Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[C:4]([F:11])[CH:3]=1.[CH2:12]([Sn](CCCC)(CCCC)C=C)[CH2:13]CC.O1C=CC=C1P(C1OC=CC=1)C1OC=CC=1.[Cl-].[Li+]>C(Cl)(Cl)Cl.CO.CN1CCCC1=O>[CH:12]([C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[C:4]([F:11])[CH:3]=1)=[CH2:13]
Reactant: C=C[Sn](CCCC)(CCCC)CCCC
Reactant: O=[N+]([O-])c1ccc(Cl)cc1F
Agent: [Cl-]
Agent: [Li+]
Agent: c1coc(P(c2ccco2)c2ccco2)c1
Solvent: ClC(Cl)Cl
Solvent: CO
Solvent: CN1CCCC1=O
Product: C=Cc1ccc([N+](=O)[O-])c(F)c1
Temperature: 120 °C
Reaction time: 1 h
Yield: 76.6 %

Procedure:
4-Chloro-2-fluoronitrobenzene (300 mg, 1.71 mmol), Pb2(dba)3 (236 mg, 0.228 mmol), tributyl (vinyl) tin (333 mg, 1.14 mmol), tri-2-furylphosphine (212 mg, 0.912 mmol) and lithium chloride (193 mg, 4.56 mmol) were added to methylpyrrolidinone (5 ml), and the mixture was stirred in a sealed tube at 120° C. for one hour. The mixture was diluted with chloroform-methanol, and filtered through a Celite Pad. After concentrating the filtrate, the concentrate was dissolved in ethyl acetate and washed with aqueous potassium fluoride. The organic layer was dried over magnesium sulfate, concentrated in vacuo, and purified by thin-layer silica gel chromatography (hexane-ethyl acetate, 5:1) to give the title compound (146 mg) as a pale yellow oil.
Reaction SMILES: [C:1]([C:3]1[CH:25]=[CH:24][C:6]2[NH:7][C:8]3[N:9]=[CH:10][CH:11]=[CH:12][C:13]=3[C:14]([CH2:19][O:20][CH:21]([CH3:23])[CH3:22])([C:15]([F:18])([F:17])[CH3:16])[C:5]=2[CH:4]=1)#[N:2].CC(O)C.CC#N.C1C(=O)N([Cl:40])C(=O)C1>CCOC(C)=O.CCCCCC>[Cl:40][C:11]1[CH:10]=[N:9][C:8]2[NH:7][C:6]3[CH:24]=[CH:25][C:3]([C:1]#[N:2])=[CH:4][C:5]=3[C:14]([CH2:19][O:20][CH:21]([CH3:22])[CH3:23])([C:15]([F:17])([F:18])[CH3:16])[C:13]=2[CH:12]=1
Reactant: CC(C)OCC1(C(C)(F)F)c2cc(C#N)ccc2Nc2ncccc21
Reactant: O=C1CCC(=O)N1Cl
Solvent: CC(C)O
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: CC(C)OCC1(C(C)(F)F)c2cc(C#N)ccc2Nc2ncc(Cl)cc21
Yield: 84.1 %

