Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:13]=[C:12]([C:14]([OH:16])=O)[CH:11]=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.[N:17]1([NH2:23])[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1>>[N:17]1([NH:23][C:14]([C:12]2[CH:11]=[CH:10][CH:9]=[C:8]([C:5]3[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=3)[N:13]=2)=[O:16])[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1
Reactant: O=C(O)c1cccc(-c2ccc(Cl)cc2)n1
Reactant: NN1CCCCC1
Product: O=C(NN1CCCCC1)c1cccc(-c2ccc(Cl)cc2)n1

Procedure:
The title compound was synthesized in analogy to Example 1, using 6-(4-chlorophenyl)-2-pyridinecarboxylic acid (CAN 135432-77-8) and 1-piperidinamine (CAN 2213-43-6) as starting materials, MS (EI): m/e=316.1 [M+H]+.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH3:17])[CH:7]=[CH:8][C:9]=1[O:10][CH:11]([F:16])[C:12]([F:15])([F:14])[F:13])([O-:3])=[O:2].[N+:18]([O-])([O-:20])=[O:19].[K+]>S(=O)(=O)(O)O>[N+:18]([C:5]1[C:4]([N+:1]([O-:3])=[O:2])=[C:9]([O:10][CH:11]([F:16])[C:12]([F:14])([F:15])[F:13])[CH:8]=[CH:7][C:6]=1[CH3:17])([O-:20])=[O:19]
Reactant: Cc1ccc(OC(F)C(F)(F)F)c([N+](=O)[O-])c1
Reactant: O=[N+]([O-])[O-]
Agent: O=S(=O)(O)O
Agent: [K+]
Product: Cc1ccc(OC(F)C(F)(F)F)c([N+](=O)[O-])c1[N+](=O)[O-]
Reaction time: 2 h

Procedure:
1.5 g (5.9 mmoles) 3-nitro-4-tetrafluoroethoxytoluene is placed in 7.5 ml concentrated sulfuric acid and 0.65 g (6.4 mmoles) potassium nitrate in 3 ml concentrated sulfuric acid is added dropwise at 0° C. After the addition is terminated it is agitated for 2 hours at ice bath temperature and then poured onto ice. The dinitro compound precipitates as an oil and is extracted with ether. The combined ether phases are washed with sodium bicarbonate solution and water and dried over sodium sulfate. When the solvent is distilled the 2,3-dinitro-4-tetrafluoroethoxytoluene remains as a yellow oil which crystalizes after standing for a short time. Yield: 1.55 g (88% of the theoretical yield), melting point: 35° C.
Reaction SMILES: [CH2:1]([N:3]([CH2:14][CH3:15])[C:4]1[CH:5]=[CH:6][C:7]([C:10]([O:12]C)=[O:11])=[N:8][CH:9]=1)[CH3:2].[OH-].[Na+].Cl>CO.O>[CH2:14]([N:3]([CH2:1][CH3:2])[C:4]1[CH:5]=[CH:6][C:7]([C:10]([OH:12])=[O:11])=[N:8][CH:9]=1)[CH3:15]
Reactant: CCN(CC)c1ccc(C(=O)OC)nc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CCN(CC)c1ccc(C(=O)O)nc1
Temperature: 25 °C

Procedure:
To a stirred solution containing 2.5 g of methyl 5-diethylaminopicolinate in 40 ml methanol is added 40 ml water and 1.04 g of a 50% solution of NaOH in water. The mixture is heated to reflux and allowed to cool to room temperature. This is repeated. The base is neutralized with concentrated HCl, and the solvents removed in vacuo. The residue is dried azeotropically with dioxane. The residue is taken extracted into ethanol. Concentration of the ethanol gives 5-diethylaminopicolinic acid as a white crystalline solid, mp 145.5°-147.5° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH:7]=[C:6]2[CH2:12][CH2:13][CH2:14][C:15](O)=O.O.ON1C2C=CC=CC=2N=N1.C(N=C=NC(C)C)(C)C.Cl.[CH3:39][S:40]([NH:43][C:44]1[CH:45]=[CH:46][C:47]2[O:52][CH2:51][CH:50]([CH2:53][NH2:54])[O:49][C:48]=2[CH:55]=1)(=[O:42])=[O:41]>CN(C=O)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH:7]=[C:6]2[CH2:12][CH2:13][CH2:14][CH2:15][NH:54][CH2:53][CH:50]1[CH2:51][O:52][C:47]2[CH:46]=[CH:45][C:44]([NH:43][S:40]([CH3:39])(=[O:42])=[O:41])=[CH:55][C:48]=2[O:49]1
Reactant: COc1ccc2[nH]cc(CCCC(=O)O)c2c1
Reactant: CS(=O)(=O)Nc1ccc2c(c1)OC(CN)CO2
Agent: CC(C)N=C=NC(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccc2[nH]cc(CCCCNCC3COc4ccc(NS(C)(=O)=O)cc4O3)c2c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 81.6 %

