Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2](=[CH2:13])[CH2:3][CH2:4][O:5][Si:6]([C:9]([CH3:12])([CH3:11])[CH3:10])([CH3:8])[CH3:7].C([Li])(C)(C)C.[Si:19]([O:26][CH2:27]/[CH:28]=[N:29]/[S@:30]([C:32]([CH3:35])([CH3:34])[CH3:33])=[O:31])([C:22]([CH3:25])([CH3:24])[CH3:23])([CH3:21])[CH3:20]>C1COCC1>[CH3:33][C:32]([S@@:30]([NH:29][C@@H:28]([C:2](=[CH2:13])[CH2:3][CH2:4][O:5][Si:6]([CH3:8])([CH3:7])[C:9]([CH3:10])([CH3:11])[CH3:12])[CH2:27][O:26][Si:19]([CH3:21])([CH3:20])[C:22]([CH3:25])([CH3:24])[CH3:23])=[O:31])([CH3:35])[CH3:34]
Reactant: CC(C)(C)[S@](=O)/N=C/CO[Si](C)(C)C(C)(C)C
Reactant: C=C(Br)CCO[Si](C)(C)C(C)(C)C
Agent: [Li]C(C)(C)C
Solvent: C1CCOC1
Product: C=C(CCO[Si](C)(C)C(C)(C)C)[C@@H](CO[Si](C)(C)C(C)(C)C)N[S@@](=O)C(C)(C)C
Temperature: -78 °C
Reaction time: 0.75 h
Yield: 73.3 %

Procedure:
To a solution of ((3-bromobut-3-en-1-yl)oxy)(tert-butyl)dimethylsilane (Intermediate 273, 24.66 g, 92.97 mmol) in THF (200 mL) at −78° C. was added tert-butyllithium (1.7M in pentane) (120 mL, 204.54 mmol) dropwise via cannula. The reaction mixture was stirred for 45 minutes at −78° C. The (S,E)-N-(2-((tert-butyldimethylsilyl)oxy)ethylidene)-2-methylpropane-2-sulfinamide (Intermediate 274, 17.2 g, 61.98 mmol) in THF (50 mL) was added dropwise. The reaction mixture was stirred for ˜1.5 hours at −78° C. The reaction was quenched with saturated sodium bicarbonate and extracted twice with ether. The combined organic extracts were dried over magnesium sulfate, filtered and concentrated. Silica gel chromatography (0%-15% ethyl acetate/hexanes) afforded the title compound (21.07 g, 73.3%) as a colorless oil.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH2:17][CH:18]2[CH2:22][CH2:21][CH2:20][CH2:19]2)[C:9]([NH:11][C:12]2[S:13][CH:14]=[CH:15][N:16]=2)=[O:10])=[CH:4][CH:3]=1.C(N(CC)C(C)C)(C)C.[N+:32]([C:35]1[CH:43]=[CH:42][C:38]([C:39](Cl)=[O:40])=[CH:37][CH:36]=1)([O-:34])=[O:33]>O1CCCC1>[CH:18]1([CH2:17][CH:8]([C:5]2[CH:4]=[CH:3][C:2]([NH:1][C:39](=[O:40])[C:38]3[CH:37]=[CH:36][C:35]([N+:32]([O-:34])=[O:33])=[CH:43][CH:42]=3)=[CH:7][CH:6]=2)[C:9](=[O:10])[NH:11][C:12]2[S:13][CH:14]=[CH:15][N:16]=2)[CH2:22][CH2:21][CH2:20][CH2:19]1
Reactant: Nc1ccc(C(CC2CCCC2)C(=O)Nc2nccs2)cc1
Reactant: O=C(Cl)c1ccc([N+](=O)[O-])cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: O=C(Nc1ccc(C(CC2CCCC2)C(=O)Nc2nccs2)cc1)c1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 21 h
Yield: 79.3 %