Procedure:
To a stirred solution of 7-cyano-5-isopropoxymethyl-5-(1,1-difluoroethyl)-5,10-dihydrobenzo[b][1,8]naphthyridine (22)(2.184 g, 6.361 mmol) in anhydrous 1:4 i-PrOH-MeCN (35 mL) at room temperature was added NCS (1.040 g, 7.633 mmol). The reaction mixture was heated to reflux for 2 h 40 min. The reaction was quenched with saturated aqueous NaHCO3 (100 mL), and extracted with EtOAc (2×). The combined organic layers were washed with brine, dried over MgSO4, filtered and concentrated in vacuo. Flash chromatography (20%-30% EtOAc-Hexane) afforded 23 (2.021 g, 84% yield) as a pale yellow solid: m.p. 79-81° C.; low resolution mass spectrum (ESI) m/z 378.3 [(M+H)+ calcd for C19H19ClF2N3O: 378.12].
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[CH:12]=[C:11]([CH2:13]O)[N:10]=[CH:9]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(Br)(Br)(Br)[Br:35]>C1COCC1>[Br:35][CH2:13][C:11]1[N:10]=[CH:9][N:8]([C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[Cl:1])[CH:12]=1
Reactant: BrC(Br)(Br)Br
Reactant: OCc1cn(-c2ccccc2Cl)cn1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: Clc1ccccc1-n1cnc(CBr)c1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
48 mg (0.16 mmol) of the compound from Example 38A and 63 mg (0.24 mmol) of triphenylphosphine were dissolved in 1.6 ml of THF, and 80 mg (0.24 mmol) of carbon tetrabromide were added at RT. The mixture was then stirred at RT for 16 h. For work-up, the mixture was filtered through 20 g of kieselguhr, the filter residue was rinsed with ethyl acetate and the filtrate was concentrated under reduced pressure. The residue was purified chromatographically on silica gel (mobile phase: cyclohexane/ethyl acetate 5:1, then 1:1). This gave 17 mg (39% of theory) of the target compound which was immediately reacted further.
Reaction SMILES: [C:1]([CH:4]1[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][S:9][CH2:8][C@@H:7]([C:17]([OH:19])=[O:18])[NH:6][C:5]1=[O:20])(O)=O.N1CCCCC1.C=O.Cl>N1C=CC=CC=1>[CH2:1]=[C:4]1[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][S:9][CH2:8][C@@H:7]([C:17]([OH:19])=[O:18])[NH:6][C:5]1=[O:20]
Reactant: O=C(O)C1CCCCCCCSC[C@@H](C(=O)O)NC1=O
Agent: C=O
Agent: Cl
Solvent: c1ccncc1
Solvent: C1CCNCC1
Product: C=C1CCCCCCCSC[C@@H](C(=O)O)NC1=O
Temperature: 65 °C
Reaction time: 2 h

Procedure:
(3R)-6-Carboxy-5-oxo-1-thia-4-azacyclotridecane-3-carboxylic acid (1.71 g, 5.64 mmol) is dissolved in pyridine (20 ml) and piperidine (0.096 g, 1.13 mmol) is added followed by paraformaldehyde (0.25 g, 8.46 mmol). The mixture is heated to 65° C. and stirred for 2 hours. The mixture is cooled to room temperature, poured into 6N hydrochloric acid (100 ml) and extracted with ethyl acetate (2×100 ml). The combined extracts are washed with brine (1×100 ml), dried (MgSO4) and solvent is evaporated to give (3R)-6-methylidene-5-oxo-1-thia-4-azacyclotridecane-3-carboxylic acid, m.p. 184°-186° C.
Reaction SMILES: [CH3:1][N:2]([CH3:6])[CH2:3][CH2:4][NH2:5].[Cl:7][C:8]1[S:12][C:11]([S:13](Cl)(=[O:15])=[O:14])=[CH:10][C:9]=1[N+:17]([O-:19])=[O:18].C(N(CC)CC)C>O1CCOCC1>[CH3:1][N:2]([CH3:6])[CH2:3][CH2:4][NH:5][S:13]([C:11]1[S:12][C:8]([Cl:7])=[C:9]([N+:17]([O-:19])=[O:18])[CH:10]=1)(=[O:15])=[O:14]
Reactant: O=[N+]([O-])c1cc(S(=O)(=O)Cl)sc1Cl
Reactant: CN(C)CCN
Solvent: CCN(CC)CC
Solvent: C1COCCO1
Product: CN(C)CCNS(=O)(=O)c1cc([N+](=O)[O-])c(Cl)s1
Temperature: 25 °C
Reaction time: 17 h
Yield: 48.6 %

Procedure:
To a stirred solution of N,N-dimethylethylenediamine (0.67 g, 7.6 mmol) in dioxane (25 ml) was added at room temperature 5-chloro-4-nitrothiophene-2-sulfonyl chloride (2.0 g, 7.64 mmol) and triethylamine (1.17 ml, 8.4 mmol). The light yellow suspension was stirred at room temperature for 17 h, and evaporated. The crude product was further purified by flash chromatography on silica gel (dichloromethane/methanol), and subsequent crystallization from ethyl acetate to yield 5-chloro-4-nitro-thiophene-2-sulfonic acid (2-dimethylamino-ethyl)-amide (1.16 g, 48%) as a light brown solid. MS (ISP) 312.0 [(M−H)−], mp 178° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5](B(O)O)=[CH:4][CH:3]=1.C([O-])([O-])=O.[Na+].[Na+].Br[C:18]1[C:19]([O:35][CH3:36])=[C:20]([C:31]([O:33][CH3:34])=[O:32])[S:21][C:22]=1[C:23]1[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][C:24]=1[Cl:30]>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:18]2[C:19]([O:35][CH3:36])=[C:20]([C:31]([O:33][CH3:34])=[O:32])[S:21][C:22]=2[C:23]2[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][C:24]=2[Cl:30])=[CH:4][CH:3]=1
Reactant: OB(O)c1ccc(Cl)cc1
Reactant: COC(=O)c1sc(-c2ccc(Cl)cc2Cl)c(Br)c1OC
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: COC(=O)c1sc(-c2ccc(Cl)cc2Cl)c(-c2ccc(Cl)cc2)c1OC
Reaction time: 18 h
Yield: 75.6 %