Procedure:
5-Methoxyindole-3-butyric acid (0.75 g, 3.2 mmole), 1-hydroxybenzotriazole hydrate (0.52 g, 3.8 mmole) and 1,3-diisopropylcarbodiimide (1.2 ml, 7.6 mmole) were combined in 100 ml of DMF and stirred at room temperature for 2 hours under a nitrogen atmosphere. To this was added dropwise 7-methylsulfonylamino-2,3-dihydro-1,4-benzodioxin-2-methanamine hydrochloride (0.9 g, 3.2 mmole) in 50 ml of DMF and the mixture was further stirred for 48 hours. The solvent was removed and the residue partitioned between dichloromethane and water. The separated dichloromethane layer was dried over anhydrous sodium sulfate, filtered and concentrated in vacuum. The residue was chromatographed on a silica gel column using first ethyl acetate and then 2.5% methanol in ethyl acetate as eluants. Fractions were concentrated and washed with a minimum amount of THF to remove a byproduct and to give 1.2 g (79%) of the desired product, (7-methylsulfonyl amino-2,3-dihydro-benzo[1,4]dioxin-2-ylmethyl)-4-(5-methoxy-1H-indol-3-yl)-butanamide, as a oily white solid.
Reaction SMILES: C([O:3][C:4](=[O:30])[CH2:5][CH:6]([N:10]1[C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=2[N:12]([CH2:19][C:20]2[C:24]3[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=3[O:22][N:21]=2)[C:11]1=[O:29])[CH2:7][CH2:8][CH3:9])C.O.[OH-].[Li+]>C1COCC1.O>[O:22]1[C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=2[C:20]([CH2:19][N:12]2[C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[N:10]([CH:6]([CH2:7][CH2:8][CH3:9])[CH2:5][C:4]([OH:30])=[O:3])[C:11]2=[O:29])=[N:21]1
Reactant: CCCC(CC(=O)OCC)n1c(=O)n(Cc2noc3ccccc23)c2ccccc21
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CCCC(CC(=O)O)n1c(=O)n(Cc2noc3ccccc23)c2ccccc21
Reaction time: 1 h
Yield: 80.6 %

Procedure:
To a stirred solution of 3-(3-1,2-benzisoxazol-3-ylmethyl-2-oxo-2,3-dihydro-benzimidazol-1-yl)-hexanoic acid ethyl ester (70 mg, 0.17 mmol) in THF (5 ml) and water (0.5 ml) was added lithium hydroxide monohydrate (22 mg, 0.52 mmol). Upon complete consumption of the starting material, the reaction was concentrated to low volume and diluted with water (20 ml) and acetic acid (0.5 ml). The resulting heterogeneous mixture was stirred for 1 h after which time the precipitated product was collected via filtration. The solid was washed with water and dried on house vacuum at 40° C. (18 h, over P2O5) to give 52 mg (80%) of the desired product. LCMS (ESMS): m/z 380.41 (M+H+).
Reaction SMILES: [CH:1]([O:4][C:5](=[O:14])[C:6]1[CH:11]=[C:10]([CH3:12])[C:9](Cl)=[N:8][CH:7]=1)([CH3:3])[CH3:2].[CH:15]([NH2:18])([CH3:17])[CH3:16]>O1CCOCC1>[CH:1]([O:4][C:5](=[O:14])[C:6]1[CH:11]=[C:10]([CH3:12])[C:9]([NH:18][CH:15]([CH3:17])[CH3:16])=[N:8][CH:7]=1)([CH3:3])[CH3:2]
Reactant: CC(C)N
Reactant: Cc1cc(C(=O)OC(C)C)cnc1Cl
Solvent: C1COCCO1
Product: Cc1cc(C(=O)OC(C)C)cnc1NC(C)C

