Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([CH2:4][CH2:5][OH:6])[CH2:3][CH2:2]1.C1(CCO)C=CC=CC=1.Cl[C:17]1[N:22]=[N:21][C:20]([N:23]2[CH2:28][CH2:27][N:26]([C:29]([C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=3[C:37]([F:40])([F:39])[F:38])=[O:30])[CH2:25][CH2:24]2)=[CH:19][CH:18]=1>>[CH:1]1([CH2:4][CH2:5][O:6][C:17]2[N:22]=[N:21][C:20]([N:23]3[CH2:24][CH2:25][N:26]([C:29]([C:31]4[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=4[C:37]([F:38])([F:40])[F:39])=[O:30])[CH2:27][CH2:28]3)=[CH:19][CH:18]=2)[CH2:3][CH2:2]1
Reactant: OCCC1CC1
Reactant: O=C(c1ccccc1C(F)(F)F)N1CCN(c2ccc(Cl)nn2)CC1
Solvent: OCCc1ccccc1
Product: O=C(c1ccccc1C(F)(F)F)N1CCN(c2ccc(OCCC3CC3)nn2)CC1

Procedure:
Following the procedure set forth above in Example 5, only making variations using 2-cyclopropylethanol to replace 2-phenylethanol to react with [4-(6-chloropyridazin-3-yl)piperazin-1-yl]-(2-trifluoromethylphenyl)methanone, the title compound was obtained as a white solid (56 mg, 74.8% yield). 1H NMR (400 MHz, CDCl3) δ 7.72, 7.60-7.63, 7.52-7.56, 7.35, 7.03, 6.87, 4.46, 3.91-3.98, 3.55, 3.46-3.50, 3.31, 1.68, 0.79-0.84, 0.43-0.46, 0.11-−0.79.
Reaction SMILES: O=[C:2]1[C:10]2[C:5](=[CH:6][C:7]([O:11][C:12]3[CH:20]=[CH:19][C:15]([C:16]([NH2:18])=[O:17])=[CH:14][N:13]=3)=[CH:8][CH:9]=2)[CH2:4][CH2:3]1.[C:21]1([CH2:27][CH2:28][CH2:29][NH2:30])[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.[BH3-]C#N.[Na+]>Cl[Ti](Cl)(Cl)Cl>[C:21]1([CH2:27][CH2:28][CH2:29][NH:30][CH:2]2[C:10]3[C:5](=[CH:6][C:7]([O:11][C:12]4[CH:20]=[CH:19][C:15]([C:16]([NH2:18])=[O:17])=[CH:14][N:13]=4)=[CH:8][CH:9]=3)[CH2:4][CH2:3]2)[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: NCCCc1ccccc1
Reactant: NC(=O)c1ccc(Oc2ccc3c(c2)CCC3=O)nc1
Agent: Cl[Ti](Cl)(Cl)Cl
Agent: [BH3-]C#N
Agent: [Na+]
Product: NC(=O)c1ccc(Oc2ccc3c(c2)CCC3NCCCc2ccccc2)nc1
Yield: 58.6 %

Procedure:
Using a method similar to Example 1, using 6-(1-oxo-indan-5-yloxy)-nicotinamide (Intermediate 4, 805 mg, 3.00 mmol), 3-phenylpropylamine (486 mg, 3.60 mmol), Ti(iPrO)4 (1.70 g, 6.00 mmol), TiCl4 (1.0M/DCM, 6.00 ml, 6.00 mmol), and NaBH3CN (377 mg, 6.00 mmol) gives the title compound (681 mg) as a light yellow solid. Mass spectrum (ion spray): m/z=388 (M+1); 1HNMR (CDCl3): 8.59 (s, 1H), 8.15 (d, 1H), 7.35 (d, 1H), 7.30-7.25 (m, 2H), 7.22-7.16 (m, 3H), 6.99 (s, 1H), 6.95 (d, 1H), 5.85 (br. s, 2H), 4.23 (t, 1H), 3.00 (m, 1H), 2.83 (m, 1H), 2.78 (t, 2H), 2.70 (m, 2H), 2.43 (m, 1H), 1.87 (m, 3H).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH2:9][C:10]([O:12]C)=[O:11])=[CH:5][CH:4]=1)#[N:2].[OH-].[Na+]>C(O)C.O>[C:1]([C:3]1[CH:4]=[CH:5][C:6]([CH2:9][C:10]([OH:12])=[O:11])=[CH:7][CH:8]=1)#[N:2]
Reactant: COC(=O)Cc1ccc(C#N)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: N#Cc1ccc(CC(=O)O)cc1