Procedure:
7.75 g of (4-chlorophenyl)boronic acid and then, dropwise, 40.93 ml of a 2M solution of Na2CO3 are added to a solution of 16.21 g of the compound of step B) in 110 ml of toluene. Argon is sparged into the reaction mixture for 30 minutes, then 2.36 g of Tetrakis are added and heating is carried out at 110° C. for 18 hours. After cooling to AT, the reaction mixture is rinsed with 80 ml of distilled water, then extraction is carried out with 80 ml of EtOAc, drying is carried out over Na2SO4, and the solvent is evaporated off under vacuum. The reaction crude is purified by silica gel chromatography, elution being carried out with heptane and then with a heptane/EtOAc mixture (85/15; v/v). 13.23 g of the expected compound are obtained.
Reaction SMILES: S(=O)(=O)(O)O.[CH2:6]([O:8][C:9](=[O:22])[CH2:10][C:11]1([C:17]([O:19][CH2:20][CH3:21])=[O:18])[CH2:15][CH2:14][CH2:13][C:12]1=O)[CH3:7].Cl.[CH:24]1([C:29]2[CH:44]=[CH:43][C:32]([CH2:33][O:34][C:35]3[CH:40]=[CH:39][C:38]([NH:41]N)=[CH:37][CH:36]=3)=[CH:31][C:30]=2[C:45]([F:48])([F:47])[F:46])[CH2:28][CH2:27][CH2:26][CH2:25]1>CCO>[CH:24]1([C:29]2[CH:44]=[CH:43][C:32]([CH2:33][O:34][C:35]3[CH:40]=[CH:39][C:38]4[NH:41][C:12]5[C:11]([CH2:10][C:9]([O:8][CH2:6][CH3:7])=[O:22])([C:17]([O:19][CH2:20][CH3:21])=[O:18])[CH2:15][CH2:14][C:13]=5[C:37]=4[CH:36]=3)=[CH:31][C:30]=2[C:45]([F:46])([F:47])[F:48])[CH2:25][CH2:26][CH2:27][CH2:28]1
Reactant: CCOC(=O)CC1(C(=O)OCC)CCCC1=O
Reactant: NNc1ccc(OCc2ccc(C3CCCC3)c(C(F)(F)F)c2)cc1
Agent: Cl
Agent: O=S(=O)(O)O
Solvent: CCO
Product: CCOC(=O)CC1(C(=O)OCC)CCc2c1[nH]c1ccc(OCc3ccc(C4CCCC4)c(C(F)(F)F)c3)cc21
Reaction time: 0.58 h
Yield: 77.2 %

Procedure:
In a 1 L flask was placed EtOH (500 mL). Sulfuric acid (2.4 g, 23.98 mmol) was added at 40° C., followed by ethyl 1-(2-ethoxy-2-oxoethyl)-2-oxocyclopentanecarboxylate (15.2 g, 62.7 mmol). (4-(4-Cyclopentyl-3-(trifluoromethyl)benzyloxy)phenyl)hydrazine hydrochloride (24.0 g, 62.0 mmol) was added and the solution became light yellow and homogenous. The reaction mixture was refluxed overnight with a Dean-Starks condenser attached. The mixture was cooled and extracted in ethyl acetate (3×100 mL). The organics were washed with water (200 mL), sodium bicarbonate solution (2×70 mL), water (100 mL), dried over magnesium sulfate, and concentrated. The residue was dissolved in hexanes/ethyl acetate (80:20, 300 mL), added silica gel (30 g) and stirred for 35 minutes. The slurry was filtered, washed with the same elution solvent (100 mL) and the filtrate was concentrated to give the title compound (26.7 g). LCMS m/z=558.5 [M+H]+.
Reaction SMILES: [N+:1]([C:4]1[CH:11]=[CH:10][C:7]([CH2:8]Br)=[CH:6][CH:5]=1)([O-:3])=[O:2].[Cl:12][C:13]1[CH:18]=[CH:17][C:16]([S:19][Si](C)(C)C)=[CH:15][CH:14]=1.C(#N)C>CN(C)P(=O)(N(C)C)N(C)C>[N+:1]([C:4]1[CH:11]=[CH:10][C:7]([CH2:8][S:19][C:16]2[CH:17]=[CH:18][C:13]([Cl:12])=[CH:14][CH:15]=2)=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: C[Si](C)(C)Sc1ccc(Cl)cc1
Reactant: O=[N+]([O-])c1ccc(CBr)cc1
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Solvent: CC#N
Product: O=[N+]([O-])c1ccc(CSc2ccc(Cl)cc2)cc1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 94.8 %