Procedure:
A solution of 6-chloro-5-methyl-nicotinic acid isopropyl ester (200 mg, 0.936 mmol) in dioxane (5 mL) and isopropylamine (3 mL) is stirred in a sealed vial at 100° C. for 1 week. The solvent is evaporated and the residue dissolved in DCM (50 mL) and washed with sat. aq. NaHCO3 solution (20 mL). The org. extract is dried over MgSO4, filtered and concentrated. The crude product is purified on prep. TLC plates with heptane:EA 1:1 to give 6-isopropylamino-5-methyl-nicotinic acid isopropyl ester (137 mg) as a yellow oil; LC-MS: tR=0.68 min, [M+1]+=237.02.
Reaction SMILES: C#N.C(=O)C1C=CC=CC=1.[C:11]([CH:13]([OH:20])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)#[N:12]>ClCCl.[Ti]>[C:11]([C@H:13]([OH:20])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)#[N:12]
Reactant: N#CC(O)c1ccccc1
Agent: [Ti]
Agent: C#N
Solvent: ClCCl
Solvent: O=Cc1ccccc1
Product: N#C[C@H](O)c1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 55 %

Procedure:
To a solution of L(+)-diethyl tartarate (412 mg) in absolute dichloromethane (20 ml), tetaraisopropyl titanate (568 mg) was dropwise added and stirred at room temperature for 30 minutes. After evaporating volatile components off in the same manner as in Example 1, to the residue, dichloromethane (20 ml) was added and stirred at room temperature to obtain a homogeneous solution. After cooling the resulting solution to 0° C., hydrogen cyanide (0.4 ml) and then benzaldehyde (212 mg) were added and stirred at room temperature for 15 hours. Thereafter, the reaction mixture was treated in the same manner as in Example 1 and analyzed by HPLC to reveal that α-cyanobenzyl alcohol was produced in the yield of 55% which contained the R(+) isomer with the enantiomer excess percentage of 77%.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][S:5](=[O:38])([C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)=[N:6][C:7](=[O:31])[C:8]1[CH:13]=[C:12]([C:14]#[C:15][C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([NH:22][C:23]([C:25]3[O:26][CH:27]=[CH:28][C:29]=3[CH3:30])=[O:24])[CH:17]=2)[CH:11]=[N:10][CH:9]=1.[F:39][CH:40]1[CH2:45][CH2:44][CH2:43][NH:42][CH2:41]1>>[F:39][CH:40]1[CH2:45][CH2:44][CH2:43][N:42]([CH2:2][CH2:3][CH2:4][S:5](=[O:38])([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)=[N:6][C:7](=[O:31])[C:8]2[CH:13]=[C:12]([C:14]#[C:15][C:16]3[CH:21]=[CH:20][CH:19]=[C:18]([NH:22][C:23]([C:25]4[O:26][CH:27]=[CH:28][C:29]=4[CH3:30])=[O:24])[CH:17]=3)[CH:11]=[N:10][CH:9]=2)[CH2:41]1
Reactant: FC1CCCNC1
Reactant: Cc1ccoc1C(=O)Nc1cccc(C#Cc2cncc(C(=O)N=S(=O)(CCCBr)c3ccccc3)c2)c1
Product: Cc1ccoc1C(=O)Nc1cccc(C#Cc2cncc(C(=O)N=S(=O)(CCCN3CCCC(F)C3)c3ccccc3)c2)c1

