-4-chloro-5-nitro-1H-pyrrolo[2,3-b]pyridine consumed. The reaction mixture was purified by column chromatography (eluting with 30˜35% ethyl acetate in hexane) to give 400 mg (43%) of 3-(1-Benzenesulfonyl-5-nitro-1H-pyrrolo[2,3-b]pyridin-4-ylamino)-3-methyl-piperidine-1-carboxylic acid benzyl ester. LCMS (Method J, ESI): RT=1.32 min, m+H=549.8; 1H NMR (400 MHz, CDCl3) δ: 9.60 (s, 1H), 9.10 (s, 1H), 8.20 (m, 2H), 7.70-7.50 (m, 4H), 7.40-7.30 (m, 5H), 5.34 (m, 2H), 3.90-3.80 (m, 1H), 2.30-2.20 (m, 1H), 1.90-1.50 (m, 9H).
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][C:5]([C:8]([N:10]2[CH2:15][CH2:14][N:13]([C:16]3[C:21]([CH3:22])=[CH:20][C:19]([CH3:23])=[CH:18][N:17]=3)[CH2:12][CH2:11]2)=[O:9])=[N:6][CH:7]=1.[CH3:24][N:25]1[CH2:29][CH2:28][NH:27][C:26]1=[O:30]>>[CH3:22][C:21]1[C:16]([N:13]2[CH2:14][CH2:15][N:10]([C:8]([C:5]3[N:4]=[CH:3][C:2]([N:27]4[CH2:28][CH2:29][N:25]([CH3:24])[C:26]4=[O:30])=[CH:7][N:6]=3)=[O:9])[CH2:11][CH2:12]2)=[N:17][CH:18]=[C:19]([CH3:23])[CH:20]=1
Reactant: Cc1cnc(N2CCN(C(=O)c3ncc(Br)cn3)CC2)c(C)c1
Reactant: CN1CCNC1=O
Product: Cc1cnc(N2CCN(C(=O)c3ncc(N4CCN(C)C4=O)cn3)CC2)c(C)c1
Yield: 40.5 %

Procedure:
Using (5-bromopyrimidin-2-yl)[4-(3,5-dimethylpyridin-2-yl)piperazin-1-yl]methanone (188 mg) described in Preparation Example 229 and 1-methylimidazolidin-2-one (50 mg) and by the reaction and treatment in the same manner as in Example 536, the title compound (80 mg) was obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH:12]([C:13]3[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=3)[N:11]([C:20]([N:22]3[CH2:27][CH2:26][CH:25]([CH2:28]O)[CH2:24][CH2:23]3)=[O:21])[C:10]([C:30]3[CH:35]=[CH:34][C:33]([C:36]([F:39])([F:38])[F:37])=[CH:32][C:31]=3[O:40][CH2:41][CH3:42])=[N:9]2)=[CH:4][CH:3]=1.C(Br)(Br)(Br)[Br:44].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C(Cl)Cl.O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH:12]([C:13]3[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=3)[N:11]([C:20]([N:22]3[CH2:27][CH2:26][CH:25]([CH2:28][Br:44])[CH2:24][CH2:23]3)=[O:21])[C:10]([C:30]3[CH:35]=[CH:34][C:33]([C:36]([F:39])([F:38])[F:37])=[CH:32][C:31]=3[O:40][CH2:41][CH3:42])=[N:9]2)=[CH:4][CH:3]=1
Reactant: BrC(Br)(Br)Br
Reactant: CCOc1cc(C(F)(F)F)ccc1C1=NC(c2ccc(Cl)cc2)C(c2ccc(Cl)cc2)N1C(=O)N1CCC(CO)CC1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Solvent: O
Product: CCOc1cc(C(F)(F)F)ccc1C1=NC(c2ccc(Cl)cc2)C(c2ccc(Cl)cc2)N1C(=O)N1CCC(CBr)CC1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 76.2 %

Procedure:
To a cooled (0° C.) solution of [4,5-bis-(4-chloro-phenyl)-2-(2-ethoxy-4-trifluoromethyl-phenyl)-4,5-dihydro-imidazol-1-yl]-[4-hydroxy methyl-piperidin-1-yl]-methanone (60 mg, 0.096 mmol) in methylene chloride (2 mL) was added carbon tetrabromide (70 mg, 0.210 mmol) followed by triphenyl phosphine (55 mg, 0.21 mmol). The reaction mixture was stirred at ambient temperature for 2.5 h. The reaction was diluted with water and extracted with methylene chloride. The organic extracts were washed with water, brine, and dried over anhydrous sodium sulfate. Evaporation of the solvents and chromatography of the residue over silica gel using 1-5% methanol in methylene chloride gave [4,5-bis-(4-chloro-phenyl)-2-(2-ethoxy-4-trifluoromethyl-phenyl)-4,5-dihydro-imidazol-1-yl]-[4-bromomethyl-piperidin-1-yl]-methanone (50 mg, 76%).
