Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([C:7]2([N:14]3[CH2:19][CH2:18][CH:17]([N:20]4[C:24]5[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=5[N:22]=[CH:21]4)[CH2:16][CH2:15]3)[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Li]CCCC.C([C:36]([O:38][CH3:39])=[O:37])#N>C1COCC1.CN(P(N(C)C)(N(C)C)=O)C>[C:1]1([C:7]2([N:14]3[CH2:15][CH2:16][CH:17]([N:20]4[C:24]5[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=5[N:22]=[C:21]4[C:36]([O:38][CH3:39])=[O:37])[CH2:18][CH2:19]3)[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13]2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: c1ccc(C2(N3CCC(n4cnc5ccccc54)CC3)CCCCCC2)cc1
Reactant: COC(=O)C#N
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: COC(=O)c1nc2ccccc2n1C1CCN(C2(c3ccccc3)CCCCCC2)CC1
Temperature: -78 °C
Reaction time: 1 h
Yield: 17 %

Procedure:
To a stirred solution of 1-[1-(1-phenylcycloheptyl)-4-piperidinyl]-1H-benzimidazole (as prepared in WO 00/008013, 7.828 g, 20.957 mmol) in THF (200 ml) and HMPA (70 ml) was added dropwise a solution of n-BuLi (1.54 M solution in hexane, 20.4 ml, 31.435 mmol) at −78° C. After 1 hour stirring at −78° C., methyl cyanoformate was added to the reaction mixture at −78° C. After 2 hours stirring, the reaction mixture was quenched with NH4Cl solution and warmed to room temperature. The reaction mixture was extracted with ethyl acetate. The extracts combined were washed with NaHCO3 solution and brine, dried (Na2SO4), filtered, and concentrated to give oil. This oil was purified by column chromatography (silica gel:200 g, ethyl acetate/n-hexane:1/2 as an eluent) to afford 1.53 g (17%) of title compound as colorless foam.
Reaction SMILES: [N+:1]([O-:4])(O)=[O:2].[Br:5][CH2:6][C:7]([C:9]1[CH:14]=[CH:13][C:12]([OH:15])=[C:11]([O:16][CH3:17])[CH:10]=1)=[O:8]>C(O)(=O)C>[Br:5][CH2:6][C:7]([C:9]1[CH:14]=[C:13]([N+:1]([O-:4])=[O:2])[C:12]([OH:15])=[C:11]([O:16][CH3:17])[CH:10]=1)=[O:8]
Reactant: O=[N+]([O-])O
Reactant: COc1cc(C(=O)CBr)ccc1O
Solvent: CC(=O)O
Product: COc1cc(C(=O)CBr)cc([N+](=O)[O-])c1O
Temperature: 25 °C

Procedure:
A solution of 38 g of fuming nitric acid (96%) in 50 ml of glacial acetic acid is added dropwise while stirring and within 30 minutes at 20°-25° to a solution of 112.5 g of 2-bromo-4'-hydroxy-3'-methoxyacetophenone in 560 ml of glacial acetic acid. Yellow-brown crystals thereby separate. After 90 minutes the reaction mixture is poured on to 300 g of ice. The crystals are filtered under suction, washed with 1000 ml of water and dissolved in 1000 ml of methylene chloride. The organic phase is washed with saturated sodium chloride solution, dried over sodium sulfate, filtered and the filtrate is evaporated at 50° in a water-jet vacuum until crystallization begins. The crystallizate, cooled to room temperature, is removed by filtration under suction and washed with a small amount of methylene chloride. There is obtained 2-bromo-4'-hydroxy-3'-methoxy-5'-nitroacetophenone of m.p. 147°-149°.
Reaction SMILES: [C:1]([O:5][C:6](=[O:14])[CH2:7][NH:8][CH:9]1[CH2:13][CH2:12][CH2:11][CH2:10]1)([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[C:22]([S:25][CH2:26][CH:27]([CH3:31])[C:28](Cl)=[O:29])(=[O:24])[CH3:23]>C(Cl)Cl>[C:1]([O:5][C:6](=[O:14])[CH2:7][N:8]([C:28](=[O:29])[CH:27]([CH3:31])[CH2:26][S:25][C:22](=[O:24])[CH3:23])[CH:9]1[CH2:10][CH2:11][CH2:12][CH2:13]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)CNC1CCCC1
Reactant: CC(=O)SCC(C)C(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)SCC(C)C(=O)N(CC(=O)OC(C)(C)C)C1CCCC1
Yield: 77.7 %