Procedure:
A solution of methyl 4-cyanophenylacetate (23.9 g; 0.136 mol) in ethanol (250 mL) was stirred at room temperature and a solution of sodium hydroxide (6.0 g; 0.15 mol) in water (25 mL) was added. After 2 hours the ethanol was removed in vacuo. Ethyl acetate (300 mL) and 5% aqueous HCl (300 mL) were added and the layers were separated. The aqueous layer was extracted with ethyl acetate (300 mL) and the combined organic layers were dried (MgSO4) and evaporated in vacuo to give the acid (21.6 g; 99%) which was used without further purification.
Reaction SMILES: C([O:5][C:6](=[O:44])[C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([NH:13][C:14]([C@H:16]2[C@H:20]([C:21]3[CH:26]=[CH:25][CH:24]=[C:23]([Cl:27])[C:22]=3[F:28])[C@:19]([C:31]3[CH:36]=[CH:35][C:34]([Cl:37])=[CH:33][C:32]=3[F:38])([C:29]#[N:30])[C@H:18]([CH2:39][C:40]([CH3:43])([CH3:42])[CH3:41])[NH:17]2)=[O:15])[CH:8]=1)(C)(C)C>C(O)(C(F)(F)F)=O.C(Cl)Cl>[Cl:27][C:23]1[C:22]([F:28])=[C:21]([C@@H:20]2[C@:19]([C:31]3[CH:36]=[CH:35][C:34]([Cl:37])=[CH:33][C:32]=3[F:38])([C:29]#[N:30])[C@H:18]([CH2:39][C:40]([CH3:43])([CH3:41])[CH3:42])[NH:17][C@H:16]2[C:14]([NH:13][C:9]2[CH:8]=[C:7]([CH:12]=[CH:11][CH:10]=2)[C:6]([OH:44])=[O:5])=[O:15])[CH:26]=[CH:25][CH:24]=1
Reactant: CC(C)(C)C[C@@H]1N[C@@H](C(=O)Nc2cccc(C(=O)OC(C)(C)C)c2)[C@H](c2cccc(Cl)c2F)[C@@]1(C#N)c1ccc(Cl)cc1F
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(C)(C)C[C@@H]1N[C@@H](C(=O)Nc2cccc(C(=O)O)c2)[C@H](c2cccc(Cl)c2F)[C@@]1(C#N)c1ccc(Cl)cc1F

Procedure:
rac 3-{[(2R,3S,4R,5S)-3-(3-Chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carbonyl]-amino}-benzoic acid t-butyl ester (20 mg, 0.031 mmol) was treated with 30% TFA/methylene chloride (10 mL) overnight. Removal of solvent and freeze drying of the residue give a white powder. 12 mg.
Reaction SMILES: Cl.[C:2]1([N:8]([CH2:32][CH2:33][C:34]([O:36][CH3:37])=[O:35])[C:9]([C:11]2[CH:31]=[CH:30][C:14]3[N:15]([CH3:29])[C:16]([CH2:18][NH:19][C:20]4[CH:25]=[CH:24][C:23]([C:26](=[NH:28])[NH2:27])=[CH:22][CH:21]=4)=[N:17][C:13]=3[CH:12]=2)=[O:10])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[C:39]([O:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH3:49])=[O:40]>ClCCl.C(O)C>[C:2]1([N:8]([CH2:32][CH2:33][C:34]([O:36][CH3:37])=[O:35])[C:9]([C:11]2[CH:31]=[CH:30][C:14]3[N:15]([CH3:29])[C:16]([CH2:18][NH:19][C:20]4[CH:25]=[CH:24][C:23]([C:26](=[NH:27])[NH:28][C:39]([O:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH3:49])=[O:40])=[CH:22][CH:21]=4)=[N:17][C:13]=3[CH:12]=2)=[O:10])[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCCCCCCCOC(=O)Cl
Reactant: COC(=O)CCN(C(=O)c1ccc2c(c1)nc(CNc1ccc(C(=N)N)cc1)n2C)c1ccccc1
Agent: Cl
Solvent: CCO
Solvent: ClCCl
Product: CCCCCCCCOC(=O)NC(=N)c1ccc(NCc2nc3cc(C(=O)N(CCC(=O)OC)c4ccccc4)ccc3n2C)cc1
Yield: 41 %