Reaction SMILES: C[O:2][C:3](=[O:35])[CH2:4][O:5][C:6]1[CH:15]=[CH:14][C:13]([Cl:16])=[C:12]2[C:7]=1[C:8]([O:31][CH:32]([F:34])[F:33])=[C:9]([CH2:19][C:20]1[CH:25]=[CH:24][C:23]([N:26]3[CH:30]=[CH:29][CH:28]=[N:27]3)=[CH:22][CH:21]=1)[C:10]([CH2:17][CH3:18])=[N:11]2.[OH-].[Li+]>O1CCCC1.Cl>[Cl:16][C:13]1[CH:14]=[CH:15][C:6]([O:5][CH2:4][C:3]([OH:35])=[O:2])=[C:7]2[C:12]=1[N:11]=[C:10]([CH2:17][CH3:18])[C:9]([CH2:19][C:20]1[CH:21]=[CH:22][C:23]([N:26]3[CH:30]=[CH:29][CH:28]=[N:27]3)=[CH:24][CH:25]=1)=[C:8]2[O:31][CH:32]([F:33])[F:34]
Reactant: CCc1nc2c(Cl)ccc(OCC(=O)OC)c2c(OC(F)F)c1Cc1ccc(-n2cccn2)cc1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CCc1nc2c(Cl)ccc(OCC(=O)O)c2c(OC(F)F)c1Cc1ccc(-n2cccn2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 64.3 %

Procedure:
A solution of [8-chloro-4-difluoromethoxy-2-ethyl-3-(4-pyrazol-1-ylbenzyl)quinolin-5-yloxy]acetic acid methyl ester (0.56 g) in tetrahydrofuran (20 mL) was treated with 1.0M aqueous lithium hydroxide solution (2.4 mL), and the resulting mixture was stirred at room temperature for 30 minutes. The mixture was diluted with 0.1M aqueous hydrochloric acid solution, concentrated under reduced pressure and then extracted with ethyl acetate. The combined extracts were washed with saturated aqueous sodium chloride solution, dried over magnesium sulfate and then concentrated under reduced pressure. The residue was purified by trituration with a mixture of methanol and water, followed by column chromatography on C-18 column to afford title compound (0.35 g).
