Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[N:2]1.C(=O)([O-])[O-].[Na+].[Na+].Cl[CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19]>CN(C)C=O>[CH2:21]([O:20][C:18](=[O:19])[CH2:17][N:2]1[N:3]=[C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]2=[N:1]1)[CH3:22]
Reactant: CCOC(=O)CCl
Reactant: c1ccc2[nH]nnc2c1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)Cn1nc2ccccc2n1
Temperature: 40 °C
Reaction time: 17 h

Procedure:
59.5 g benzotriazole (0.50 mol) was dissolved in 700 ml dimethylformamide. 160 g Sodium carbonate (1.5 mol) was added and then dropwise 73.5 g ethyl chloroacetate (0.60 mol). The stirred mixture was slowly heated to 40° C., and kept at that temperature for 17 h. The solvent was evaporated and the residue was extracted with ethyl acetate. GC showed one major and one minor product. The minor product ethyl-2-(2-benzotriazolyl)acetate was isolated by fractional crystallization from cold mixtures of ethanol and ethyl acetate.
Reaction SMILES: C1([O:7][C:8](=O)[N:9]([C:19]2[CH:24]=[C:23]([O:25][C:26]3[CH:31]=[CH:30][C:29]([NH:32][C:33]([C:35]4([C:38](=[O:47])[NH:39][C:40]5[CH:45]=[CH:44][C:43]([F:46])=[CH:42][CH:41]=5)[CH2:37][CH2:36]4)=[O:34])=[CH:28][C:27]=3[F:48])[CH:22]=[CH:21][N:20]=2)C(OC2C=CC=CC=2)=O)C=CC=CC=1.Cl.Cl.[N:52]1([CH:56]2[CH2:61][CH2:60][NH:59][CH2:58][CH2:57]2)[CH2:55][CH2:54][CH2:53]1.C(N(CC)CC)C>CN(C)C=O>[N:52]1([CH:56]2[CH2:61][CH2:60][N:59]([C:8]([NH:9][C:19]3[CH:24]=[C:23]([O:25][C:26]4[CH:31]=[CH:30][C:29]([NH:32][C:33]([C:35]5([C:38]([NH:39][C:40]6[CH:41]=[CH:42][C:43]([F:46])=[CH:44][CH:45]=6)=[O:47])[CH2:37][CH2:36]5)=[O:34])=[CH:28][C:27]=4[F:48])[CH:22]=[CH:21][N:20]=3)=[O:7])[CH2:58][CH2:57]2)[CH2:55][CH2:54][CH2:53]1
Reactant: O=C(Oc1ccccc1)N(C(=O)Oc1ccccc1)c1cc(Oc2ccc(NC(=O)C3(C(=O)Nc4ccc(F)cc4)CC3)cc2F)ccn1
Reactant: C1CN(C2CCNCC2)C1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: O=C(Nc1cc(Oc2ccc(NC(=O)C3(C(=O)Nc4ccc(F)cc4)CC3)cc2F)ccn1)N1CCC(N2CCC2)CC1
Reaction time: 24 h
Yield: 59 %

Procedure:
To a solution of [4-(2-fluoro-4-{[1-(4-fluorophenylcarbamoyl)cyclopropanecarbonyl]amino}phenoxy)pyridin-2-yl]-N-(phenoxycarbonyl)carbamic acid phenyl ester (66 mg) in N,N-dimethylformamide (1.0 ml) were added 4-(azetidin-1-yl)piperidine dihydrochloride (85 mg) and triethylamine (0.112 ml) at room temperature, followed by stirring for 24 hr. The reaction mixture was partitioned between ethyl acetate and water. The organic layer was washed with a saturated aqueous solution of ammonium chloride and brine in this order, and dried over anhydrous sodium sulfate. The solvent was concentrated under reduced pressure. The resultant residue was purified by silica gel column chromatography (Fuji Silysia NH, eluent; ethyl acetate, then ethyl acetate:methanol=95:5). Fractions containing the target compound were concentrated under reduced pressure. A solid was precipitated by addition of diethyl ether:heptane=1:3 to the resultant residue. The solid was collected by filtration and dried under aeration to provide the titled compound as white powder (34.6 mg, 59%).
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:10]2[N:11]([N:16]=[CH:17][CH:18]=2)[CH:12]=[C:13](Br)[CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:19][N:20]1[CH:24]=[C:23](B2OC(C)(C)C(C)(C)O2)[CH:22]=[N:21]1.[F-].[K+].F[B-](F)(F)F.C([PH+](C(C)(C)C)C(C)(C)C)(C)(C)C>CN(C=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:8][C:9]1[C:10]2[N:11]([N:16]=[CH:17][CH:18]=2)[CH:12]=[C:13]([C:23]2[CH:22]=[N:21][N:20]([CH3:19])[CH:24]=2)[CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cn1cc(B2OC(C)(C)C(C)(C)O2)cn1
Reactant: Brc1cc(OCc2ccccc2)c2ccnn2c1
Agent: [Pd]
Agent: CC(C)(C)[PH+](C(C)(C)C)C(C)(C)C
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Product: Cn1cc(-c2cc(OCc3ccccc3)c3ccnn3c2)cn1
Temperature: 100 °C
Reaction time: 2 h