Procedure:
To a stirred and chilled (0°-5° C.) solution of N-cyclopentylglycine t-butyl ester (60 g, 0.3 mol) and triethylamine (75 ml, 0.5 mol) in methylene chloride (200 ml) was added dropwise 3-acetylthio-2-methylpropanoyl chloride (54 g, 0.3 mol) dissolved in methylene chloride (250 ml). The reaction mixture was stirred overnight. It was filtered free of solid material which was then washed with fresh methylene chloride. Washings and filtrate were combined and concentrated. The residue was dissolved in ethyl acetate and washed with saturated aqueous sodium bicarbonate (1000 ml), brine (600 ml), 5% HCl (3×500 ml), brine (500 ml), saturated sodium bicarbonate (5×500 ml). The organic layer was now separated, dried (Na2SO4 and MgSO4), filtered and concentrated to yield the desired product (80.1 g, 78%) as a brown oil.
Reaction SMILES: [CH2:1]([OH:4])[CH:2]=[CH2:3].[H-].[Na+].Cl[C:8]1[C:12]([C:13]2[CH:14]=[N:15][CH:16]=[CH:17][CH:18]=2)=[N:11][S:10][N:9]=1.O>O1CCCC1>[CH2:1]([O:4][C:8]1[C:12]([C:13]2[CH:14]=[N:15][CH:16]=[CH:17][CH:18]=2)=[N:11][S:10][N:9]=1)[CH:2]=[CH2:3]
Reactant: C=CCO
Reactant: Clc1nsnc1-c1cccnc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: C=CCOc1nsnc1-c1cccnc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of allyl alcohol (650 mg, 9 mmol) and sodium hydride (310 mg,9 mmol) in dry tetrahydrofuran was added a solution of 3-(3-chloro-1,2,5-thiadiazol-4-yl)pyridine (590 mg, 3 mmol) in dry tetrahydrofuran. The reaction mixture was stirred at room temperature for 1 h. Water was added and the mixture was extracted with ether. The ether phase was dried and evaporated to give the title compound.
Reaction SMILES: [NH2:1][C@H:2]([C:4]1[N:9]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[C:8](=[O:16])[C:7]2=[C:17]([CH3:20])[CH:18]=[CH:19][N:6]2[N:5]=1)[CH3:3].Cl[C:22]1[N:27]=[CH:26][N:25]=[C:24]([NH2:28])[C:23]=1[I:29].[F-].[Cs+].C(N(CC)C(C)C)(C)C>>[NH2:28][C:24]1[N:25]=[CH:26][N:27]=[C:22]([NH:1][C@H:2]([C:4]2[N:9]([C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=3)[C:8](=[O:16])[C:7]3=[C:17]([CH3:20])[CH:18]=[CH:19][N:6]3[N:5]=2)[CH3:3])[C:23]=1[I:29]
Reactant: Cc1ccn2nc([C@H](C)N)n(-c3ccccc3)c(=O)c12
Reactant: Nc1ncnc(Cl)c1I
Agent: [Cs+]
Agent: [F-]
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccn2nc([C@H](C)Nc3ncnc(N)c3I)n(-c3ccccc3)c(=O)c12
Yield: 59.1 %