Reaction SMILES: [C:1]([O:4][C:5]1[CH:14]=[C:13]2[C:8]([C:9](Cl)=[N:10][CH:11]=[N:12]2)=[CH:7][C:6]=1[O:16][CH3:17])(=[O:3])[CH3:2].[N:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[CH2:24][O:25][C:26]1[C:27]([CH3:33])=[CH:28][C:29]([NH2:32])=[CH:30][CH:31]=1>>[C:1]([O:4][C:5]1[CH:14]=[C:13]2[C:8]([C:9]([NH:32][C:29]3[CH:30]=[CH:31][C:26]([O:25][CH2:24][C:19]4[CH:20]=[CH:21][CH:22]=[CH:23][N:18]=4)=[C:27]([CH3:33])[CH:28]=3)=[N:10][CH:11]=[N:12]2)=[CH:7][C:6]=1[O:16][CH3:17])(=[O:3])[CH3:2]
Reactant: COc1cc2c(Cl)ncnc2cc1OC(C)=O
Reactant: Cc1cc(N)ccc1OCc1ccccn1
Product: COc1cc2c(Nc3ccc(OCc4ccccn4)c(C)c3)ncnc2cc1OC(C)=O
Yield: 64 %

Procedure:
Using an analogous procedure to that described in Example 1 except that the reaction mixture was heated to reflux for 3 hours, 7-acetoxy-4-chloro-6-methoxyquinazoline was reacted with 5-amino-2-tolyl 2-pyridylmethyl ether to give 7-acetoxy-6-methoxy-4-[3-methyl-4-(2-pyridylmethoxy)anilino]quinazoline in 64% yield;
Reaction SMILES: [CH3:1][S:2]([CH2:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[CH:13]=[C:14]3[CH2:20][CH:19]([CH:21]4[CH2:26][CH2:25][N:24]([C:27]#[N:28])[CH2:23][CH2:22]4)[O:18][C:15]3=[CH:16][N:17]=2)=[CH:8][CH:7]=1)(=[O:4])=[O:3].[OH:29][NH:30][C:31](=N)[CH:32]([CH3:34])[CH3:33]>>[CH:32]([C:31]1[N:28]=[C:27]([N:24]2[CH2:25][CH2:26][CH:21]([CH:19]3[O:18][C:15]4=[CH:16][N:17]=[C:12]([C:9]5[CH:8]=[CH:7][C:6]([CH2:5][S:2]([CH3:1])(=[O:3])=[O:4])=[CH:11][CH:10]=5)[CH:13]=[C:14]4[CH2:20]3)[CH2:22][CH2:23]2)[O:29][N:30]=1)([CH3:34])[CH3:33]
Reactant: CS(=O)(=O)Cc1ccc(-c2cc3c(cn2)OC(C2CCN(C#N)CC2)C3)cc1
Reactant: CC(C)C(=N)NO
Product: CC(C)c1noc(N2CCC(C3Cc4cc(-c5ccc(CS(C)(=O)=O)cc5)ncc4O3)CC2)n1

Procedure:
The title compound is prepared from 4-[5-(4-methanesulfonylmethyl-phenyl)-2,3-dihydro-furo[2,3-c]pyridin-2-yl]-piperidine-1-carbonitrile and N-hydroxy-isobutyramidine following a procedure analogous to that described in Example 2. LC (method 6): tR=1.46 min; Mass spectrum (ESI+): m/z=483 [M+H]+.
Reaction SMILES: [Li+].[OH-].[O:3]=[C:4]1[N:10]([CH:11]2[CH2:16][CH2:15][N:14]([C:17]([O:19][C@@H:20]([C:32]([O:34]C)=[O:33])[CH2:21][C:22]3[CH:27]=[C:26]([CH3:28])[C:25]([O:29][CH3:30])=[C:24]([CH3:31])[CH:23]=3)=[O:18])[CH2:13][CH2:12]2)[CH2:9][CH2:8][C:7]2[CH:36]=[CH:37][CH:38]=[CH:39][C:6]=2[NH:5]1>O.C1COCC1>[O:3]=[C:4]1[N:10]([CH:11]2[CH2:12][CH2:13][N:14]([C:17]([O:19][C@@H:20]([C:32]([OH:34])=[O:33])[CH2:21][C:22]3[CH:27]=[C:26]([CH3:28])[C:25]([O:29][CH3:30])=[C:24]([CH3:31])[CH:23]=3)=[O:18])[CH2:15][CH2:16]2)[CH2:9][CH2:8][C:7]2[CH:36]=[CH:37][CH:38]=[CH:39][C:6]=2[NH:5]1
Reactant: COC(=O)[C@@H](Cc1cc(C)c(OC)c(C)c1)OC(=O)N1CCC(N2CCc3ccccc3NC2=O)CC1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: COc1c(C)cc(C[C@@H](OC(=O)N2CCC(N3CCc4ccccc4NC3=O)CC2)C(=O)O)cc1C
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of 11.3 mg (0.47 mmol) LiOH*H2O in 8 mL water was added to a solution of 160 mg (0.31 mmol) (R)-2-(4-methoxy-3,5-dimethyl-phenyl)-1-methoxycarbonyl-ethyl 4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate in 15 mL THF and the reaction mixture was stirred for 1 h at RT. The mixture was evaporated down i.vac., the residue was taken up in 150 mL water and acidified with 2 M HCl. The precipitate formed was separated off and dried.