Procedure:
Prepared analogously to Example 90 from 1-methyl-2-[N-(4-amidinophenyl)aminomethyl]benzimidazol-5-yl-carboxylic acid-N-phenyl-N-(2-methoxycarbonylethyl)amide hydrochloride and n-octyl chloroformate. Yield: 41% of theory, C36H44N6O5 (640.8); Rf value: 0.43 (silica gel; dichloromethane/ethanol=19:1); EKA mass spectrum: (M+H)+=641; (M+Na)+=663.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N1C=CC=CC=1.C[C:27]1([C:51]([NH2:53])=[O:52])[C:32]([CH3:34])([CH3:33])[S:31][CH2:30][CH2:29][N:28]1[S:35]([C:38]1[CH:43]=[CH:42][C:41]([O:44][CH2:45][C:46]#[C:47][CH2:48][CH2:49]O)=[CH:40][CH:39]=1)(=[O:37])=[O:36].C(Br)(Br)(Br)[Br:55]>C1COCC1>[Br:55][CH2:49][CH2:48][C:47]#[C:46][CH2:45][O:44][C:41]1[CH:42]=[CH:43][C:38]([S:35]([N:28]2[CH2:29][CH2:30][S:31][C:32]([CH3:34])([CH3:33])[CH:27]2[C:51]([NH2:53])=[O:52])(=[O:36])=[O:37])=[CH:39][CH:40]=1
Reactant: BrC(Br)(Br)Br
Reactant: CC1(C)SCCN(S(=O)(=O)c2ccc(OCC#CCCO)cc2)C1(C)C(N)=O
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: c1ccncc1
Solvent: C1CCOC1
Product: CC1(C)SCCN(S(=O)(=O)c2ccc(OCC#CCCBr)cc2)C1C(N)=O
Reaction time: 3 h

Procedure:
To a solution of 2.123 g (8.093 mmol) of triphenylphosphine and 0.373 mL (4.61 mmol) of pyridine in 40 mL of dry THF under nitrogen was added 1.73 g (4.046 mmol) of methyl 4-({4-[(5-hydroxy-2-pentynyl)oxy]phenyl}sulfonyl)-2,2-dimethyl-3-thiomorpholine carboxamide. The solution was cooled in a water bath and 1.34 g (4.046 mmol) of carbon tetrabromide was added and the resulting mixture was stirred for 3h. The resulting suspension was filtered and the filtrate was concentrated in vacuo. The residue was chromatographed on silica gel eluting with ethyl acetate:hexanes (1:8) to provide 1.726 g (87%) of methyl 4-({4-[(5-bromo-2-pentynyl)oxy]phenyl}sulfonyl-2,2-dimethyl-3-thiomorpholine carboxamide as a pale yellow oil. Electrospray Mass Spec: 492.0 (M+H)+
Reaction SMILES: [Br:1][CH2:2][C:3](Br)=[O:4].[N:6]1[CH:11]=[CH:10][CH:9]=[N:8][C:7]=1[N:12]1[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]1.C(N(CC)CC)C>C1COCC1>[Br:1][CH2:2][C:3]([N:15]1[CH2:16][CH2:17][N:12]([C:7]2[N:6]=[CH:11][CH:10]=[CH:9][N:8]=2)[CH2:13][CH2:14]1)=[O:4]
Reactant: O=C(Br)CBr
Reactant: c1cnc(N2CCNCC2)nc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: O=C(CBr)N1CCN(c2ncccn2)CC1
Temperature: 25 °C
Yield: 0.1 %