Procedure:
(S)-2-(1-Aminoethyl)-5-methyl-3-phenylpyrrolo[2,1-f][1,2,4]triazin-4(3H)-one (0.55 g, 2.05 mmol) was treated with 6-chloro-5-iodopyrimidin-4-amine (1 g, 3.29 mol), cesium fluoride (0.62 g, 4.08 mmol), N,N-diisopropylethylamine (1.79 mL, 10.28 mol) according to Preparation 13. The residue was purified using SP1® Purification System (0% to 100%, hexane-ethyl acetate) to give 0.59 g (59% yield) of the title compound as a solid. Purity 100%.
Reaction SMILES: [C:1]1([C:7]2[CH:8]=[C:9]3[C:13](=[C:14]([C:16]([NH2:18])=[O:17])[CH:15]=2)[NH:12][CH:11]=[C:10]3[CH:19]2[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:25]([NH:28][C:29]1[S:30][C:31]([S:35](Cl)(=[O:37])=[O:36])=[C:32]([CH3:34])[N:33]=1)(=[O:27])[CH3:26].C(N(CC)CC)C>>[C:25]([NH:28][C:29]1[S:30][C:31]([S:35]([N:22]2[CH2:23][CH2:24][CH:19]([C:10]3[C:9]4[C:13](=[C:14]([C:16]([NH2:18])=[O:17])[CH:15]=[C:7]([C:1]5[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=5)[CH:8]=4)[NH:12][CH:11]=3)[CH2:20][CH2:21]2)(=[O:36])=[O:37])=[C:32]([CH3:34])[N:33]=1)(=[O:27])[CH3:26]
Reactant: NC(=O)c1cc(-c2ccccc2)cc2c(C3CCNCC3)c[nH]c12
Reactant: CC(=O)Nc1nc(C)c(S(=O)(=O)Cl)s1
Solvent: CCN(CC)CC
Product: CC(=O)Nc1nc(C)c(S(=O)(=O)N2CCC(c3c[nH]c4c(C(N)=O)cc(-c5ccccc5)cc34)CC2)s1

Procedure:
Following the general procedure in example 267, 5-(phenyl)-3-(4-piperidinyl)-1H-indole-7-carboxamide (32 mg, 0.1 mmol), 2-(acetylamino)-4-methyl-1,3-thiazole-5-sulfonyl chloride (38.2 mg, 0.15 mmol) and triethylamine (0.06 mL, 0.3 mmol) were reacted to form the desired product which was purified by Gilson HPLC (CH3CN/Water, 0.1% TFA) (4.0 mg, 7.5%).
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:20][CH3:21])=[CH:9][C:10]=2[O:12][CH:13]2[CH2:18][CH2:17][N:16]([CH3:19])[CH2:15][CH2:14]2)[N:5]=[CH:4][N:3]=1.[Cl:22][C:23]1[CH:32]=[CH:31][CH:30]=[C:29]2[C:24]=1[CH:25]=[CH:26][CH:27]=[C:28]2[NH2:33].Cl>C(O)(C)C>[ClH:1].[ClH:22].[Cl:22][C:23]1[CH:32]=[CH:31][CH:30]=[C:29]2[C:24]=1[CH:25]=[CH:26][CH:27]=[C:28]2[NH:33][C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:20][CH3:21])=[CH:9][C:10]=2[O:12][CH:13]2[CH2:18][CH2:17][N:16]([CH3:19])[CH2:15][CH2:14]2)[N:5]=[CH:4][N:3]=1
Reactant: COc1cc(OC2CCN(C)CC2)c2c(Cl)ncnc2c1
Reactant: Nc1cccc2c(Cl)cccc12
Agent: Cl
Solvent: CC(C)O
Product: COc1cc(OC2CCN(C)CC2)c2c(Nc3cccc4c(Cl)cccc34)ncnc2c1
Temperature: 25 °C
Yield: 159.7 %

Procedure:
A mixture of 4-chloro-7-methoxy-5-(N-methylpiperidin-4-yloxy)quinazoline (0.08 g), 5-chloro-1-naphthylamine (0.055 g), 6.2M hydrogen chloride in isopropanol (0.044 ml) and isopropanol (3 ml) was stirred and heated to reflux for 2 hours. The mixture was cooled to ambient temperature and the precipitate was isolated, washed with diethyl ether and dried under vacuum. There was thus obtained the title compound (0.129 g), a portion of which was treated with a saturated methanolic ammonia solution. The mixture was filtered and the filtrate was evaporated to give the free base; NMR Spectrum: (CDCl3) 1.9-2.1 (m, 4H), 2.22 (s, 3H), 2.25-2.4 (m, 2H), 2.6-2.7 (m, 2H), 3.94 (s, 3H), 4.7 (br s, 1H), 6.6 (s, 1H), 6.9 (s, 1H), 7.4 (m, 1H), 7.62 (d, 1H), 7.7 (m, 1H), 8.0 (m, 2H), 8.25 (d, 1H), 8.46 (s, 1H), 9.9 (br s, 1H); Mass Spectrum: M+H+ 449 and 451.
Reaction SMILES: [C:1]([O:4][C:5]1[CH:10]=[CH:9][C:8]([CH2:11][CH:12]=[CH2:13])=[CH:7][C:6]=1[O:14][CH3:15])(=[O:3])[CH3:2].[CH3:16][O:17][SiH:18]([O:21][CH3:22])[O:19][CH3:20]>[H+].[H+].Cl[Pt-2](Cl)(Cl)(Cl)(Cl)Cl>[C:1]([O:4][C:5]1[CH:10]=[CH:9][C:8]([CH2:11][CH2:12][CH2:13][Si:18]([O:21][CH3:22])([O:19][CH3:20])[O:17][CH3:16])=[CH:7][C:6]=1[O:14][CH3:15])(=[O:3])[CH3:2]
Reactant: CO[SiH](OC)OC
Reactant: C=CCc1ccc(OC(C)=O)c(OC)c1
Agent: Cl[Pt-2](Cl)(Cl)(Cl)(Cl)Cl
Agent: [H+]
Product: COc1cc(CCC[Si](OC)(OC)OC)ccc1OC(C)=O
Temperature: 25 °C
Reaction time: 0.67 h