Procedure:
1.50 g (7.0 mmoles) of 4-nitrobenzyl bromide was added to a mixture of 1.36 g (6.3 mmoles) of 4-chlorophenylthio(trimethyl)silane, 20 ml of acetonitrile and 2.3 ml of hexamethylphosphoric triamide and the conversion was complete after stirring for 5 minutes at room temperature. The reaction mixture was evaporated to dryness and the residue was dissolved in 50 ml of ethyl acetate. The solution was washed sequentially with water (twice 10 ml), 10 ml of a 1N KOH solution and water (twice 10 ml), dried and evaporated to dryness. The solid residue was washed with heptane on a sintered glass filter and the crystals obtained were vacuum dried at room temperature to obtain 1.67 g (95% yield) of 4-chlorophenyl 4-nitrobenzyl sulfide melting at 66°-68° C.
Reaction SMILES: CS(O[C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][C:15]=1[C:16](=[O:20])[CH2:17][CH2:18][Cl:19])[NH:12][C:11](=[O:21])[CH2:10][CH2:9]2)(=O)=O.[H][H]>C(O)C.[Pd]>[Cl:19][CH2:18][CH2:17][C:16]([C:15]1[CH:14]=[C:13]2[C:8]([CH2:9][CH2:10][C:11](=[O:21])[NH:12]2)=[CH:7][CH:6]=1)=[O:20]
Reactant: [H][H]
Reactant: CS(=O)(=O)Oc1cc2c(cc1C(=O)CCCl)NC(=O)CC2
Agent: [Pd]
Solvent: CCO
Product: O=C1CCc2ccc(C(=O)CCCl)cc2N1