Procedure:
A solution of 2-(4-amino-phenyl)-3-cyclopentyl-N-thiazol-2-yl-propionamide (prepared in Example 3, 63.0 mg, 0.20 mmol) in tetrahydrofuran (10 mL) was treated with N,N-diisopropylethylamine (0.04 mL, 0.24 mmol) and 4-nitro-benzoyl chloride (49.0 mg, 0.26 mmol). The reaction mixture was stirred at 25° C. for 21 h. At this time, the reaction was concentrated in vacuo. The residue was triturated with diethyl ether to afford N-{4-[2-cyclopentyl-1-(thiazol-2-ylcarbamoyl)-ethyl]-phenyl}-4-nitro-benzamide (73.7 mg, 79.3%) as a pale yellow solid: mp 236-238° C.; FAB-HRMS m/e calcd for C24H24N4O4S (M+H)+ 465.1596, found 465.1617.
Reaction SMILES: [CH2:1]([NH:8][CH2:9][CH2:10][O:11][C:12]1[CH:17]=[CH:16][C:15]([OH:18])=[CH:14][CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[O:19]1[CH:21]([CH2:22][O:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH2:20]1>CC(O)C>[CH2:1]([N:8]([CH2:20][CH:21]([OH:19])[CH2:22][O:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[CH2:9][CH2:10][O:11][C:12]1[CH:13]=[CH:14][C:15]([OH:18])=[CH:16][CH:17]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: c1ccc(OCC2CO2)cc1
Reactant: Oc1ccc(OCCNCc2ccccc2)cc1
Solvent: CC(C)O
Product: Oc1ccc(OCCN(Cc2ccccc2)CC(O)COc2ccccc2)cc1

Procedure:
A mixture of N-benzyl-2-(p-hydroxyphenoxy)-ethylamine (2.5 g) and 1,2-epoxy-3-phenoxypropane (1.54 g) in propan-2-ol (50 ml) was heated under reflux for 72 hours. The solvent was removed by evaporation to give N-benzyl-N-(2-p-hydroxyphenoxyethyl)-2-hydroxy-3-phenoxypropylamine as an oil which was essentially pure as indicated by thin layer chromatography (TLC) [using silica plates and 5% methanol in dichloromethane as eluant] and was used without purification.
Reaction SMILES: [CH2:1]=[O:2].[CH2:3]([SH:15])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14].CCCCCC>O>[OH:2][CH2:1][S:15][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14]
Reactant: C=O
Reactant: CCCCCCCCCCCCS
Solvent: O
Solvent: CCCCCC
Product: CCCCCCCCCCCCSCO
Temperature: 100 °C
Yield: 91.8 %

Procedure:
162.2 grams of a 37% by weight aqueous solution of formaldehyde (equivalent to 2 moles), 404 grams of n-dodecyl mercaptan (equivalent to 2 moles) and 250 milliliters of hexane were placed in a one liter flask equipped with an overhead azeotropic mixture condenser and a condensed water and hexane component separator. A fixed bed of Amberlyst 15 acid-type ion exchange resin catalyst was provided, and the reaction mixture in the flask was circulated by a pump from the flask through the catalyst bed and back to the flask at a rate of about 2 milliliters per minute for a time period of 4 hours. While the reaction mixture was being circulated through the catalyst bed, it was heated to a temperature of approximately 100° C. whereby the azeotropic mixture formed by the hexane and water in the flask was vaporized, withdrawn from the flask and condensed. The water component of the condensed azeotropic mixture was separated from the hexane component and withdrawn, and the hexane was returned to the reaction flask. A 91.8% yield of dodecyl hydroxymethyl sulfide was realized after the hexane was removed by vacuum evaporation.
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][N:11]2[CH:16]=[CH:15][C:14]([O:17][CH2:18][C:19]3[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=3)=[CH:13][C:12]2=[O:26])=[CH:5][CH:4]=1.[NH:27]1[CH2:32][CH2:31][CH:30]([NH:33][C:34](=[O:36])[CH3:35])[CH2:29][CH2:28]1.C(N(C(C)C)C(C)C)C>>[F:25][C:22]1[CH:23]=[CH:24][C:19]([CH2:18][O:17][C:14]2[CH:15]=[CH:16][N:11]([CH2:10][CH2:9][C:6]3[CH:7]=[CH:8][C:3]([CH2:2][N:27]4[CH2:32][CH2:31][CH:30]([NH:33][C:34](=[O:36])[CH3:35])[CH2:29][CH2:28]4)=[CH:4][CH:5]=3)[C:12](=[O:26])[CH:13]=2)=[CH:20][CH:21]=1
Reactant: CC(=O)NC1CCNCC1
Reactant: O=c1cc(OCc2ccc(F)cc2)ccn1CCc1ccc(CBr)cc1
Solvent: CCN(C(C)C)C(C)C
Product: CC(=O)NC1CCN(Cc2ccc(CCn3ccc(OCc4ccc(F)cc4)cc3=O)cc2)CC1