Procedure:
In the same reactor vessel, the 3-(4-acetoxy-3-methoxyphenyl)propene was heated to 80° C. and then charged with chloroplatinic acid (0.79 grams). Trimethoxysilane (1990 grams, 16.3 moles) was added with stirring to the reaction mixture over a period of 40 minutes. An ice bath was used to maintain the reaction mixture at a temperature of between 100 and 108° C. After the addition of the trimethoxysilane, the reaction mixture was held at 90° C. for 1 hour and then the mixture was cooled to room temperature. The product was distilled under vacuum at 143° C. and 1 mm Hg.
Reaction SMILES: Cl[C:2]1[CH:7]=[N:6][CH:5]=[C:4]([Cl:8])[N:3]=1.C(N(CC)CC)C.[CH2:16]1[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[C@@H:18]([NH2:25])[C@H:17]1[OH:26]>CCCCO>[Cl:8][C:4]1[N:3]=[C:2]([NH:25][C@@H:18]2[C:19]3[C:24](=[CH:23][CH:22]=[CH:21][CH:20]=3)[CH2:16][C@@H:17]2[OH:26])[CH:7]=[N:6][CH:5]=1
Reactant: N[C@@H]1c2ccccc2C[C@@H]1O
Reactant: Clc1cncc(Cl)n1
Solvent: CCN(CC)CC
Solvent: CCCCO
Product: O[C@H]1Cc2ccccc2[C@H]1Nc1cncc(Cl)n1
Temperature: 115 °C
Yield: 54.5 %