Procedure:
3.0 Grams of 6-methylsulfonyloxy-7-(3-chloropropionyl)-3,4-dihydrocarbostyril and 0.5 g of palladium black were suspended in 200 ml of ethanol and the suspension was subjected to catalytic reduction under 3 atmospheric pressure of hydrogen gas at a room temperature for 5 hours under stirring condition. The reaction mixture was filtered and the mother liquor was concentrated under a reduced pressure to obtain a residue. The residue was recrystallized from ethanol to obtain 1.2 g of 7-(3-chloropropionyl)-3,4-dihydrocarbostyril in colorless powdery-like crystals. Melting point: 159°-161° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([N:11]2[C:19]3[C:14](=[C:15]([F:29])[C:16]([O:20][C:21]4[CH:26]=[CH:25][N:24]=[C:23]([CH2:27][OH:28])[CH:22]=4)=[CH:17][CH:18]=3)[CH:13]=[C:12]2[CH3:30])=[O:10])=[CH:4][C:3]=1[C:31]([F:34])([F:33])[F:32].[CH3:35][S:36](Cl)(=[O:38])=[O:37]>ClCCl.[NH4+].[Cl-]>[F:29][C:15]1[C:16]([O:20][C:21]2[CH:26]=[CH:25][N:24]=[C:23]([CH2:27][O:28][S:36]([CH3:35])(=[O:38])=[O:37])[CH:22]=2)=[CH:17][CH:18]=[C:19]2[C:14]=1[CH:13]=[C:12]([CH3:30])[N:11]2[C:9](=[O:10])[NH:8][C:5]1[CH:6]=[CH:7][C:2]([F:1])=[C:3]([C:31]([F:33])([F:32])[F:34])[CH:4]=1
Reactant: CS(=O)(=O)Cl
Reactant: Cc1cc2c(F)c(Oc3ccnc(CO)c3)ccc2n1C(=O)Nc1ccc(F)c(C(F)(F)F)c1
Agent: [Cl-]
Agent: [NH4+]
Solvent: ClCCl
Product: Cc1cc2c(F)c(Oc3ccnc(COS(C)(=O)=O)c3)ccc2n1C(=O)Nc1ccc(F)c(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
4-Fluoro-5-(2-hydroxymethyl-pyridin-4-yloxy)-2-methyl-indole-1-carboxylic acid (4-fluoro-3-trifluoromethyl-phenyl)-amide (370 mg, 0.775 mmol) is placed in dichloromethane (10 mL) and methanesulfonyl chloride (0.15 mL, 1.92 mmol) and TEA (0.4 ml, 2.87 mmol) are added. The reaction is stirred at rt for 20 min before being diluted with dichloromethane and saturated aqueous NH4Cl. The aqueous layer is extracted further with dichloromethane. The combined organic layers are washed with brine and dried over Na2SO4, filtered, and concentrated to give the title compound.
Reaction SMILES: [Cl:1][C:2]1[C:7](=[O:8])[N:6]([C:9]2[CH:10]=[C:11]([CH:19]=[CH:20][C:21]=2[CH3:22])[C:12]([NH:14][CH2:15][C:16](N)=[O:17])=[O:13])[CH:5]=[N:4][C:3]=1[O:23][CH2:24][C:25]1[CH:30]=[CH:29][C:28]([F:31])=[CH:27][C:26]=1[F:32].Cl.N[CH2:35]C(N)=O>>[Cl:1][C:2]1[C:7](=[O:8])[N:6]([C:9]2[CH:10]=[C:11]([CH:19]=[CH:20][C:21]=2[CH3:22])[C:12]([NH:14][CH2:15][C@@H:16]([OH:17])[CH3:35])=[O:13])[CH:5]=[N:4][C:3]=1[O:23][CH2:24][C:25]1[CH:30]=[CH:29][C:28]([F:31])=[CH:27][C:26]=1[F:32]
Reactant: Cc1ccc(C(=O)NCC(N)=O)cc1-n1cnc(OCc2ccc(F)cc2F)c(Cl)c1=O
Reactant: NCC(N)=O
Agent: Cl
Product: Cc1ccc(C(=O)NC[C@H](C)O)cc1-n1cnc(OCc2ccc(F)cc2F)c(Cl)c1=O

Procedure:
The title compound was prepared using a procedure similar to that used in Step 4 of the synthesis of 3-[5-chloro-4-[(2,4-difluorobenzyl)oxy]-6-oxopyrimidin-1(6H)-yl]-N-[1-(aminocarbonyl)methyl]-4-methylbenzamide by substituting (S)-(+)-1-amino-2-propanol for glycineamide HCl. 1H NMR (CD3OD/400 MHz) δ8.32 (s, 1H), 7.92 (m, 1H), 7.77 (s, 1H), 7.61 (q, 1H, J=8.0 Hz), 7.53 (d, 1H, J=8.0 Hz), 7.02 (m, 2H), 5.60 (m, 2H), 3.93 (m, 1H), 3.39 (m, 2H), 2.20 (s, 3H), 1.18 (d, 3H, J=6.4 Hz). ESHRMS m/z 464.1154 (M+H calculated for C22H21ClF2N3O4 requires 464.1183).
Reaction SMILES: Cl.[C:2]([NH:6][CH2:7][CH2:8]Cl)([CH3:5])([CH3:4])[CH3:3].C(=O)([O-])[O-].[K+].[K+].[CH3:16][NH:17][CH3:18]>>[C:2]([NH:6][CH2:7][CH2:8][N:17]([CH3:18])[CH3:16])([CH3:5])([CH3:4])[CH3:3]
Reactant: CC(C)(C)NCCCl
Reactant: CNC
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CN(C)CCNC(C)(C)C
Temperature: 140 °C
Yield: 56 %