Procedure:
N-[1-(4-{2-[4-(4-Fluoro-benzyloxy)-2-oxo-2H-pyridin-1-yl]-ethyl}-benzyl)-piperidin-4-yl]-acetamide is prepared as example 7.1c from 80 mg (0.19 mmol) 1-[2-(4-bromomethyl-phenyl)ethyl]-4-(4-fluoro-benzyloxy)-1H-pyridin-2-one (example 7.1b), 41 mg (0.29 mmol) N-piperidin-4-yl-acetamide and 70 μL (0.40 mmol) N-ethyl-diisopropylamine as base.
Reaction SMILES: [N+:1]([CH:4]=[C:5](SC)[NH:6][CH2:7][CH2:8][S:9][CH2:10][C:11]1[S:15][C:14]([NH2:16])=[N:13][N:12]=1)([O-:3])=[O:2].[CH2:19]([NH2:21])[CH3:20]>>[N+:1]([CH:4]=[C:5]([NH:21][CH2:19][CH3:20])[NH:6][CH2:7][CH2:8][S:9][CH2:10][C:11]1[S:15][C:14]([NH2:16])=[N:13][N:12]=1)([O-:3])=[O:2]
Reactant: CSC(=C[N+](=O)[O-])NCCSCc1nnc(N)s1
Reactant: CCN
Product: CCNC(=C[N+](=O)[O-])NCCSCc1nnc(N)s1

Procedure:
Reaction of 1-nitro-2-methylthio-2-[2-((2-amino-5-(1,3,4)-thiadiazolyl)methylthio)ethylamino]ethylene (see Example 85(i)) with ethylamine by the procedure of Example 8(ii) gives the title product.
Reaction SMILES: [ClH:1].[C:2]1([CH:8]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[N:9]2[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][CH2:17][NH:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[N+:25]([O-])=O)[CH2:11][CH2:10]2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H][H]>[Ni].CO>[ClH:1].[NH2:25][C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=1[NH:18][CH2:17][CH2:16][CH2:15][N:12]1[CH2:11][CH2:10][N:9]([CH:8]([C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=2)[C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[CH2:14][CH2:13]1
Reactant: O=[N+]([O-])c1ccccc1NCCCN1CCN(C(c2ccccc2)c2ccccc2)CC1
Reactant: [H][H]
Agent: [Ni]
Agent: Cl
Solvent: CO
Product: Nc1ccccc1NCCCN1CCN(C(c2ccccc2)c2ccccc2)CC1

Procedure:
A mixture of 15 parts of 4-(diphenylmethyl) N-(2-nitrophenyl)-1-piperazinepropanamine hydrochloride in 160 parts of methanol is hydrogenated at normal pressure and at room temperature with 5 parts of Raney-nickel catalyst. After the calculated amount of hydrogen is taken up, the catalyst is filtered off over hyflo and the filtrate is evaporated. The solid residue is crystallized from a mixture of 2-propanol and 2,2'-oxybispropane. The product is filtered off and dried, yielding N-(2-aminophenyl)-4-(diphenylmethyl)-1-piperazinepropanamine hydrochloride; mp. 223.1° C.
Reaction SMILES: [Br:1]Br.[Cl:3][C:4]1[CH:5]=[C:6]([CH:23]=[CH:24][C:25]=1[Cl:26])[CH2:7][NH:8][C:9]([NH:11][C:12]1[S:13][CH:14]=[C:15]([CH2:17][O:18][CH2:19][CH2:20][O:21][CH3:22])[N:16]=1)=[O:10]>C(Cl)Cl>[Br:1][C:14]1[S:13][C:12]([NH:11][C:9]([NH:8][CH2:7][C:6]2[CH:23]=[CH:24][C:25]([Cl:26])=[C:4]([Cl:3])[CH:5]=2)=[O:10])=[N:16][C:15]=1[CH2:17][O:18][CH2:19][CH2:20][O:21][CH3:22]
Reactant: COCCOCc1csc(NC(=O)NCc2ccc(Cl)c(Cl)c2)n1
Reactant: BrBr
Solvent: ClCCl
Product: COCCOCc1nc(NC(=O)NCc2ccc(Cl)c(Cl)c2)sc1Br