Procedure:
To a solution of 2,6-dichloropyrazine (5.0 g, 34 mmol) in n-BuOH (30 mL) was added triethylamine (6.8 g, 9.4 mL, 67 mmol) and (1R,2S)-(+)-cis-1-amino-2-indanol (5.0 g, 34 mmol). The mixture was heated at 115° C. overnight. The solution was cooled to rt and concentrated. Dissolve material in EtOAc (200 mL) and remove insoluble material by vacuum filtration. Wash filtrate sequentially with 4 N NaOH and sat. aq. NaCl. Dry organic extract over MgSO4, filter and concentrate. Purify by biotage MPLC (90 g column, 10% ethyl acetate/hexanes) to afford 4.85 g (57%) of (1R,2S)-1-[(6-chloropyrazin-2-yl)amino]-2,3-dihydro-1H-inden-2-ol as a solid: 1H NMR (CDCl3) δ 2.83-2.87, 3.08-3.13, 3.32, 4.54, 5.11, 5.28-5.31, 7.18-7.28, 7.73, 8.12; MS (ESI+) for C13H12ClN3O m/z 262 (M+H)+.
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[O:3][C:4]1[CH:11]=[C:8]([CH:9]=O)[C:7]([OH:12])=[CH:6][CH:5]=1.C(=O)(OC(C)(C)C)[NH2:16].C([SiH](CC)CC)C.FC(F)(F)C(O)=O>C(#N)C>[NH2:16][CH2:9][C:8]1[CH:11]=[C:4]([O:3][C:2]([F:14])([F:13])[F:1])[CH:5]=[CH:6][C:7]=1[OH:12]
Reactant: O=Cc1cc(OC(F)(F)F)ccc1O
Reactant: CC(C)(C)OC(N)=O
Agent: CC[SiH](CC)CC
Solvent: CC#N
Solvent: O=C(O)C(F)(F)F
Product: NCc1cc(OC(F)(F)F)ccc1O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of 5-(trifluoromethoxy)salicylaldehyde (4.85 mmol, 1.0 g), tert-butyl carbamate (14.55 mmol, 1.70 g), triethylsilane (14.55 mmol, 2.3 mL), trifluoroacetic acid (9.7 mmol, 0.72 mL) in acetonitrile was stirred at room temperature overnight. The reaction was quenched with saturated NaHCO3 and extracted with EtOAc. The combined organic layers were dried over Na2SO4 and purified by silica gel chromatography (15%-100% EtOAc/hexane). The resulting yellow solid was then dissolved in a mixture of TFA (10 mL) and dichloromethane (20 mL) and stirred for 2 hours at room temperature. The volatile solvents were then removed by rotovap to afford 2-(aminomethyl)-4-(trifluoromethoxy)phenol as a yellow oil. 1H NMR (CD3OD) 7.28 (s, 1H), 7.22 (m, 1H), 6.97 (m, 1H), 4.13 (s, 2H), 1.59 (s, 1H).
Reaction SMILES: [CH2:1]=[CH:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[C:9]([OH:14])(=[O:13])[C:10]([CH3:12])=[CH2:11].C(C1C=CC=CC=1)C.C(S)CCCCCCCCCCC.C(OOC1(OOC(C)(C)C)CC(C)CC(C)(C)C1)(C)(C)C>>[CH:1]([CH2:12][C:10](=[CH2:11])[C:9]([OH:14])=[O:13])=[CH:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: C=C(C)C(=O)O
Reactant: C=Cc1ccccc1
Agent: CC1CC(C)(C)CC(OOC(C)(C)C)(OOC(C)(C)C)C1
Agent: CCCCCCCCCCCCS
Solvent: CCc1ccccc1
Product: C=C(CC=Cc1ccccc1)C(=O)O

Procedure:
A mixture of 78.0 parts by weight of styrene, 2.0 parts by weight of methacrylic acid, 20 parts by weight of ethylbenzene, 0.02 parts by weight of n-dodecyl mercaptan, and 0.03 parts by weight of 1,1-bis(t-butylperoxy)-3,3,5-trimethylcyclohexane as an initiator was continuously supplied into a coil type complete mixing reactor at a rate of 2.5 l/hr. so that the reaction mixture was allowed to undergo polymerization at a temperature of 150° C. for an average retention time of 2 hours with a polymer solid concentration of 47%. Subsequently, the polymerization solution was introduced into a 230° C. devolatizing apparatus where the unreacted monomers and the solvent were removed to obtain a styrene-methacrylic acid copolymer. The copolymer thus obtained exhibited a styrene/methacrylic acid weight ratio of 96/4, a weight-average molecular weight of 120,000 and a number-average molecular weight of 63,000 (hereinafter referred to as "SMAA-3").
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:10]=[C:9]([S:11]([CH3:14])(=[O:13])=[O:12])[CH:8]=[CH:7][C:6]=1Cl)(=[O:4])=[O:3].[C:16]([C:20]1[O:24][N:23]=[C:22]([OH:25])[CH:21]=1)([CH3:19])([CH3:18])[CH3:17].C(=O)([O-])[O-].[K+].[K+].CS(C)=O>O>[C:16]([C:20]1[O:24][N:23]([C:6]2[CH:7]=[CH:8][C:9]([S:11]([CH3:14])(=[O:13])=[O:12])=[CH:10][C:5]=2[S:2]([CH3:1])(=[O:4])=[O:3])[C:22](=[O:25])[CH:21]=1)([CH3:19])([CH3:18])[CH3:17]
Reactant: CC(C)(C)c1cc(O)no1
Reactant: CS(=O)(=O)c1ccc(Cl)c(S(C)(=O)=O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: CC(C)(C)c1cc(=O)n(-c2ccc(S(C)(=O)=O)cc2S(C)(=O)=O)o1
Reaction time: 4 h
Yield: 61.2 %