Procedure:
20.2 g bromacetylbromide was dropped to 16.5 g 1-pyrimidin-2-yl-piperazin and 10.2 g triethylamine in 250 mL THF. The reaction was stirred over night at RT and evaporated. The residue was extracted with DCM and water. The organic layer was evaporated and the residue was crystallized with petrolether and then purified by chromatography on silica gel (DCM/MeOH:95/5) to yield 36 mg of the desired compound.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][CH:3]=[N:2]1.Cl[C:7]1[N:8]=[C:9]([NH:18][CH2:19][C:20]2[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[C:22]([Cl:28])[CH:21]=2)[C:10]2[C:15]([Cl:16])=[C:14]([CH3:17])[S:13][C:11]=2[N:12]=1>>[N:1]1([C:7]2[N:8]=[C:9]([NH:18][CH2:19][C:20]3[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[C:22]([Cl:28])[CH:21]=3)[C:10]3[C:15]([Cl:16])=[C:14]([CH3:17])[S:13][C:11]=3[N:12]=2)[CH:5]=[CH:4][CH:3]=[N:2]1
Reactant: c1cn[nH]c1
Reactant: COc1ccc(CNc2nc(Cl)nc3sc(C)c(Cl)c23)cc1Cl
Product: COc1ccc(CNc2nc(-n3cccn3)nc3sc(C)c(Cl)c23)cc1Cl

Procedure:
Following the procedure of Example 97, the reaction of pyrazole with 2,5-dichloro-6-methyl-4-(3-chloro-4-methoxybenzylamino)-thieno-[2,3-d]-pyrimidine gives 2-(pyrazol-1-yl)-5-chloro-6-methyl-4-(3-chloro-4-methoxybenzylamino)-thieno-[2,3-d]-pyrimidine.
Reaction SMILES: [Cl:1][C:2]1[CH:12]=[C:11]([NH:13][C:14]([N:16]([CH3:18])[CH3:17])=[O:15])[CH:10]=[CH:9][C:3]=1[O:4][CH2:5][CH:6]1[O:8][CH2:7]1.[CH:19]([NH2:22])([CH3:21])[CH3:20]>C(O)C>[Cl:1][C:2]1[CH:12]=[C:11]([NH:13][C:14]([N:16]([CH3:18])[CH3:17])=[O:15])[CH:10]=[CH:9][C:3]=1[O:4][CH2:5][CH:6]([OH:8])[CH2:7][NH:22][CH:19]([CH3:21])[CH3:20]
Reactant: CN(C)C(=O)Nc1ccc(OCC2CO2)c(Cl)c1
Reactant: CC(C)N
Solvent: CCO
Product: CC(C)NCC(O)COc1ccc(NC(=O)N(C)C)cc1Cl
Reaction time: 4 h

Procedure:
A solution of 40 g of 1-[o-chloro-p-(N',N'-dimethyl-ureido)-phenoxy]-2,3-epoxy-propane and 40 g of isopropylamine in 40 ml of ethanol is heated to boiling for 4 hours. Thereafter the mixture is concentrated by evaporation in vacuo and the residue is dissolved in 2 N hydrochloric acid. After extraction with ether, the hydrochloric acid layer is separated off and rendered alkaline by adding concentrated sodium hydroxide solution. The base which has separated out is extracted by shaking with methylene chloride. After evaporation of the solvent and after recrystallisation of the residue from ethyl acetate, the 1-[o-chloro-p-(N',N'-dimethylureido)-phenoxy]-2-hydroxy-3-isopropylamino-propane of formula ##STR18## is obtained in crystals of melting point 130° C.
Reaction SMILES: [Br:1][C:2]1[CH:8]=[CH:7][C:5](N)=[C:4]([C:9]2[CH2:13][CH2:12][O:11][N:10]=2)[C:3]=1[CH3:14].[CH3:15][S:16]SC.N(OCCCC)=O.Cl>[Cu].O>[Br:1][C:2]1[C:3]([CH3:14])=[C:4]([C:9]2[CH2:13][CH2:12][O:11][N:10]=2)[C:5]([S:16][CH3:15])=[CH:7][CH:8]=1
Reactant: Cc1c(Br)ccc(N)c1C1=NOCC1
Reactant: CSSC
Agent: [Cu]
Agent: CCCCON=O
Agent: Cl
Solvent: O
Product: CSc1ccc(Br)c(C)c1C1=NOCC1
Reaction time: 1 h
Yield: 89 %