Procedure:
Bromine (120 μL, 0.12 mmol, IM in CH2Cl2) was added dropwise to a CH2Cl2 (5 mL) solution of 1-(3,4-dichlorobenzyl)-3-(4-((2-methoxyethoxy)methyl)thiazol-2-yl)urea (39 mg, 0.1 mmol). The bromination was instantaneous. The mixture was washed with dilute Na2SO3 solution, dried and evaporated to afford the title compound. 1H NMR (400 MHz, CDCl3): 11.38 (1H, br), 7.70 (1H, br), 7.45 (d, 1H), 7.39 (d, 1H), 7.19 (dd, 1H), 4.50 (s, 2H), 4.39 (d, 2H), 3.53 (m, 2H), 3.38 (m, 2H), 3.20 (s, 3H). MS (ES+): M/Z 470 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]([NH:10][CH3:11])[S:5][C:6]=1[C:7](=[O:9])[CH3:8].[H-].[Na+].[CH3:14]I>C1COCC1.CCOC(C)=O>[CH3:11][N:10]([CH3:14])[C:4]1[S:5][C:6]([C:7](=[O:9])[CH3:8])=[C:2]([CH3:1])[N:3]=1
Reactant: CNc1nc(C)c(C(C)=O)s1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC(=O)c1sc(N(C)C)nc1C
Reaction time: 2 h

Procedure:
A mixture of 1-(4-methyl-2-methylamino-thiazol-5-yl)-ethanone (0.40 g, 2.4 mmol) in THF (2 mL) was treated with NaH (0.113 g, 4.7 mmol). After heating at 40° C. for 0.5 h MeI (0.35 g, 2.4 mmol) was added. Heating was continued for a further 2 h. After cooling, the solution was diluted with EtOAc, washed with brine, and dried over MgSO4. The solvent was evaporated to afford 1-(2-dimethylamino-4-methyl-thiazol-5-yl)-ethanone as a yellow solid. 1H-NMR (CDCl3) δ: 2.36 (s, 3H, CH3), 2.51 (s, 3H, CH3), 3.10 (s, 6H, CH3).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[O:12][CH3:13])[N:8]=[C:7]([CH3:14])[CH:6]=[C:5]2O.O=P(Cl)(Cl)[Cl:18]>C(OCC)C>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[O:12][CH3:13])[N:8]=[C:7]([CH3:14])[CH:6]=[C:5]2[Cl:18]
Reactant: COc1cc2nc(C)cc(O)c2cc1Br
Reactant: O=P(Cl)(Cl)Cl
Solvent: CCOCC
Product: COc1cc2nc(C)cc(Cl)c2cc1Br
Temperature: 60 °C
Yield: 76.8 %

Procedure:
A suspension of 4.6 g (17.5 mmol) of 6-bromo-7-methoxy-2-methyl-quinolin-4-ol in 14.8 ml (158 mmol) of POCl3 was heated at 60° C. for 20 h with stirring. It was then cooled to RT and 50 ml of diethyl ether were added. The solid that precipitated was filtered off by suction and dried in a high vacuum to give 3.85 g of the 6-bromo-4-chloro-7-methoxy-2-methyl-quinoline as a dark brown solid. El mass spectrum, m/e: 287 (M calculated for C11H9BrClNO: 287).
Reaction SMILES: [F:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6](O)=[N:7][CH:8]=[N:9]2)=[CH:4][C:3]=1[N+:13]([O-:15])=[O:14].O=S(Cl)[Cl:18]>CN(C=O)C>[Cl:18][C:6]1[C:5]2[C:10](=[CH:11][C:2]([F:1])=[C:3]([N+:13]([O-:15])=[O:14])[CH:4]=2)[N:9]=[CH:8][N:7]=1
Reactant: O=S(Cl)Cl
Reactant: O=[N+]([O-])c1cc2c(O)ncnc2cc1F
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1cc2c(Cl)ncnc2cc1F
Yield: 94.4 %