Procedure:
After mixing 1 g of 2,4-bismethanesulfonylchlorobenzene, 1 g of 5-t-butyl-3-hydroxyisoxazole, 1 g of potassium carbonate, and 8 ml of dimethyl sulfoxide, the reaction was performed for 4 hours at 80° C. After the reaction was over, the reaction mixture obtained was poured into water and extracted with ethyl acetate. Then, the ethyl acetate was distilled off from the extract under reduced pressure and the residue thus formed was recrystallized from a mixture of water and methanol to provide 0.85 g of the desired compound with a yield of 61.2%. The melting point thereof was 166° C. to 168° C.
Reaction SMILES: [NH2:1][C:2]1[C:3]([F:24])=[CH:4][C:5]([I:23])=[C:6]([C:8]2[C:9](=[O:22])[N:10]([CH2:20][CH3:21])[C:11]3[C:16]([CH:17]=2)=[CH:15][N:14]=[C:13]([NH:18][CH3:19])[CH:12]=3)[CH:7]=1.[C:25]1([N:31]=[C:32]=[O:33])[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.N1C=CC=CC=1>C(Cl)Cl>[CH2:20]([N:10]1[C:11]2[C:16](=[CH:15][N:14]=[C:13]([NH:18][CH3:19])[CH:12]=2)[CH:17]=[C:8]([C:6]2[C:5]([I:23])=[CH:4][C:3]([F:24])=[C:2]([NH:1][C:32]([NH:31][C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)=[O:33])[CH:7]=2)[C:9]1=[O:22])[CH3:21]
Reactant: O=C=Nc1ccccc1
Reactant: CCn1c(=O)c(-c2cc(N)c(F)cc2I)cc2cnc(NC)cc21
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCn1c(=O)c(-c2cc(NC(=O)Nc3ccccc3)c(F)cc2I)cc2cnc(NC)cc21
Temperature: 25 °C
Reaction time: 3 h
Yield: 30.5 %

Procedure:
A suspension of 3-(5-amino-4-fluoro-2-iodophenyl)-1-ethyl-7-(methylamino)-1,6-naphthyridin-2(1H)-one (0.310 g, 0.707 mmol) in DCM (10 mL) was treated with phenyl isocyanate (0.100 g, 0.839 mmol) followed by pyridine (0.060 g, 0.759 mmol) and stirred at RT for 3 h. The mixture was concentrated to dryness and purified via silica gel chromatography (EtOAc/Hex) to afford 1-(5-(1-ethyl-7-(methylamino)-2-oxo-1,2-dihydro-1,6-naphthyridin-3-yl)-2-fluoro-4-iodophenyl)-3-phenylurea (120 mg, 29% yield). 1H NMR (400 MHz, DMSO-d6): δ 9.08 (s, 1H), 8.66 (s, 1H), 8.41 (s, 1H), 8.14 (d, J=8.3 Hz, 1H), 7.77 (d, J=10.6 Hz, 1H), 7.64 (s, 1H), 7.41 (d, J=8.0 Hz, 2H), 7.26 (t, J=7.7 Hz, 2H), 7.05 (m, 2H), 6.24 (s, 1H), 4.14 (d, J=8.1 Hz, 2H), 2.86 (d, J=4.8 Hz, 3H), 1.22 (t, J=7.0 Hz, 3H); MS (ESI) m/z: 558.1 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([CH:11]3[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]3)=[CH:7][NH:8]2)=[CH:4][CH:3]=1.[O:17]1[CH2:19][C@H:18]1[CH2:20][O:21][C:22]1[CH:30]=[CH:29][CH:28]=[C:27]2[C:23]=1[CH:24]=[CH:25][NH:26]2>CO.CS(C)=O>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([CH:11]3[CH2:16][CH2:15][N:14]([CH2:19][C@H:18]([OH:17])[CH2:20][O:21][C:22]4[CH:30]=[CH:29][CH:28]=[C:27]5[C:23]=4[CH:24]=[CH:25][NH:26]5)[CH2:13][CH2:12]3)=[CH:7][NH:8]2)=[CH:4][CH:3]=1
Reactant: Clc1ccc2c(C3CCNCC3)c[nH]c2c1
Reactant: c1cc(OC[C@@H]2CO2)c2cc[nH]c2c1
Solvent: CO
Solvent: CS(C)=O
Product: O[C@H](COc1cccc2[nH]ccc12)CN1CCC(c2c[nH]c3cc(Cl)ccc23)CC1