Procedure:
114.7 g (0.45 mol) of 4-bromo-2-(4,5-dihydroisoxazol-3-yl)-3-methylaniline, 857 mg of copper powder and 1000 ml of dimethyl disulfide are initially charged. Over a period of one hour, 49.2 g of n-butyl nitrite are metered in at 58-65° C., and the mixture is stirred until the reaction has gone to completion (about 1-3 hours). At 20-25° C., 130 ml of conc. hydrochloric acid are added, and the mixture is stirred for 20-30 minutes. 130 ml of water are added, and the phases are then separated. Washing is repeated twice. The organic phase is concentrated, giving 114.4 g of product (yield: 89%).
Reaction SMILES: [CH3:1][S:2][C:3]1[CH:8]=[CH:7][C:6]([N+:9]([O-:11])=[O:10])=[CH:5][CH:4]=1.I(O)(=O)(=O)=[O:13].S([O-])([O-])(=O)=S.[Na+].[Na+]>C(#N)C.[Fe](Cl)(Cl)Cl>[CH3:1][S:2]([C:3]1[CH:4]=[CH:5][C:6]([N+:9]([O-:11])=[O:10])=[CH:7][CH:8]=1)=[O:13]
Reactant: CSc1ccc([N+](=O)[O-])cc1
Reactant: [O-][I+3]([O-])([O-])O
Agent: Cl[Fe](Cl)Cl
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: CC#N
Product: CS(=O)c1ccc([N+](=O)[O-])cc1
Temperature: 25 °C

Procedure:
A suspension of 25.0 g (147.8 mmol) 1-methylsulfanyl-4-nitro-benzene and 0.69 g (4.2 mmol) iron(III) chloride (anhydrous) in 120 ml acetonitrile is treated with 36.0 g (158.1 mmol) periodic acid and stirred at room temperature. At the start of heat evolution, the mixture is transiently cooled with an ice-bath, so that the temperature does not rise above 30° C. After the heat evolution has subsided, the mixture is stirred at room temperature for a further 10 mins. The mixture is poured into a solution of 150 g sodium thiosulphate in 1000 ml ice-water and then extracted with DCM. The combined organic phases are washed with saturated NaCl solution, dried (Na2SO4), filtered and concentrated. The remaining residue is recrystallised from toluene. 23.6 g (128.0 mmol, corresponding to 86% of theor.) of the product is obtained.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([NH:8][C:9](=[O:20])[CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([N+:17]([O-:19])=[O:18])[CH:12]=2)[CH:5]=[CH:6][CH:7]=1.Cl.[Cl:22][C:23]1[N:28]=[C:27](Cl)[C:26]([Cl:30])=[CH:25][N:24]=1.C(=O)([O-])[O-].[K+].[K+].C(N(CC)CC)C>CN(C=O)C>[Cl:22][C:23]1[N:28]=[C:27]([NH:1][C:2]2[CH:3]=[C:4]([NH:8][C:9](=[O:20])[CH2:10][C:11]3[CH:16]=[CH:15][CH:14]=[C:13]([N+:17]([O-:19])=[O:18])[CH:12]=3)[CH:5]=[CH:6][CH:7]=2)[C:26]([Cl:30])=[CH:25][N:24]=1
Reactant: Nc1cccc(NC(=O)Cc2cccc([N+](=O)[O-])c2)c1
Reactant: Clc1ncc(Cl)c(Cl)n1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: O=C(Cc1cccc([N+](=O)[O-])c1)Nc1cccc(Nc2nc(Cl)ncc2Cl)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 54.7 %