Procedure:
In a manner similar to that described for example 508, N-[(3-bromopropyl)(oxido)phenyl--sulfanylidene]-5-({3-[(3-methyl-2-furoyl)amino]phenyl}ethynyl)nicotinamide and 3-fluoropiperidine were converted to the title compound.
Reaction SMILES: [CH3:1][O:2][P:3]([CH2:7][P:8]([O:12][CH3:13])([O:10][CH3:11])=[O:9])([O:5][CH3:6])=[O:4].Br[CH2:15][C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17].CC(C)([O-])C.[K+]>C1COCC1>[C:19]([O:18][C:16](=[O:17])[CH2:15][CH:7]([P:3]([O:5][CH3:6])([O:2][CH3:1])=[O:4])[P:8]([O:10][CH3:11])([O:12][CH3:13])=[O:9])([CH3:22])([CH3:21])[CH3:20]
Reactant: CC(C)(C)OC(=O)CBr
Reactant: COP(=O)(CP(=O)(OC)OC)OC
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: COP(=O)(OC)C(CC(=O)OC(C)(C)C)P(=O)(OC)OC
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To an ice cooled solution of bis(dimethoxyphosphoryl)methane (4.64 g, 20 mmol) and tert-butyl bromoacetate (7.35 ml, 50 mmol) in dry THF (40 ml) under nitrogen was added potassium tert-butoxide (5.8 g, 43 mmol). The reaction mixture was stirred at room temperature overnight and then quenched with 4 ml of saturated ammonium chloride. The volatiles were removed in vacuum and by two cycles of toluene addition and evaporation. Flash chromatography in dichloromethane:methanol, 95:5 on gave the product as an oil. Yield 4.0 g.
Reaction SMILES: [OH:1][C:2]1([C:5]([O:7][CH2:8][CH3:9])=[O:6])[CH2:4][CH2:3]1.CC1C=CC(S(O)(=O)=O)=CC=1.[CH2:21]1[CH2:26][O:25][CH:24]=[CH:23][CH2:22]1>C(Cl)Cl>[O:25]1[CH2:26][CH2:21][CH2:22][CH2:23][CH:24]1[O:1][C:2]1([C:5]([O:7][CH2:8][CH3:9])=[O:6])[CH2:4][CH2:3]1
Reactant: C1=COCCC1
Reactant: CCOC(=O)C1(O)CC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: ClCCl
Product: CCOC(=O)C1(OC2CCCCO2)CC1
Temperature: 25 °C
Reaction time: 20 h
Yield: 87.5 %

Procedure:
To a solution of ethyl 1-hydroxycyclopropanecarboxylate (1040 mg, 8.000 mmol) and PTSA (137 mg, 0.800 mmol) in DCM (20 mL) was added a solution of DHP (1344 mg, 16.00 mmol) in DCM (10 mL) dropwise at 0° C. The mixture was stirred for 20 h at room temperature. After concentration, the residue was purified by silica gel column chromatography eluting with petroleum ether/ethyl acetate (10/1) to afford the title compound (1500 mg, 85%) as oil. LC-MS (ESI): m/z=215 (M+H)+.
Reaction SMILES: [F:1][C:2]1([F:17])[O:6][C:5]2[CH:7]=[CH:8][C:9]([C:11]3([C:14]([OH:16])=O)[CH2:13][CH2:12]3)=[CH:10][C:4]=2[O:3]1.S(Cl)(Cl)=O.[CH3:22][C:23]1[CH:24]=[CH:25][C:26]([NH2:29])=[N:27][CH:28]=1.C(N(CC)CC)C>ClCCl.CN(C)C=O>[F:17][C:2]1([F:1])[O:6][C:5]2[CH:7]=[CH:8][C:9]([C:11]3([C:14]([NH:29][C:26]4[CH:25]=[CH:24][C:23]([CH3:22])=[CH:28][N:27]=4)=[O:16])[CH2:12][CH2:13]3)=[CH:10][C:4]=2[O:3]1
Reactant: O=C(O)C1(c2ccc3c(c2)OC(F)(F)O3)CC1
Reactant: Cc1ccc(N)nc1
Solvent: O=S(Cl)Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: Cc1ccc(NC(=O)C2(c3ccc4c(c3)OC(F)(F)O4)CC2)nc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 48.8 %