Procedure:
The title compound was prepared in a fashion similar to that described in Example 193 from 6-chloro-3-(piperidin-4-yl)-1H-indole (1.00 g, 4.3 mmol) and (S)-(+)-4-(oxiranylmethoxy)-1H-indole (0.81 g, 4.3 mmol). The product was isolated as a white foam. Yield 1.15 g (64%). mp 90°-95° C. FDMS m/e=423 (M+ of free base). α[D]589 =+8.81 (c=0.98, methanol/dimethylsulfoxide).
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[O:10][CH:11]([CH3:13])[CH3:12])[C:5]#[N:6].Cl.[NH2:15][OH:16].CCN(C(C)C)C(C)C>CCO>[OH:16][NH:15][C:5](=[NH:6])[C:4]1[CH:7]=[CH:8][C:9]([O:10][CH:11]([CH3:12])[CH3:13])=[C:2]([I:1])[CH:3]=1
Reactant: NO
Reactant: CC(C)Oc1ccc(C#N)cc1I
Agent: Cl
Solvent: CCO
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)Oc1ccc(C(=N)NO)cc1I
Temperature: 50 °C
Reaction time: 18 h
Yield: 95.3 %

Procedure:
A suspension of 3-iodo-4-isopropoxybenzonitrile (0.576 g; 2 mmol), HCl×NH2OH (0.276 g; 4 mmol) and DIPEA (0.69 ml; 4 mmol) in EtOH (50 ml) was stirred for 18 h at 50° C. The solvent was distilled off and the residue was diluted to 50 ml with EtOAc and washed with H2O. The organic layer was separated, dried over MgSO4 and filtered. The filtrate was distilled off to give the title product (0.61 g; 95%), as colourless solid. 1H-NMR (CDCl3) 8.0 (d, 1H, J=2.22 Hz); 7.55 (dd, 1H, J=9.54, 2.28 Hz); 6.77 (d, 1H, J=8.7 Hz); 4.95 (b, 2H); 4.69-4.63 (m, 1H); 1.42 (d, 6H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]2[C:9]([CH:10]3[CH2:15][CH2:14][N:13]([CH2:16][CH2:17][CH2:18][N:19]4[C:27]5[CH2:26][CH2:25][N:24]([S:28]([CH3:31])(=[O:30])=[O:29])[CH2:23][C:22]=5[C:21]([C:32]5[CH:37]=[CH:36][C:35]([C:38]([F:41])([F:40])[F:39])=[CH:34][CH:33]=5)=[N:20]4)[CH2:12][CH2:11]3)=[C:8]([C:42](O)=[O:43])[S:7][C:6]=2[CH:45]=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[CH2:79]([CH2:81][NH2:82])[OH:80]>CN(C=O)C>[OH:80][CH2:79][CH2:81][NH:82][C:42]([C:8]1[S:7][C:6]2[CH:45]=[C:2]([F:1])[CH:3]=[CH:4][C:5]=2[C:9]=1[CH:10]1[CH2:11][CH2:12][N:13]([CH2:16][CH2:17][CH2:18][N:19]2[C:27]3[CH2:26][CH2:25][N:24]([S:28]([CH3:31])(=[O:29])=[O:30])[CH2:23][C:22]=3[C:21]([C:32]3[CH:33]=[CH:34][C:35]([C:38]([F:40])([F:41])[F:39])=[CH:36][CH:37]=3)=[N:20]2)[CH2:14][CH2:15]1)=[O:43]
Reactant: CS(=O)(=O)N1CCc2c(c(-c3ccc(C(F)(F)F)cc3)nn2CCCN2CCC(c3c(C(=O)O)sc4cc(F)ccc34)CC2)C1
Reactant: NCCO
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CS(=O)(=O)N1CCc2c(c(-c3ccc(C(F)(F)F)cc3)nn2CCCN2CCC(c3c(C(=O)NCCO)sc4cc(F)ccc34)CC2)C1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 75.4 %