Procedure:
7-fluoro-6-nitroquinazolin-4-ol (15 g, 0.072 mol) was added to 150 ml SOCl2 and 10 drops of DMF was added. The solution was heated to reflux for 4 hours which become a clear solution, then the SOCl2 was removed under reduce pressure to give 4-chloro-7-fluoro-6-nitroquinazoline as yellow powder 15.4 g (94.4% yield).
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][C:11]([CH2:13][N:14]3[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]3)=[N:10][N:9]=2)=[CH:4][CH:3]=1.[CH:20]1([NH:23][C:24](=[O:41])[C:25]2[CH:30]=[CH:29][C:28]([CH3:31])=[C:27](B3OC(C)(C)C(C)(C)O3)[CH:26]=2)[CH2:22][CH2:21]1>>[CH:20]1([NH:23][C:24]([C:25]2[CH:30]=[C:29]([C:2]3[CH:7]=[CH:6][C:5]([C:8]4[O:12][C:11]([CH2:13][N:14]5[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]5)=[N:10][N:9]=4)=[CH:4][CH:3]=3)[C:28]([CH3:31])=[CH:27][CH:26]=2)=[O:41])[CH2:21][CH2:22]1
Reactant: Cc1ccc(C(=O)NC2CC2)cc1B1OC(C)(C)C(C)(C)O1
Reactant: Ic1ccc(-c2nnc(CN3CCCCC3)o2)cc1
Product: Cc1ccc(C(=O)NC2CC2)cc1-c1ccc(-c2nnc(CN3CCCCC3)o2)cc1

Procedure:
Example 13 was prepared from 1-[5-(4-iodophenyl)-[1,3,4]oxadiazol-2-ylmethyl]-piperidine (intermediate 9) and N-cyclopropyl-4-methyl-3-(4,4,5,5-tetramethyl-[1,3,2]-dioxaborolan-2-yl)benzamide (Intermediate 17).
Reaction SMILES: [CH3:1][C:2]1[C:3]([CH:13]=[O:14])=[CH:4][NH:5][C:6]=1[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[H-].[Na+].C1OCCOCCOCCOCCOC1.[O:32]1[C:37]2[CH:38]=[CH:39][CH:40]=[C:41]([S:42](Cl)(=[O:44])=[O:43])[C:36]=2[O:35][CH2:34][CH2:33]1>>[O:32]1[C:37]2[CH:38]=[CH:39][CH:40]=[C:41]([S:42]([N:5]3[C:6]([C:7]4[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=4)=[C:2]([CH3:1])[C:3]([CH:13]=[O:14])=[CH:4]3)(=[O:44])=[O:43])[C:36]=2[O:35][CH2:34][CH2:33]1
Reactant: O=S(=O)(Cl)c1cccc2c1OCCO2
Reactant: Cc1c(C=O)c[nH]c1-c1ccccc1
Agent: C1COCCOCCOCCOCCO1
Agent: [H-]
Agent: [Na+]
Product: Cc1c(C=O)cn(S(=O)(=O)c2cccc3c2OCCO3)c1-c1ccccc1

Procedure:
Using 4-methyl-5-phenyl-1H-pyrrole-3-carbaldehyde (185 mg), sodium hydride (60% in oil, 116 mg), 15-crown-5 (881 mg) and 2,3-dihydro-1,4-benzodioxine-5-sulfonyl chloride (516 mg), a procedure as in Reference Example 219 was performed to give the title compound as a pale-yellow amorphous (yield 295 mg, 77%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:9]=[C:10]([I:13])[C:11]=1[OH:12])[C:5]([O:7][CH3:8])=[O:6].[C:14](=O)([O-])[O-].[K+].[K+].COS(=O)(=O)OC>CN(C)C=O>[Cl:1][C:2]1[CH:3]=[C:4]([CH:9]=[C:10]([I:13])[C:11]=1[O:12][CH3:14])[C:5]([O:7][CH3:8])=[O:6]
Reactant: COC(=O)c1cc(Cl)c(O)c(I)c1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: COS(=O)(=O)OC
Solvent: CN(C)C=O
Product: COC(=O)c1cc(Cl)c(OC)c(I)c1
Temperature: 25 °C
Reaction time: 5 h
Yield: 94.4 %