Procedure:
To a solution of N-(3-aminophenyl)-2-(3-nitrophenyl)acetamide-hydrogen chloride (0.11 g, 0.35 mmol) and 2,4,5-trichloropyrimidine (0.065 g, 0.35 mmol) in DMF (1 mL) was added potassium carbonate (0.20 g, 1.4 mmol). The resulting mixture was stirred overnight at room temperature. Additional triethylamine (0.099 mL, 0.71 mmol) was then added an stirred overnight again. The reaction was quenched with sat'd NH4Cl and water. EtOAc was added and the layers separated. The aqueous was extracted with EtOAc. The combined organics were washed with water and brine then dried (MgSO4), filtered, and concentrated. The resulted mixture was purified by column chromatography to give the desired product (0.080 g, 53%). LCMS for C18H13Cl2N5O3 (M+H)+: m/z=418.0, 419.9. 1H NMR (400 MHz, DMSO-d6): δ 10.33 (s, 1H), 9.53 (s, 1H), 8.35 (s, 1H), 8.23 (t, J=2.0 Hz, 1H), 8.12 (ddd, J=8.2, 2.4, 1.0 Hz, 1H), 7.82 (t, J=2.0 Hz, 1H), 7.78 (dt, J=7.8, 1.4 Hz, 1H), 7.62 (t, J=7.9 Hz, 1H), 7.36 (dt, J=8.0, 1.7 Hz, 1H), 7.30 (t, J=7.8 Hz, 1H), 7.25 (dt, J=8.0, 1.7 Hz, 1H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[N:4][N:5]([CH3:15])[C:6]=1[C:7]1[CH:8]=[C:9]([C:12]([OH:14])=O)[S:10][CH:11]=1.[NH2:16][C@@H:17]([CH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=1[C:37]([F:40])([F:39])[F:38])[CH2:18][N:19]1[C:27](=[O:28])[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[C:20]1=[O:29].C(N(C(C)C)CC)(C)C.C1CN([P+](Br)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F>C(Cl)Cl>[O:28]=[C:27]1[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[C:20](=[O:29])[N:19]1[CH2:18][C@@H:17]([NH:16][C:12]([C:9]1[S:10][CH:11]=[C:7]([C:6]2[N:5]([CH3:15])[N:4]=[CH:3][C:2]=2[F:1])[CH:8]=1)=[O:14])[CH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=1[C:37]([F:39])([F:38])[F:40]
Reactant: Cn1ncc(F)c1-c1csc(C(=O)O)c1
Reactant: N[C@@H](Cc1ccccc1C(F)(F)F)CN1C(=O)c2ccccc2C1=O
Agent: Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: Cn1ncc(F)c1-c1csc(C(=O)N[C@@H](Cc2ccccc2C(F)(F)F)CN2C(=O)c3ccccc3C2=O)c1
Reaction time: 1 h
Yield: 65.2 %

Procedure:
To a solution of 4-(4-fluoro-1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxylic acid (84 mg, 0.372 mmol), 2-{(2S)-2-amino-3-[2-(trifluoromethyl)phenyl]propyl}-1H-isoindole-1,3(2H)-dione (130 mg, 0.372 mmol)[from Preparation 6], diisopropylethyl amine (323 uL, 1.86 mmol) in DCM (4 mL) was added PyBrop (208 mg, 0.446 mmol) in one portion. After 1 h, the reaction contents were partitioned between H2O/DCM. The aqueous phase was washed several times with DCM and the combined organic fractions were dried over Na2SO4, concentrated and purified via column chromatography (silica, 0.5% MeOH-DCM) affording the title compound (135 mg, 65%) as a white solid: LCMS (ES) m/z=557 (M+H)+.
Reaction SMILES: Cl[C:2]1[C:7]([NH:8][CH:9]=[O:10])=[C:6]([Cl:11])[N:5]=[C:4]([NH:12][CH:13]=[O:14])[N:3]=1.[CH3:15][C:16]1([CH3:24])[O:20][C@H:19]([CH2:21][O:22][NH2:23])[CH2:18][O:17]1.C(N(C(C)C)CC)(C)C>COCCOCCOC>[Cl:11][C:6]1[C:7]([NH:8][CH:9]=[O:10])=[C:2]([NH:23][O:22][CH2:21][C@@H:19]2[CH2:18][O:17][C:16]([CH3:24])([CH3:15])[O:20]2)[N:3]=[C:4]([NH:12][CH:13]=[O:14])[N:5]=1
Reactant: CC1(C)OC[C@@H](CON)O1
Reactant: O=CNc1nc(Cl)c(NC=O)c(Cl)n1
Solvent: COCCOCCOC
Solvent: CCN(C(C)C)C(C)C
Product: CC1(C)OC[C@@H](CONc2nc(NC=O)nc(Cl)c2NC=O)O1
Temperature: 100 °C
Reaction time: 4 h