Procedure:
1-(2,2-Difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarboxylic acid (2.32 g, 9.58 mmol) was placed in an oven-dried flask under nitrogen. Thionyl chloride (3 mL) and N,N-dimethylformamide (0.3 mL) were added and the solution was allowed to stir for 30 minutes at room temperature. The excess thionyl chloride was removed under vacuum and the resulting solid was suspended in anhydrous dichloromethane (10 mL). This solution was then slowly added to a solution 5-methylpyridin-2-amine (0.798 g, 7.38 mmol) in anhydrous dichloromethane (10 mL) containing triethylamine (4.11 mL, 29.5 mmol). The resulting mixture was allowed to stir for 15 hours at room temperature. The crude product was then washed two times with a 1M aqueous solution of hydrochloric acid, two times with a saturated aqueous solution of sodium bicarbonate, and finally two times with a saturated aqueous solution of sodium chloride. The organic layer was dried over sodium sulfate, evaporated to near dryness, and then purified on 120 g of silica gel utilizing a gradient of 0-30% ethyl acetate in hexanes to yield the pure product (1.20 g, 3.60 mmol, 48.7%). ESI-MS m/z calc. 332.1. found 333.1 (M+1)+. Retention time 1.48 minutes.
Reaction SMILES: [C:1]1([C:11]2([CH2:16][C:17]([NH2:19])=[NH:18])[CH2:15][CH2:14][CH2:13][CH2:12]2)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.Cl.[C:21]([O:25][C:26](=[O:41])/[C:27](/O)=[C:28](\[O:32][CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)/[C:29](O)=[O:30])([CH3:24])([CH3:23])[CH3:22].C[O-].[Na+]>CO.CCCCCC.C(OCC)(=O)C>[C:21]([O:25][C:26]([C:27]1[C:28]([O:32][CH2:33][C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)=[C:29]([OH:30])[N:19]=[C:17]([CH2:16][C:11]2([C:1]3[C:10]4[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=4)[CH:4]=[CH:3][CH:2]=3)[CH2:15][CH2:14][CH2:13][CH2:12]2)[N:18]=1)=[O:41])([CH3:24])([CH3:22])[CH3:23]
Reactant: N=C(N)CC1(c2cccc3ccccc23)CCCC1
Reactant: CC(C)(C)OC(=O)/C(O)=C(\OCc1ccccc1)C(=O)O
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)c1nc(CC2(c3cccc4ccccc34)CCCC2)nc(O)c1OCc1ccccc1
Temperature: 0 °C
Yield: 48 %

Procedure:
To a stirred solution of 2-(1-naphthalen-1-yl-cyclopentyl)-acetamidine; hydrochloride (343) (4.5 g, crude) in methanol (30 mL) were added (E,Z)-2-benzyloxy-3-hydroxy-but-2-enedioic acid 4-tert-butyl ester 1-methyl ester (4) (5.759 g, 18.7 mmol) and the reaction mixture was cooled to 0° C. in a ice bath. To this reaction mixture was then added sodium methoxide (25% in methanol, 10.1 mL, 46.74 mmol) and the reaction mixture was stirred at room temperature for 18 h (silica TLC, 50% ethyl acetate in hexane; Rf=0.5). The reaction mixture was diluted with ethyl acetate (100 mL) and washed with water (50 mL) and brine (50 mL). The organic phase was thereafter dried and concentrated under vacuum to get a crude mass which was purified by CombiFlash eluted with a gradient mixture of ethyl acetate and hexane to get pure 5-benzyloxy-6-hydroxy-2-(1-naphthalen-1-yl-cyclopentylmethyl)-pyrimidine-4-carboxylic acid tert-butyl ester (344) (4.1 g, 48%, 2 steps) as a brown sticky mass.
Reaction SMILES: [F:1][C:2]1[CH:20]=[CH:19][C:5]([CH2:6][N:7]2[C:11]3=[CH:12][N:13]=[C:14]([C:16]([OH:18])=O)[CH:15]=[C:10]3[CH:9]=[CH:8]2)=[CH:4][CH:3]=1.Cl.[CH2:22]([NH:29][OH:30])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>>[CH2:22]([N:29]([OH:30])[C:16]([C:14]1[CH:15]=[C:10]2[CH:9]=[CH:8][N:7]([CH2:6][C:5]3[CH:4]=[CH:3][C:2]([F:1])=[CH:20][CH:19]=3)[C:11]2=[CH:12][N:13]=1)=[O:18])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: ONCc1ccccc1
Reactant: O=C(O)c1cc2ccn(Cc3ccc(F)cc3)c2cn1
Agent: Cl
Product: O=C(c1cc2ccn(Cc3ccc(F)cc3)c2cn1)N(O)Cc1ccccc1