Procedure:
A stirred solution of 20 mg (0.03 mmol) of 6-fluoro-3-(1-{3-[5-methanesulfonyl-3-(4-trifluoromethyl-phenyl)-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-1-yl]-propyl}-piperidin-4-yl)-benzo[b]thiophene-2-carboxylic acid in 0.3 mL of dry DMF was treated with 14 mg (0.036 mmol) of HBTU and 8 μL (0.045 mmol) of DIEA. The solution was stirred for 5 min before the addition of 0.01 mL (0.15 mmol) of ethanol amine. The reaction was stirred at room temperature for 30 min then partitioned between EtOAc (30 mL) and saturated NaHCO3 (20 mL). The aqueous layer was further extracted with EtOAc (2×20 mL). The combined organic layers were then washed with brine, dried over Na2SO4, and concentrated. Purification by column chromatography (silica, 5-10% of 2 N NH3 in MeOH/CH2Cl2) yielded 16 mg (76%) of a white solid. MS (electrospray): exact mass calculated for C33H37F4N5O4S2: 707.22; m/z found, 708.2 [M+H]+. 1H NMR (CDCl3, 400 MHz): 7.97 (br s, 1H), 7.73 and 7.66 (A and B of AB quartet, J=8.41 Hz, 4H), 7.49 (dd, J=8.41, 2.35 Hz, 1H), 7.15 (dt, J=8.61, 2.54 Hz, 1H), 6.41 (t, J=5.67 Hz, 1H), 4.56 (s, 2H), 4.16 (t, J=7.04 Hz, 2H), 3.84 (dd, J=5.28, 4.70 Hz, 2H), 3.70 (t, J=5.67 Hz, 2H), 3.62 (m, 2H), 3.58 (br s, 1H), 3.05 (br m, 2H), 2.97 (t, J=5.67 Hz, 2H), 2.91 (s, 3H), 2.40 (br m, 4H), 2.13 (br m, 4H), 1.84 (br d, J=12.32 Hz, 2H).
Reaction SMILES: [NH2:1][C@@H:2]1[CH2:7][CH2:6][CH2:5][N:4]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:3]1.[H-].[Na+]>C1COCC1.CCOC(C)=O>[O:9]=[C:8]1[NH:4][CH2:3][CH2:2][CH2:7][N:1]1[C@@H:2]1[CH2:7][CH2:6][CH2:5][N:4]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:3]1
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H](N)C1
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC[C@@H](N2CCCNC2=O)C1
Temperature: 25 °C
Reaction time: 3 h
Yield: 168.7 %

Procedure:
(R)-tert-Butyl 3-aminopiperidine-1-carboxylate (1.28 g, 6.4 mmol) was dissolved in 15 mL dry THF. To it was added 3-chloropropyl isocyante (660 μL, 6.4 mmol), and the mixture was stirred at RT for 3 hours. To it was added NaH (60% in mineral oil, 310 mg, 7.68 mmol) and the mixture was stirred for overnight. Another batch of NaH (310 mg, 7.68 mmol) was then added to drive the cyclization to completion, The mixture was diluted with 200 mL EtOAc, washed with water, dried, concentrated and subjected to silica flash column using 0 to 5% MeOh in DCM to isolate (R)-tert-butyl 3-(2-oxotetrahydropyrimidin-1(2H)-yl)piperidine-1-carboxylate (408) (1.53 g, 84%) as a white solid. It was dissolved in 50 mL dry THF. To the solution was added NaH (440 mg, 10.80 mmol), and the mixture was stirred for 15 min at RT. Then iodomethane (680 μL, 10.80 mmol) was added, and it was stirred at RT for overnight. It was diluted with 200 mL EtOAc and 30 mL water. The organic phase was separated, washed with water, dried, concentrated and subjected to silica flash column with 0 to 4% MeOH in DCM to isolate (R)-tert-butyl 3-(3-methyl-2-oxotetrahydropyrimidin-1(2H)-yl)piperidine-1-carboxylate (409) (1.52 g, 95%) as a white solid. It was treated with 20 mL commercial 4N HCl in dioxane at RT for 30 min to yield (R)-1-methyl-3-(piperidin-3-yl)tetrahydropyrimidin-2(1H)-one hydrochloride (410) (1.27 g) as a white solid after evaporation in vacuo to dryness.