Procedure:
Methyl 3-chloro-4-hydroxy-5-iodobenzoate (3.00 g) was dissolved in N,N-dimethylformamide (20 mL), and potassium carbonate (3.98 g) and dimethylsulfuric acid (1.82 mL) were added to the solution, and then the mixture was stirred at room temperature for 5 hours. The reaction solution was filtered and water was added, and then the reaction mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, and then dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure to obtain the title compound (2.96 g) as a pale yellow crystal.
Reaction SMILES: CS(O[CH2:6][C:7]1[CH:8]=[N:9][C:10]2[C:15]([CH:16]=1)=[CH:14][CH:13]=[C:12]([O:17][CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([Cl:25])[CH:20]=1)[CH:11]=2)(=O)=O.ClC1C=C(C=CC=1)COC1C=C2C(C=C(CO)C=[N:39]2)=CC=1.CCN(C(C)C)C(C)C.CS(Cl)(=O)=O>C1COCC1>[Cl:25][C:21]1[CH:20]=[C:19]([CH:24]=[CH:23][CH:22]=1)[CH2:18][O:17][C:12]1[CH:11]=[C:10]2[C:15]([CH:16]=[C:7]([CH2:6][NH2:39])[CH:8]=[N:9]2)=[CH:14][CH:13]=1
Reactant: CS(=O)(=O)OCc1cnc2cc(OCc3cccc(Cl)c3)ccc2c1
Reactant: OCc1cnc2cc(OCc3cccc(Cl)c3)ccc2c1
Agent: CS(=O)(=O)Cl
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: NCc1cnc2cc(OCc3cccc(Cl)c3)ccc2c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 76 %

Procedure:
(7-((3-Chlorobenzyl)oxy)quinolin-3-yl)methyl methanesulfonate. To a solution of (7-((3-chlorobenzyl)oxy)quinolin-3-yl)methanol (Example 35, 55 mg, 0.18 mmol) in THF (1.8 mL) was added DIPEA (0.064 mL, 0.37 mmol), followed by methanesulfonyl chloride (0.014 mL, 0.18 mmol). The reaction was stirred at ambient temperature overnight. The crude reaction was loaded directly onto a column, purification (FCC, SiO2, 0-40%, EtOAc/hexanes) afforded the title compound as a white solid (44 mg, 76%). 1H NMR (400 MHz, CDCl3) δ 8.85 (d, J=2.3 Hz, 1H), 8.10 (s, 1H), 7.74 (d, J=9.0 Hz, 1H), 7.48 (d, J=9.4 Hz, 2H), 7.41-7.28 (m, 4H), 5.20 (s, 2H), 4.76 (s, 2H). [M+H]=318.2
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][CH:3]=1.C([Li])CCC.[O:15]=[C:16]1[CH2:22][CH2:21][CH2:20][N:19]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:18][CH2:17]1>C1COCC1>[OH:15][C:16]1([C:2]2[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][CH:3]=2)[CH2:22][CH2:21][CH2:20][N:19]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:18][CH2:17]1
Reactant: COc1ccc(Br)cc1
Reactant: CC(C)(C)OC(=O)N1CCCC(=O)CC1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: COc1ccc(C2(O)CCCN(C(=O)OC(C)(C)C)CC2)cc1
Temperature: -78 °C
Reaction time: 2 h
Yield: 45 %