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:42][C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1)[CH2:10][C@@H:11]1[O:15][C:14]([CH3:17])([CH3:16])[N:13]([C:18]([O:20][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[O:19])[C@H:12]1[CH2:28][C:29]1[CH:34]=[CH:33][C:32](OC(=O)C(F)(F)F)=[CH:31][CH:30]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Li+].[Cl-].C([Sn](CCCC)(CCCC)[C:56]1[CH:57]=[N:58][CH:59]=[CH:60][CH:61]=1)CCC>CN(C=O)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:42][C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1)[CH2:10][C@@H:11]1[O:15][C:14]([CH3:16])([CH3:17])[N:13]([C:18]([O:20][CH2:21][C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=2)=[O:19])[C@H:12]1[CH2:28][C:29]1[CH:30]=[CH:31][C:32]([C:56]2[CH:57]=[N:58][CH:59]=[CH:60][CH:61]=2)=[CH:33][CH:34]=1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CCCC[Sn](CCCC)(CCCC)c1cccnc1
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)C[C@@H]1OC(C)(C)N(C(=O)OCc2ccccc2)[C@H]1Cc1ccc(OC(=O)C(F)(F)F)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cl-]
Agent: [Li+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)C[C@@H]1OC(C)(C)N(C(=O)OCc2ccccc2)[C@H]1Cc1ccc(-c2cccnc2)cc1
Temperature: 100 °C
Yield: 72.3 %

Procedure:
A solution containing the product from Example 23I(0.200 g, 0.283 mmol) in DMF (3 mL) was treated with LiCl (0.120 g, 2.83 mmol), dichlorobis(triphenylphosphine)palladium(II) (0.060 g, 0.085 mmol), and 3-tri-n-butylstannylpyridine (0.200 mL, 0.870 mmol), heated at 100° C. for 16 hours, cooled and partitioned between ethyl acetate and water. The organic phase was washed with brine and dried over MgSO4, filtered and concentrated. The residue was chromatographed on silica gel eluting with 0-25% ethyl acetate in dichloromethane to give the title compound (0.130 g, 72% yield).
Reaction SMILES: [CH2:1]([O:3][C:4]([CH2:6][NH:7][CH2:8][CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])=[O:5])[CH3:2].C(=O)(O)[O-].[Na+].[CH2:20]([O:27][C:28](Cl)=[O:29])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>C(O)C.O>[CH2:20]([O:27][C:28]([CH:8]([NH:7][CH2:6][C:4]([O:3][CH2:1][CH3:2])=[O:5])[CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])=[O:29])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: CCOC(=O)CCNCC(=O)OCC
Reactant: O=C(Cl)OCc1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: CCOC(=O)CNC(CC(=O)OCC)C(=O)OCc1ccccc1

Procedure:
0.95 kg of ethyl 3-(ethoxycarbonylmethylamino)propionate (4.68 mol) was dissolved in 2.85 L of ethanol and 2.85 L of water. To this solution, 0.41 kg of sodium bicarbonate (4.91 mol) was added under stirring. Subsequently, 0.84 kg of benzylchloroformate (4.91 mol) was added dropwise at an internal temperature of 28 to 35° C. and the mixture was stirred at an internal temperature of 28 to 35° C. for 2 hours. Ethanol was evaporated under reduced pressure and 9.51 L of ethyl acetate was added. The mixture was then stirred for 5 minutes. The mixture was allowed to stand and the organic layer (top layer) was collected. To this layer, 4.8 L of water was added and the mixture was stirred for 5 minutes. The mixture was allowed to stand again and the organic layer (top layer) was collected. To this layer, 4.8 L of 28% brine was added and the mixture was stirred for 5 minutes. The mixture was allowed to stand again and the organic layer (top layer) was collected. To this layer, 0.57 kg of anhydrous sodium sulfate was added and the mixture was stirred for 1 hour. The solid was separated by filtration and washed with 0.95 L of ethyl acetate. The filtrate and the wash were combined and concentrated under reduced pressure. The resulting product was dried under reduced pressure at an external temperature of 50° C. for 30 minutes. This gave 1.64 kg of a crude product of the title compound as a colorless oil. This product was used in the subsequent step without further purification.