Procedure:
A mixture of 4,6-dichloro-2,5-diformamidopyrimidine (7.3 g, 31.1 mmol), (S)-2,2-dimethyl-1,3-dioxolan-4-ylmethoxyamine (4.6 g, 31.1 mmol) and diisopropylethylamine (8.03 g, 62.1 mmol) in diglyme (125 ml) was stirred at 100° C. for 4 h. The reaction was filtered, evaporated and the residue chromatographed twice in chloroform-methanol 15:1 affording (S)-4-chloro-2,5-diformamido-6-(2,2-dimethyl-1,3-dioxolan-4-ylmethoxyamino)pyrimidine(2.6 g, 24%). υmax (CHCl3) 3400, 1700, 1580, 1560 and 1470 cm-1 ; δH (CDCl3) 1.39(3H,S,CH3), 1.48(3H,S,CH3) , 3.60-4.65(5H,m,CH2ONH+CH2OCMe2 +CHOCMe2), 7.96(1H,br.m, D2O exchangeable, NH), 8.34(1H,S,CHO), 9.25(2H,br.m,D2O exchangeable, 2XNH) and 9.50(1H,S,CHO); m/z 344(M+ -H,<1%), 330(M+ -CH3, <1%).
Reaction SMILES: [CH:1]1([N:6]2[C:15]3[C:10](=[CH:11][C:12]([F:18])=[C:13](F)[C:14]=3[F:16])[C:9](=[O:19])[C:8]([C:20]([OH:22])=[O:21])=[CH:7]2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH2:23]([NH:25][CH2:26][CH:27]1[CH2:31][CH2:30][NH:29][CH2:28]1)[CH3:24]>C(#N)C>[CH:1]1([N:6]2[C:15]3[C:10](=[CH:11][C:12]([F:18])=[C:13]([N:29]4[CH2:30][CH2:31][CH:27]([CH2:26][NH:25][CH2:23][CH3:24])[CH2:28]4)[C:14]=3[F:16])[C:9](=[O:19])[C:8]([C:20]([OH:22])=[O:21])=[CH:7]2)[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: O=C(O)c1cn(C2CCCC2)c2c(F)c(F)c(F)cc2c1=O
Reactant: CCNCC1CCNC1
Solvent: CC#N
Product: CCNCC1CCN(c2c(F)cc3c(=O)c(C(=O)O)cn(C4CCCC4)c3c2F)C1
Yield: 74.2 %

Procedure:
To 0.86 g (2.7 mmol) of the 1-cyclopentyl-6,7,8-trifluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid in 10 ml of acetonitrile was added 0.40 g (2.7 mmol) of 1,8-diazobicyclo[5.4.0]undec-7-ene and 0.36 g (2.7 mmol) of 3-[(ethylamino)methyl]pyrrolidine. The mixture was refluxed for seven hours, cooled, filtered, and the solids washed with ether to give 0.84 g of 1-cyclopentyl-7-[3-[(ethylamino)methyl]-1-pyrrolidinyl]-6,8-difluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid, mp 214°-217° C.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][C:3]2[CH:6]([NH:10][C:11](=[O:13])[CH3:12])[CH2:7][CH2:8][CH2:9][C:2]1=2.[Mn]([O-])(=O)(=O)=[O:15].[K+].S([O-])([O-])(=O)=O.[Mg+2]>CC(C)=O>[O:15]=[C:9]1[C:2]2[S:1][CH:5]=[CH:4][C:3]=2[CH:6]([NH:10][C:11](=[O:13])[CH3:12])[CH2:7][CH2:8]1
Reactant: CC(=O)NC1CCCc2sccc21
Reactant: O=[Mn](=O)(=O)[O-]
Agent: O=S(=O)([O-])[O-]
Agent: [K+]
Agent: [Mg+2]
Solvent: CC(C)=O
Product: CC(=O)NC1CCC(=O)c2sccc21