Procedure:
To a solution of 1-bromo-4-methoxybenzene (0.88 g, 4.7 mmol) in THF (50 mL) was added n-butyllithium (2.9 mL, 4.7 mmol) at −78° C. The reaction mixture was stirred at −78° C. for 2 h, then added to a flask containing tert-butyl 4-oxoazepane-1-carboxylate (1 g, 4.7 mmol) in THF, cooled to −78° C. The reaction mixture was stirred at −78° C. for 30 min and then at 0° C. for 15 min. It was then quenched with saturated ammonium chloride solution and extracted with ethyl acetate. The organic phase was dried over sodium sulfate, filtered, and concentrated. The crude product was purified by flash chromatography on silica gel using hexane/ethyl acetate as the eluant to yield tert-butyl 4-hydroxy-4-(4-methoxyphenyl)azepane-1-carboxylate (0.68 g, 45%). LCMS: R.T. 0.96 min. LCMS (ES-API), m/z 320 (M−H).
Reaction SMILES: [OH:1][CH2:2][CH2:3][NH:4][C:5]([NH:7]C1C=CC([N+]([O-])=O)=CC=1)=[O:6].[C:17]([O:25]CC)(=O)[CH2:18][C:19]([O:21]CC)=O.[O-]CC.[Na+]>C(O)C>[OH:1][CH2:2][CH2:3][N:4]1[C:17](=[O:25])[CH2:18][C:19](=[O:21])[NH:7][C:5]1=[O:6]
Reactant: O=C(NCCO)Nc1ccc([N+](=O)[O-])cc1
Reactant: CCOC(=O)CC(=O)OCC
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Product: O=C1CC(=O)N(CCO)C(=O)N1
Yield: 96 %

Procedure:
In a 1 liter round-bottom flask equipped with an overhead stirrer and reflux condenser was placed N-(2-hydroxyethyl)-N'-(4-nitrophenyl)urea (40.0 grams, 0.178 mol), diethyl malonate (71.2 grams, 0.445 mol), and ethanol (560 mL). Sodium ethoxide in ethanol (21 wt %, 69.2 grams, 0.214 mol) was added and the reaction mixture was heated to reflux for 6 hours. The reaction mixture was cooled and the ethanol was removed under vacuum. Methylene chloride (500 mL) and water (500 mL) were added. The layers were separated and the aqueous layer was further washed with a second portion of methylene chloride to extract a by-product, 4-nitroaniline which was discarded. The aqueous layer was acidified with 6N HCl (50 mL) and an oily phase precipitated. The oil layer was separated and stirred with 70 mL of benzene. After several minutes the oil turned into a chunky, aggregated solid. The benzene was decanted off and the chunky solid was broken up and triturated with hot benzene. The solution was cooled and suction filtered to isolate the solid, which was oven-dried yielding N-(2-hydroxyethyl)barbituric acid (29.4 grams). Additional product (6.2 grams) crystallized out of the water layer upon standing overnight. The additional product was collected by suction filtration and dried.
Reaction SMILES: [Cl:1][C:2]1[C:7]([NH2:8])=[CH:6][CH:5]=[CH:4][N:3]=1.[CH:9](NC(C)C)(C)C.[Li].IC.[NH4+].[Cl-]>C1COCC1>[Cl:1][C:2]1[C:7]([NH:8][CH3:9])=[CH:6][CH:5]=[CH:4][N:3]=1
Reactant: Nc1cccnc1Cl
Reactant: CC(C)NC(C)C
Agent: [Cl-]
Agent: [Li]
Agent: [NH4+]
Solvent: CI
Solvent: C1CCOC1
Product: CNc1cccnc1Cl
Temperature: 0 °C
Reaction time: 1 h
Yield: 89.1 %

Procedure:
To a solution of 2-chloro-3-pyridinamine (0.0465 mol) in THF (45ml) at −78° C. under N2 flow, lithium diisopropylamine (0.0513 mol, 2 M) was added dropwise. The mixture was allowed to warm to 0° C. and was stirred for 1 hour and then cooled to −78° C. Then iodomethane (0.0582 mol) was added and the reaction mixture was allowed to warm to room temperature and was stirred for 16 hours. A saturated NH4Cl-solution was added and the mixture was extracted with ethyl acetate. The separated organic layer was dried, filtered and the solvent was evaporated. The residue was purified by short open column chromatography over silica gel (eluent: hexane/ethyl acetate 80/20). The product fractions were collected and the solvent was evaporated, yielding 5.91 g of 2-chloro-N-methyl-3-pyridinamine (intermediate 28).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][N:11]=[CH:10][C:9]=2[C:13]([OH:15])=O)=[CH:4][CH:3]=1.[OH:16][C:17]1([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]1>>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[O:12][N:11]=[CH:10][C:9]=2[C:13]([N:20]2[CH2:19][CH2:18][C:17]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)([OH:16])[CH2:22][CH2:21]2)=[O:15])=[CH:6][CH:7]=1
Reactant: Cc1ccc(-c2oncc2C(=O)O)cc1
Reactant: OC1(c2ccccc2)CCNCC1
Product: Cc1ccc(-c2oncc2C(=O)N2CCC(O)(c3ccccc3)CC2)cc1