Procedure:
The title compound was prepared by coupling of 1-(4-fluorobenzyl)-1H-pyrrolo[2,3-c]pyridine-5-carboxylic acid with N-benzyl hydroxylamine hydrochloride in a manner similar to step (c) of example 1. 1H NMR (DMSO-d6) δ; 8.92 (s, 1H), 8.11 (s, 1H), 7.91 (d, 1H, J=2.8 Hz), 7.26–7.38 (m, 7H), 7.16 (d, 2H, J=8.5 Hz), 6.72 (d, 1H, J=2.8 Hz), 5,58 (s, 2H), 4.97 (s, 2H). LCMS (API-ES, M+H+): 376.1, HRMS calcd for C22H19FN3O2 (M+H) 376.1461. found 376.1448. Anal. (C22H18FN3O2) C, H, N. HPLC: 100% purity.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][N:5]=[CH:4][C:3]=1[N:8]1[CH2:12][CH2:11][NH:10][C:9]1=[O:13].I[C:15]1[CH:16]=[C:17]2[C:21](=[CH:22][CH:23]=1)[N:20]([CH2:24][O:25][CH2:26][CH2:27][Si:28]([CH3:31])([CH3:30])[CH3:29])[C:19](=[O:32])[C:18]2([CH3:34])[CH3:33].N[C@@H]1CCCC[C@H]1N.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>[Cu](I)I.O1CCOCC1>[CH3:33][C:18]1([CH3:34])[C:17]2[C:21](=[CH:22][CH:23]=[C:15]([N:10]3[CH2:11][CH2:12][N:8]([C:3]4[CH:4]=[N:5][CH:6]=[CH:7][C:2]=4[CH3:1])[C:9]3=[O:13])[CH:16]=2)[N:20]([CH2:24][O:25][CH2:26][CH2:27][Si:28]([CH3:31])([CH3:30])[CH3:29])[C:19]1=[O:32]
Reactant: CC1(C)C(=O)N(COCC[Si](C)(C)C)c2ccc(I)cc21
Reactant: Cc1ccncc1N1CCNC1=O
Agent: I[Cu]I
Agent: N[C@@H]1CCCC[C@H]1N
Agent: O=P([O-])([O-])[O-]
Solvent: C1COCCO1
Product: Cc1ccncc1N1CCN(c2ccc3c(c2)C(C)(C)C(=O)N3COCC[Si](C)(C)C)C1=O
Yield: 52 %

Procedure:
Using the same reaction conditions as in Example 14, 1-(4-methyl-pyridin-3-yl)-imidazolidin-2-one (I-14b: 0.123 g, 0.0007 mol) was reacted with 5-iodo-3,3-dimethyl-1-(2-trimethylsilanyl-ethoxymethyl)-1,3-dihydro-indol-2-one (0.29 g, 0.0007 mol), 1,4-dioxane (20 mL), copper iodide (0.013 g, 0.00007 mol), trans-1,2-diamino cyclohexane (0.028 g, 0.00025 mol) and potassium phosphate (356 mg, 0.00168 mol) to afford the crude product. Purification by column chromatography on silica gel (80% ethylacetate in hexane) afforded 170 mg of 3,3-Dimethyl-5-[3-(4-methyl-pyridin-3-yl)-2-oxo-imidazolidin-1-yl]-1-(2-trimethylsilanyl-ethoxymethyl)-1,3-dihydro-indol-2-one (52.14% yield).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:28])[CH2:5][C:6]1([C:9]2[CH:14]=[CH:13][C:12]([C:15]3[CH:20]=[CH:19][C:18]([C:21]4[O:25][N:24]=[C:23]([CH3:26])[C:22]=4[NH2:27])=[CH:17][CH:16]=3)=[CH:11][CH:10]=2)[CH2:8][CH2:7]1)[CH3:2].Br[C:30]1[CH:35]=[CH:34][CH:33]=[C:32]([C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)[N:31]=1>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH2:1]([O:3][C:4](=[O:28])[CH2:5][C:6]1([C:9]2[CH:10]=[CH:11][C:12]([C:15]3[CH:20]=[CH:19][C:18]([C:21]4[O:25][N:24]=[C:23]([CH3:26])[C:22]=4[NH:27][C:30]4[CH:35]=[CH:34][CH:33]=[C:32]([C:36]5[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=5)[N:31]=4)=[CH:17][CH:16]=3)=[CH:13][CH:14]=2)[CH2:8][CH2:7]1)[CH3:2]
Reactant: CCOC(=O)CC1(c2ccc(-c3ccc(-c4onc(C)c4N)cc3)cc2)CC1
Reactant: Brc1cccc(-c2ccccc2)n1
Agent: [Pd+2]
Agent: [Pd]
Agent: CC(=O)[O-]
Product: CCOC(=O)CC1(c2ccc(-c3ccc(-c4onc(C)c4Nc4cccc(-c5ccccc5)n4)cc3)cc2)CC1