Procedure:
2-(t-Butylamino)ethylchloride hydrochloride (1.2 g, 7.0 mmol) is dissolved in aqueous dimethylamine solution (40% by weight, 22 mL) in a sealed tube. The mixture is heated in a 140° C. oil bath for six hours, allowed to cool to room temperature, and then is saturated with solid potassium carbonate. The mixture is extracted thrice with ethyl acetate. The combined extracts are dried over anhydrous sodium sulfate, decanted, and concentrated under reduced pressure to give N-t-butyl,N′,N′-dimethylethylenediamine as a light brown liquid (0.57 g, 56%). The crude material is carried on to the following step without further purification.
Reaction SMILES: [CH2:1]([C@@H:4]1[C:9]2[N:10]=[C:11]([C:21]3[CH:26]=[CH:25][C:24]([NH:27][C:28]([NH:30][CH2:31][CH3:32])=[O:29])=[CH:23][CH:22]=3)[N:12]=[C:13]([N:14]3[CH2:19][CH2:18][O:17][CH2:16][C@@H:15]3[CH3:20])[C:8]=2[CH2:7][CH2:6][N:5]1[C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])[CH:2]=[CH2:3].C(C1C2N=C(Cl)N=C(N3CCOC[C@@H]3C)C=2CCN1C(OC(C)(C)C)=O)C=C>>[CH2:1]([C@H:4]1[C:9]2[N:10]=[C:11]([C:21]3[CH:26]=[CH:25][C:24]([NH:27][C:28]([NH:30][CH2:31][CH3:32])=[O:29])=[CH:23][CH:22]=3)[N:12]=[C:13]([N:14]3[CH2:19][CH2:18][O:17][CH2:16][C@@H:15]3[CH3:20])[C:8]=2[CH2:7][CH2:6][N:5]1[C:33]([O:35][C:36]([CH3:38])([CH3:37])[CH3:39])=[O:34])[CH:2]=[CH2:3]
Reactant: C=CC[C@@H]1c2nc(-c3ccc(NC(=O)NCC)cc3)nc(N3CCOC[C@@H]3C)c2CCN1C(=O)OC(C)(C)C
Agent: C=CCC1c2nc(Cl)nc(N3CCOC[C@@H]3C)c2CCN1C(=O)OC(C)(C)C
Product: C=CC[C@H]1c2nc(-c3ccc(NC(=O)NCC)cc3)nc(N3CCOC[C@@H]3C)c2CCN1C(=O)OC(C)(C)C

Procedure:
and (R)-tert-butyl 8-allyl-2-(4-(3-ethylureido)phenyl)-4-((S)-3-methylmorpholino)-5,6-dihydropyrido[3,4-d]pyrimidine-7(8H)-carboxylate (fc2): Compounds fc1 and fc2 were prepared according to the procedure described in Example 2 step 2 by reacting tert-butyl 8-allyl-2-chloro-4-((S)-3-methylmorpholino)-5,6-dihydropyrido[3,4-d]pyrimidine-7(8H)-carboxylate with (4-ethylureido)phenylboronic acid pinacol ester. The diastereoisomers were separated by chrial column chromatography. LC-MS: m/z=+537 (M+H)+.
Reaction SMILES: [CH2:1]([C:3]1[CH:24]=[C:6]2[C:7]([C:11](=[O:23])[CH:12](C(OC)=O)[CH2:13][C:14]([O:16]CC)=[O:15])=[CH:8][CH:9]=[CH:10][N:5]2[N:4]=1)[CH3:2].[OH-].[K+]>Br>[CH2:1]([C:3]1[CH:24]=[C:6]2[C:7]([C:11](=[O:23])[CH2:12][CH2:13][C:14]([OH:16])=[O:15])=[CH:8][CH:9]=[CH:10][N:5]2[N:4]=1)[CH3:2]
Reactant: CCOC(=O)CC(C(=O)OC)C(=O)c1cccn2nc(CC)cc12
Agent: Br
Agent: [K+]
Agent: [OH-]
Product: CCc1cc2c(C(=O)CCC(=O)O)cccn2n1
Temperature: 130 °C
Reaction time: 1 h