Procedure:
The title compound was prepared from 5-(4-methylphenyl)isoxazole-4-carboxylic acid (10.2 mg, 0.050 mmol) and 4-hydroxy-4-phenylpiperidine (10.6 mg, 0.060 mmol) as described in synthetic method B and thereafter purified by preparative HPLC method B to give a solid (3.9 mg). HRMS calcd for C22H22N2O3: 362.1630, found 362.1623.
Reaction SMILES: CO[C:3]([C:5]1[C:13]2[C:8](=[CH:9][C:10]([C:14]3[CH:19]=[C:18]([F:20])[C:17]([O:21][CH2:22][O:23][CH2:24][CH2:25][Si:26]([CH3:29])([CH3:28])[CH3:27])=[CH:16][C:15]=3[CH2:30][CH3:31])=[CH:11][CH:12]=2)[N:7]([CH:32]2[CH2:37][CH2:36][CH2:35][CH2:34][O:33]2)[N:6]=1)=[NH:4].[C:38]([O:42][C:43]([N:45]1[CH2:50][CH2:49][C:48]([O:54][CH2:55][CH3:56])([O:51][CH2:52][CH3:53])[CH:47]([NH2:57])[CH2:46]1)=[O:44])([CH3:41])([CH3:40])[CH3:39].C(O)(=O)C>C(O)C>[C:38]([O:42][C:43]([N:45]1[CH2:50][CH2:49][C:48]([O:54][CH2:55][CH3:56])([O:51][CH2:52][CH3:53])[CH:47]([NH:57][C:3]([C:5]2[C:13]3[C:8](=[CH:9][C:10]([C:14]4[CH:19]=[C:18]([F:20])[C:17]([O:21][CH2:22][O:23][CH2:24][CH2:25][Si:26]([CH3:29])([CH3:27])[CH3:28])=[CH:16][C:15]=4[CH2:30][CH3:31])=[CH:11][CH:12]=3)[N:7]([CH:32]3[CH2:37][CH2:36][CH2:35][CH2:34][O:33]3)[N:6]=2)=[NH:4])[CH2:46]1)=[O:44])([CH3:39])([CH3:41])[CH3:40]
Reactant: CCc1cc(OCOCC[Si](C)(C)C)c(F)cc1-c1ccc2c(C(=N)OC)nn(C3CCCCO3)c2c1
Reactant: CCOC1(OCC)CCN(C(=O)OC(C)(C)C)CC1N
Solvent: CC(=O)O
Solvent: CCO
Product: CCOC1(OCC)CCN(C(=O)OC(C)(C)C)CC1NC(=N)c1nn(C2CCCCO2)c2cc(-c3cc(F)c(OCOCC[Si](C)(C)C)cc3CC)ccc12
Temperature: 50 °C
Yield: 117.3 %

Procedure:
To a solution of 6-[2-ethyl-5-fluoro-4-(2-trimethylsilanyl-ethoxymethoxy)-phenyl]-1-(tetrahydro-pyran-2-yl)-1H-indazole-3-carboximidic acid methyl ester (Preparation 7, 31.4 g, 59.5 mmol) in ethanol (140 mL) was added a solution of 3-amino-4,4-diethoxy-piperidine-1-carboxylic acid tert-butyl ester (US-2004/0229862, 18.02 g, 62.48 mmol) in ethanol (100 mL). Acetic acid (6.81 mL, 119 mmol) was added and the reaction mixture was heated at 50° C. for 18 hours. The reaction mixture was concentrated in vacuo and azeotroped with toluene (100 mL) to give the title compound as a foam (54.7 g).