Procedure:
Prepared according to the procedure described in Example 68, Step 2, using {1-[4′-(4-amino-3-methyl-isoxazol-5-yl)-biphenyl-4-yl]-cyclopropyl}-acetic acid ethyl ester and 2-bromo-6-phenyl-pyridine. Additionally, palladium(II) acetate was used as the catalyst in place of tris(dibenzylideneacetone)dipalladium(0).
Reaction SMILES: [CH2:1]([N:3]([S:9]([C:12]1[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=1)(=[O:11])=[O:10])[C:4](=[CH2:8])[C:5]([OH:7])=O)[CH3:2].CCOC(OC(OCC)=O)=O.[F:30][C:31]([F:48])([F:47])[O:32][C:33]1[CH:38]=[CH:37][C:36]([C:39]2[CH:44]=[C:43]([CH2:45][NH2:46])[CH:42]=[CH:41][N:40]=2)=[CH:35][CH:34]=1>C1COCC1>[F:18][C:15]1[CH:16]=[CH:17][C:12]([S:9]([N:3]([CH2:1][CH3:2])[C:4](=[CH2:8])[C:5]([NH:46][CH2:45][C:43]2[CH:42]=[CH:41][N:40]=[C:39]([C:36]3[CH:35]=[CH:34][C:33]([O:32][C:31]([F:48])([F:30])[F:47])=[CH:38][CH:37]=3)[CH:44]=2)=[O:7])(=[O:11])=[O:10])=[CH:13][CH:14]=1
Reactant: C=C(C(=O)O)N(CC)S(=O)(=O)c1ccc(F)cc1
Reactant: NCc1ccnc(-c2ccc(OC(F)(F)F)cc2)c1
Agent: CCOC(=O)OC(=O)OCC
Solvent: C1CCOC1
Product: C=C(C(=O)NCc1ccnc(-c2ccc(OC(F)(F)F)cc2)c1)N(CC)S(=O)(=O)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 22.9 %

Procedure:
A solution of acid 4B (0.25 g, 1 mmol) in THF (20 mL) was added with DEPC (0.17 mL, 1.3 mol eq) and the mixture was stirred at room temperature for about 5 minutes. Then [2-[4-(trifluoromethoxy)phenyl]-4-pyridyl]methanamine 21B (0.27 g, 1.1 mol eq) and a catalytic amount of TEA were added, then the reaction mixture was stirred at room temperature overnight. The solvent was removed under reduced pressure, the residue was suspended in EtOAc (30 mL) and washed with water (50 mL) and brine. The separated organic phase, after drying over Na2SO4, was evaporated under reduced pressure and the residue purified by flash chromatography (7:3 EtOAc:Petroleum ether) to afford a pale orange solid (0.12 g) after crystallization from a mixture of diethyl ether/petroleum ether.
Reaction SMILES: C[O:2][C:3]([CH:5]1[CH2:17][CH2:16][C:15]2[C:14]3[C:9](=[CH:10][CH:11]=[C:12]([Cl:18])[CH:13]=3)[NH:8][C:7]=2[CH2:6]1)=O.[NH3:19]>CO>[Cl:18][C:12]1[CH:13]=[C:14]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7]1[CH2:6][CH:5]([C:3]([NH2:19])=[O:2])[CH2:17][CH2:16][C:15]2=1
Reactant: COC(=O)C1CCc2c([nH]c3ccc(Cl)cc23)C1
Reactant: N
Solvent: CO
Product: NC(=O)C1CCc2c([nH]c3ccc(Cl)cc23)C1
Temperature: 25 °C
Reaction time: 40 h