Procedure:
One molar equivalent of N-(4,5,6,7-tetrahydrobenzo[b]thien-4-yl)acetamide is oxidized in aqueous acetone at 10° C. to 15° C. with 2.66 moles of potassium permanganate in the pH range of 7 to 9 in the presence of magnesium sulfate buffer for a period of time from about 3 to 5 hours to afford N-(4,5,6,7-tetrahydro-7-oxobenzo[b]thien-4-yl)acetamide. The thus-obtained oxo-acetamide is hydrolyzed in aqueous hydrochloric acid to the corresponding amine. This amine is then reacted with sodium or potassium cyanate in an aqueous medium at about pH 6.5, and at a temperature of about 60° C. to 65° C., to afford the animal growth-promoting 4,5,6,7-tetrahydro-7-oxobenzo[b]thien-4-ylurea of formula (A). Oxidation of 4,5,6,7-tetrahydrobenzo[b]thien-4-ylurea under reaction conditions, similar to those described above, also affords the aforesaid urea of formula (A). The above reaction sequence may be graphically illustrated as follows: ##STR10##
Reaction SMILES: I[C:2]1[CH:16]=[CH:15][C:5]([O:6][CH2:7][CH2:8][N:9]2[CH2:14][CH2:13][O:12][CH2:11][CH2:10]2)=[CH:4][CH:3]=1.C(#N)C.[CH3:20][Si:21]([C:24]#[CH:25])([CH3:23])[CH3:22]>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I.C(N(CC)CC)C>[CH3:20][Si:21]([C:24]#[C:25][C:2]1[CH:16]=[CH:15][C:5]([O:6][CH2:7][CH2:8][N:9]2[CH2:14][CH2:13][O:12][CH2:11][CH2:10]2)=[CH:4][CH:3]=1)([CH3:23])[CH3:22]
Reactant: Ic1ccc(OCCN2CCOCC2)cc1
Reactant: C#C[Si](C)(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCN(CC)CC
Solvent: CC#N
Product: C[Si](C)(C)C#Cc1ccc(OCCN2CCOCC2)cc1
Temperature: 60 °C
Reaction time: 16 h

Procedure:
A resealable tube was charged with 4-[2-(4-iodo-phenoxy)-ethyl]-morpholine 100b (2.00 g, 6.00 mmol), acetonitrile (40 mL), and triethylamine (5 mL). Dichlorobis(triphenylphosphine)palladium (II) (0.211 g, 0.30 mmol), copper (I) iodide (0.057 g, 0.30 mmol), and (trimethylsilyl)acetylene (0.766 g, 1.10 mL, 7.80 mmol) were added. The system was purged with argon, the tube was sealed, and the mixture stirred at 60° C. for 16 h. The reaction mixture was concentrated to afford 4-[2-(4-trimethylsilanylethynyl-phenoxy)-ethyl]-morpholine 101b as a dark brown solid which was used without purification. MS (MH+) 304.2; Calculated 303 for C17H25NO2Si.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][C:10]=1[CH3:11])[NH:7][N:6]=[CH:5]2.[F:12][C:13]1[CH:18]=[CH:17][C:16](B(O)O)=[CH:15][CH:14]=1.N1C=CC=CC=1>C(Cl)Cl.C(O[Cu]OC(=O)C)(=O)C>[Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][C:10]=1[CH3:11])[N:7]([C:16]1[CH:17]=[CH:18][C:13]([F:12])=[CH:14][CH:15]=1)[N:6]=[CH:5]2
Reactant: Cc1cc2[nH]ncc2cc1Br
Reactant: OB(O)c1ccc(F)cc1
Agent: CC(=O)O[Cu]OC(C)=O
Solvent: ClCCl
Solvent: c1ccncc1
Product: Cc1cc2c(cnn2-c2ccc(F)cc2)cc1Br
Reaction time: 4 h
Yield: 64.1 %

Procedure:
To a solution of 5-bromo-6-methyl-1H-indazole (2.89 g, 13.69 mmol,) in DCM (137 mL) was added 4-fluorophenylboronic acid (3.83 g, 27.4 mmol), diacetoxycopper (2.48 g, 13.7 mmol), pyridine (2.2 mL, 27.4 mmol) and 4 Å molecular sieves. The reaction was stirred open to air for about 4 h. The reaction mixture was filtered through a pad of Celite® rinsing with EtOAc (80 mL) and then concentrated to about (60 mL) under reduced pressure. Water was added (40 mL) and the layers were separated. The aqueous layer was back extracted with EtOAc (20 mL). The combined organic layers were dried over MgSO4, filtered and concentrated under reduced pressure. The resulting residue was purified by column chromatography (SiO2, EtOAc/heptane 100:0 to 0:20) to afford 5-bromo-1-(4-fluorophenyl)-6-methyl-1H-indazole (2.68 g, 8.78 mmol, 64%). LC-MS (Table 1, Method g) Rt=2.75 min, m/z 305, 307 (M+H)+. 1H NMR (CDCl3) δ 8.07 (s, 1H), 7.98 (s, 1H), 7.69-7.59 (m, 2H), 7.52 (s, 1H), 7.28-7.18 (m, 2H), 2.53 (s, 3H).