Procedure:
The compound of Example 182 (as a mixture) was dissolved in 47% hydrobromic acid (20 mL) and the mixture was stirred at 130° C. for 1 hour. After cooling, a 20% aqueous potassium hydroxide solution was added to make the mixture basic. The mixture was then washed with diethyl ether and diluted hydrochloric acid was added to make the aqueous layer acidic. The mixture was extracted with ethyl acetate and the organic layer was washed with water and saturated brine and dried over anhydrous sodium sulfate. Evaporation of the solvent afforded a pale yellow powder. The crude product was used in the subsequent reaction without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C@@H:8]2[C@@H:13]([C:14]3[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=3)[N:12]([C@@H:21]([CH2:24][CH3:25])[CH:22]=O)[C:11](=[O:26])[C@:10]([CH2:28][C:29]([OH:31])=[O:30])([CH3:27])[CH2:9]2)[CH:5]=[CH:6][CH:7]=1.Cl.[F:33][C:34]([F:41])([F:40])[C:35]1([OH:39])[CH2:38][NH:37][CH2:36]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[Cl:1][C:2]1[CH:3]=[C:4]([C@@H:8]2[C@@H:13]([C:14]3[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=3)[N:12]([C@@H:21]([CH2:24][CH3:25])[CH2:22][N:37]3[CH2:38][C:35]([OH:39])([C:34]([F:41])([F:40])[F:33])[CH2:36]3)[C:11](=[O:26])[C@:10]([CH2:28][C:29]([OH:31])=[O:30])([CH3:27])[CH2:9]2)[CH:5]=[CH:6][CH:7]=1
Reactant: OC1(C(F)(F)F)CNC1
Reactant: CC[C@@H](C=O)N1C(=O)[C@@](C)(CC(=O)O)C[C@H](c2cccc(Cl)c2)[C@H]1c1ccc(Cl)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: ClCCCl
Product: CC[C@@H](CN1CC(O)(C(F)(F)F)C1)N1C(=O)[C@@](C)(CC(=O)O)C[C@H](c2cccc(Cl)c2)[C@H]1c1ccc(Cl)cc1
Reaction time: 18 h

Procedure:
To a solution of 2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxo-1-((S)-1-oxobutan-2-yl)piperidin-3-yl)acetic acid (70 mg, 0.151 mmol; Example 210, Step A) in DCE (3 mL) was added 53.8 mg (0.303 mmol) of 3-(trifluoromethyl)azetidin-3-ol hydrochloride (U.S. patent application publication no 2007/0275930) and sodium triacetoxyborohydride (64.2 mg, 0.303 mmol). After stirring for 18 hours, the mixture was partitioned between water and DCM. The aqueous layer was washed with DCM. The combined organic layers were washed with sat. aq. NaCl solution, dried over anhydrous Na2SO4, filtered and the filtrate was concentrated. The residue was purified by preparative thin layer chromatography on silica gel (eluent: 50% ethyl acetate/hexanes) to afford the title compound.
Reaction SMILES: [CH3:1][C:2]1([S:5]([N:8]2[CH2:11][CH:10]([O:12][Si](CC)(CC)CC)[CH2:9]2)(=[O:7])=[O:6])[CH2:4][CH2:3]1.C(=O)(O)[O-].[Na+]>O1CCCC1.O.C(O)(=O)C>[CH3:1][C:2]1([S:5]([N:8]2[CH2:9][CH:10]([OH:12])[CH2:11]2)(=[O:7])=[O:6])[CH2:4][CH2:3]1
Reactant: CC[Si](CC)(CC)OC1CN(S(=O)(=O)C2(C)CC2)C1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: CC1(S(=O)(=O)N2CC(O)C2)CC1

Procedure:
A solution of 1-[(1-methylcyclopropyl)sulfonyl]-3-[(triethylsilyl)oxy]azetidine (0.125 g, 0.41 mmol) in tetrahydrofuran (3 mL), water (1 mL) and acetic acid (1 mL) was stirred at room temperature for four hours. The mixture was neutralized by pouring into a solution of sodium bicarbonate. The product was extracted with ethyl acetate, the extracts were washed with brine, dried over sodium sulfate, decanted and concentrated to afford product, used without further purification (64 mg, 82%).
Reaction SMILES: [CH3:1][CH2:2][CH2:3][CH2:4][CH2:5][O:6]N=O.[CH2:9]=[C:10]=[O:11].[C]=O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[Cl-].C([N+](CCCC)(CCCC)CCCC)CCC.CN1CCCC1=O.CCCCCCC>[CH3:1][CH2:2][CH2:3][CH2:4][CH2:5][O:6][C:10]([CH3:9])=[O:11]
Reactant: CCCCCON=O
Reactant: C=C=O
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [C]=O
Agent: [Cl-]
Solvent: CCCCCCC
Solvent: CN1CCCC1=O
Product: CCCCCOC(C)=O
Reaction time: 4 h
Yield: 14 %