Procedure:
A mixture of 2.5 g. of methyl-6-chloro-1,2,3,4-tetrahydrocarbazole-2-carboxylate, 20 g. of liquid ammonia and 150 ml. of methanol was placed in a pressure bottle. The mixture was shaken at 60° for 40 hours (internal pressure 60 lb/in2). Upon cooling to room temperature, the mixture was concentrated to dryness yielding 2.1 g. of product. Following a crystallization from ethyl acetate, 0.8 g. of 6-chloro-1,2,3,4-tetrahydrocarbazole-2-carboxylic acid amide was obtained, m.p. 203°-204°.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([Cl:8])[N:5]=[CH:4][C:3]=1[C:9]([NH2:11])=[O:10].[CH2:12](OC(OCC)OCC)C>C(OCC)C>[Cl:8][C:6]1[N:5]=[CH:4][C:3]2[C:9](=[O:10])[NH:11][CH:12]=[N:1][C:2]=2[CH:7]=1
Reactant: CCOC(OCC)OCC
Reactant: NC(=O)c1cnc(Cl)cc1N
Solvent: CCOCC
Product: O=c1[nH]cnc2cc(Cl)ncc12
Temperature: 140 °C

Procedure:
4-Amino-6-chloro-pyridine-3-carboxamide (2, 4.5 g, 26.23 mmol) was added to a pressure tube and triethylorthoformate (30 mL) was added. The reaction vessel was sealed and heated to 140° C. for 11 h. After the cyclization was complete, the reaction mixture was concentrated under reduced pressure, and to the solid obtained was added diethyl ether. The solid was filtered, washed with diethyl ether and dried in vacuum to afford 7-chloro-3H-pyrido[4,3-d]pyrimidin-4-one (3) as brown solid. MS (ESI) m/z 181.90 [M+1]+.
Reaction SMILES: [Mg].[CH3:2][O:3][CH:4]([O:12][CH3:13])[C:5]1[CH:10]=[CH:9][CH:8]=[C:7](Br)[CH:6]=1.[CH3:14][C:15]([CH3:19])=[CH:16][CH2:17]Br.[Cl-].[NH4+]>C(OCC)C.O1CCCC1>[CH3:2][O:3][CH:4]([O:12][CH3:13])[C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([CH2:17][CH:16]=[C:15]([CH3:19])[CH3:14])[CH:6]=1
Reactant: CC(C)=CCBr
Reactant: COC(OC)c1cccc(Br)c1
Agent: [Cl-]
Agent: [Mg]
Agent: [NH4+]
Solvent: CCOCC
Solvent: C1CCOC1
Product: COC(OC)c1cccc(CC=C(C)C)c1
Temperature: 25 °C
Yield: 89.7 %

Procedure:
Magnesium metal (1.2 g) was added to 2 ml of tetrahydrofuran. With stirring at room temperature, 20 ml of a solution of 2.0 g of 3-bromobenzaldehyde dimethyl acetal in a 1:1 mixture of tetrahydrofuran and ethyl ether was added dropwise over the course of 1 hour. With stirring under ice cooling, 15 ml of a tetrahydrofuran solution of 2.25 g of 3-methyl-2-butenyl bromide was added to the resulting solution. The temperature of the mixture was returned to room temperature, and then it was stirred for 1 hour. A saturated aqueous solution of ammonium chloride was added to the reaction mixture to terminate the reaction. Ethyl ether was added, and the reaction mixture was treated in a customary manner to give 1.71 g (yield 90%) of 3-(3-methyl-2-butenyl)benzaldehyde dimethyl acetal as a colorless oil.