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]2[N:8]([C:9]=1[C:10]1[CH:15]=[CH:14][N:13]=[C:12](O)[N:11]=1)[CH:7]=[CH:6][S:5]2.P(Cl)(Cl)([Cl:19])=O>>[Cl:1][C:2]1[N:3]=[C:4]2[N:8]([C:9]=1[C:10]1[CH:15]=[CH:14][N:13]=[C:12]([Cl:19])[N:11]=1)[CH:7]=[CH:6][S:5]2
Reactant: Oc1nccc(-c2c(Cl)nc3sccn23)n1
Reactant: O=P(Cl)(Cl)Cl
Product: Clc1nccc(-c2c(Cl)nc3sccn23)n1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A mixture of EXAMPLE 80D (9.97 g, 39.5 mmol) and phosphoryl trichloride (110 ml, 1184 mmol) was stirred at 80° C. for 5 hours. The mixture was cooled to room temperature, then concentrated to dryness. Water (150 mL) was added cautiously. The mixture was cooled with an ice bath and adjusted to pH˜11 with concentrated aqueous NaOH, then stirred for 30 minutes. The solid was collected by filtration, washed with water (3×50 mL), and dried in a vacuum oven overnight at ˜50° C. to provide the title compound. (ESI(+)) m/e 271.1 (M+H)+.
Reaction SMILES: [NH2:1][CH:2]1[CH2:7][CH2:6][N:5]([C:8]2[CH:13]=[CH:12][C:11]([C:14]3[NH:23][C:22](=[O:24])[C:21]4[C:16](=[CH:17][C:18]([O:27][CH3:28])=[CH:19][C:20]=4[O:25][CH3:26])[N:15]=3)=[CH:10][CH:9]=2)[CH2:4][CH2:3]1.[CH3:29][S:30](Cl)(=[O:32])=[O:31].CCN(CC)CC>C(Cl)Cl>[CH3:26][O:25][C:20]1[CH:19]=[C:18]([O:27][CH3:28])[CH:17]=[C:16]2[C:21]=1[C:22](=[O:24])[NH:23][C:14]([C:11]1[CH:12]=[CH:13][C:8]([N:5]3[CH2:4][CH2:3][CH:2]([NH:1][S:30]([CH3:29])(=[O:32])=[O:31])[CH2:7][CH2:6]3)=[CH:9][CH:10]=1)=[N:15]2
Reactant: COc1cc(OC)c2c(=O)[nH]c(-c3ccc(N4CCC(N)CC4)cc3)nc2c1
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1cc(OC)c2c(=O)[nH]c(-c3ccc(N4CCC(NS(C)(=O)=O)CC4)cc3)nc2c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 58.4 %

Procedure:
A mixture of 2-(4-(4-aminopiperidin-1-yl)phenyl)-5,7-dimethoxyquinazolin-4(3H)-one (0.105 g, 0.28 mmol), methanesulfonylchloride (0.035 g, 0.30 mmol), and Et3N (0.057 g. 0.56 mmol) in CH2Cl2 (10 mL) was stirred at room temperature under nitrogen for 2 hours. The mixture was concentrated, redissolved in THF (5 mL), 2 M NaOH (5 mL) added and stirred for 20 minutes. The pH was adjusted to 8 with 1 M HCl and the mixture extracted with CH2Cl2 (3×150 mL). The organic phase was dried over anhydrous MgSO4, filtered, and concentrated. The residue was purified by silica gel chromatography, eluting with 1:1 CH2Cl2/(92:7:1 CHCl3/MeOH/concentrated NH4OH) to 100% 92:7:1 CHCl3/MeOH/concentrated NH4OH. Further purification by reverse-phase HPLC. eluting with 10% to 90% CH3CN in H2O with 0.1% TFA. afforded the title compound as a yellow solid (0.075 g, 58%). 1H NMR (300 MHz, DMSO-d6): δ11.75 (s, 1H), 8.08 (d, J=9.0 Hz, 2H), 7.13 (d, J=7.3 Hz, 1H), 7.00 (d, J=9.0 Hz, 2H), 6.66 (d, J=2.3 Hz, 1H), 6.46 (d, J=2.3 Hz, 1H), 3.81-3.94 (m, 8H), 3.34-3.47 (m, 1H), 2.90 (m, 6H), 1.87-1.95 (m, 2H), 1.42-1.54 (m, 2H); ESI MS m/z 459 [M+H]+.