Procedure:
To the same reaction vessel as in Example 9 were charged bistriphenylphosphinedibromopalladium (0.198 g, 0.25 mmole), stannous chloride (0.095 g, 0.5 mmole), tetra-n-butylammonium chloride (0.139 g, 0.5 mmole) and n-amyl nitrite (55 ml, 368.9 mmoles), together with n-heptane (175 ml) and N-methylpyrrolidone (25 ml). Then, ketene, carbon monooxide and nitrogen were introduced to the mixture at the rate of 11.4 ml/min (0.51 mmole/min), 300 ml/min and 100 ml/min, respectively, and the reaction was effected at 90° C. for 4 hours. During the reaction, 10 ml of a solution of triphenylphosphine (0.061 g, 0.25 mmole) and stannous chloride (0.0475 g, 0.25 mmole) of N-methylpyrrolidone was added to the reaction system in 2.5 ml portions every 1 hour. The gas chromatographic analysis revealed that di-n-amyl malonate (103.9 mmoles, 84.9%) and n-amyl acetate (17.1 mmoles, 14.0%) were obtained.
Reaction SMILES: [Cl:1][C:2]1[C:12]([CH:13]=O)=[CH:11][CH:10]=[C:9]([Si:15]([CH3:18])([CH3:17])[CH3:16])[C:3]=1[C:4]([NH:6][CH2:7][CH3:8])=[O:5].[N+:19]([CH3:22])([O-:21])=[O:20].[OH-].[Na+].Cl>CO>[Cl:1][C:2]1[C:12](/[CH:13]=[CH:22]/[N+:19]([O-:21])=[O:20])=[CH:11][CH:10]=[C:9]([Si:15]([CH3:18])([CH3:17])[CH3:16])[C:3]=1[C:4]([NH:6][CH2:7][CH3:8])=[O:5]
Reactant: C[N+](=O)[O-]
Reactant: CCNC(=O)c1c([Si](C)(C)C)ccc(C=O)c1Cl
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CCNC(=O)c1c([Si](C)(C)C)ccc(/C=C/[N+](=O)[O-])c1Cl
Yield: 26.2 %

Procedure:
To a solution of the compound of Example 223 (0.199 g, 0.7 mmol) in methanol (5 mL) at 0° C. was added nitromethane (0.3 mL, 5.0 mmol) and 2.5 N NaOH (2.3 mL, 5.8 mmol) portionwise over 2 h. The suspension was dissolved by addition of ice-cold water and cold 2 N HCl (10 mL) was added. The precipitate was filtered and washed with water to afford the crude title compound. The crude product was purified by recrystallization from aq methanol to afford the title compound as a light yellow fluffy solid (60 mg, 26%). m.p. 104-106° C.
Reaction SMILES: [Cl:1][CH2:2][C:3](=[O:10])[CH2:4][C:5]([O:7][CH2:8][CH3:9])=[O:6].[CH:11](=O)[CH3:12].N1CCCCC1.Cl.[Cl-].[Na+]>C(OCC)(=O)C>[CH:11](=[C:4]([C:3](=[O:10])[CH2:2][Cl:1])[C:5]([O:7][CH2:8][CH3:9])=[O:6])[CH3:12]
Reactant: CCOC(=O)CC(=O)CCl
Reactant: CC=O
Agent: Cl
Agent: [Cl-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1CCNCC1
Product: CC=C(C(=O)CCl)C(=O)OCC
Temperature: -75 °C
Reaction time: 2 h

Procedure:
50 parts by weight of ethyl 4-chloroacetoacetate and 76 parts by volume of ethyl acetate are taken, covered with a layer of nitrogen and cooled to -75° C. 33 parts by weight of acetaldehyde are added to the cold solution and a solution of 0.43 part by volume of piperidine in 3 parts by volume of ethyl acetate is then allowed to run in over a period of 50 minutes. The solution is now warmed to 0° C. in the course of 40 minutes and is stirred at this temperature for 2 hours. After addition of 121 parts by volume of 1N hydrochloric acid and 16 parts by weight of sodium chloride, the mixture is worked up. The organic phase is separated off and the aqueous phase is extracted again with 45 parts by volume of ethyl acetate. The combined organic phases are extracted twice with a solution of in each case 16 parts by weight of sodium chloride in 55 parts by volume of water and dried. After the solvent has been stripped off, 51.9 parts by weight of product remain, which can be further processed in the crude form.