Reaction SMILES: [CH2:1]([C@H:6]1[CH2:11][CH2:10][C@H:9]([CH:12]=O)[CH2:8][CH2:7]1)[CH2:2][CH2:3][CH2:4][CH3:5].[Cl-].[CH3:15][O:16]C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>O1CCCC1>[CH2:1]([C@H:6]1[CH2:7][CH2:8][C@H:9]([CH2:12][CH:15]=[O:16])[CH2:10][CH2:11]1)[CH2:2][CH2:3][CH2:4][CH3:5]
Reactant: CCCCC[C@H]1CC[C@H](C=O)CC1
Reactant: COC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cl-]
Solvent: C1CCOC1
Product: CCCCC[C@H]1CC[C@H](CC=O)CC1

Procedure:
In a manner analogous to that described in Example 2, paragraphs (a) and (b), trans-4-pentylcyclohexanecarboxaldehyde was reacted in a Wittig reaction with methoxymethyl-triphenylphosphonium chloride and potassium t-butylate and the resulting enol ether was subsequently hydrolyzed in tetrahydrofuran/2N hydrochloric acid to give (trans-4-pentylcyclohexyl)acetaldehyde.
Reaction SMILES: [N+:1]([O-:4])(O)=[O:2].[OH:5][CH:6]1[C:11]([CH3:13])([CH3:12])[O:10][C:9]2[CH:14]=[CH:15][S:16][C:8]=2[CH:7]1[N:17]1[CH2:21][CH2:20][CH2:19][C:18]1=[O:22].[K+].[Br-]>C(O)(=O)C>[OH:5][CH:6]1[C:11]([CH3:12])([CH3:13])[O:10][C:9]2[CH:14]=[C:15]([N+:1]([O-:4])=[O:2])[S:16][C:8]=2[CH:7]1[N:17]1[CH2:21][CH2:20][CH2:19][C:18]1=[O:22]
Reactant: CC1(C)Oc2ccsc2C(N2CCCC2=O)C1O
Reactant: O=[N+]([O-])O
Agent: [Br-]
Agent: [K+]
Solvent: CC(=O)O
Product: CC1(C)Oc2cc([N+](=O)[O-])sc2C(N2CCCC2=O)C1O
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
Nitric acid (90%, 1.2 mL, 26.9 mmol) was added to a solution of 5,6- dihydro-6-hydroxy-5,5-dimethyl-7-(2-oxopyrrolidin-1-yl)-7H-thieno[3,2-b]pyran (1.0 g, 3.74 mmol]in acetic acid (30 mL) at 18° C., and stirred at rt for 1.5 h. The resultant solution was poured into ice water (200 mL). Within 10 min a yellow solid crystallized which was collected by filtration, washed with water and triturated in diethyl ether to give the product, 0.487 g (42%), as a yellow solid: mp 214°-217° C.; IR (KBr): 3216, 1655 and 1512 cm-1 ; MS: m/z 313 (MH+); 1H NMR (DMSO-d6): δ1.23 (s, 3H), 1.43 (s, 3H), 2.00 (m, 2H), 2.36 (m, 2H), 3.16 (m, 1H), 3.20 (m, 1H), 3.80 (d, J=9.5 Hz, 1H), 4.98 (d, J=9.5 Hz, 1H), 5.92 (bs, 1H, exchanges with D2O) and 7.75 (s, 1H).