Procedure:
4-(benzyloxy)-6-bromopyrazolo[1,5-a]pyridine (1.27 g, 4.19 mmol), 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (1.74 g, 8.38 mmol), tris(dibenzylideneacetone)dipalladium (0) (192 mg, 0.209 mmol), potassium fluoride (803 mg, 13.8 mmol), and tri-t-butylphosphonium tetrafluoroborate (122 mg, 0.419 mmol) were suspended in DMF (21 mL), sparged with argon for 10 minutes, then heated to 100° C. After 2 h, the reaction mixture was cooled to ambient temperature, diluted in ethyl acetate, washed with saturated aqueous sodium hydrogen carbonate and brine. The combined aqueous layers were saturated with NaCl and extracted with ethyl acetate (5×50 ml). The combined organic layers were dried over sodium sulfate, filtered and concentrated. The residue was purified by column chromatography on silica gel (methanol/ethyl acetate gradient). Fractions containing pure 4-(benzyloxy)-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridine were set aside and fractions that were impure by TLC analysis were combined and repurified in a similar manner to afford a second batch of pure 4-(benzyloxy)-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridine.
Reaction SMILES: Cl[C:2]1[C:11]([CH3:12])=[C:10]([Cl:13])[C:9]2[C:4](=[CH:5][C:6]([O:15][CH3:16])=[C:7]([Cl:14])[CH:8]=2)[N:3]=1.C([Sn](CCCC)(CCCC)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][N:23]=1)CCC>C1(C)C=CC=CC=1>[Cl:13][C:10]1[C:9]2[C:4](=[CH:5][C:6]([O:15][CH3:16])=[C:7]([Cl:14])[CH:8]=2)[N:3]=[C:2]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][N:23]=2)[C:11]=1[CH3:12]
Reactant: COc1cc2nc(Cl)c(C)c(Cl)c2cc1Cl
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccccn1
Solvent: Cc1ccccc1
Product: COc1cc2nc(-c3ccccn3)c(C)c(Cl)c2cc1Cl

Procedure:
The dichloride was prepared according to Procedure E using 2,4,6-trichloro-7-methoxy-3-methylquinoline (0.69 g, 2.49 mmol), 2-(tributylstannyl)pyridine (1.01 mL, 2.74 mmol), palladium tetrakistriphenylphosphine (0.29 g, 0.25 mmol) in toluene (5.00 mL) to give 4,6-dichloro-7-methoxy-3-methyl-2-(pyridin-2-yl)quinoline as a white solid. Mass Spectrum (ESI) m/e=319.0 (M+1).
Reaction SMILES: Cl[C:2]([F:14])([CH2:5][C:6]([Cl:13])([CH3:12])[CH:7]([O:10][CH3:11])[O:8][CH3:9])[C:3]#[N:4].Cl.CN(C)C=O>[Hg].C(#N)C.[Cd]>[Cl:13][C:6]([CH3:12])([CH:7]([O:8][CH3:9])[O:10][CH3:11])[CH2:5][CH:2]([F:14])[C:3]#[N:4]
Reactant: COC(OC)C(C)(Cl)CC(F)(Cl)C#N
Agent: Cl
Agent: [Cd]
Agent: [Hg]
Solvent: CC#N
Solvent: CN(C)C=O
Product: COC(OC)C(C)(Cl)CC(F)C#N
Yield: 357.7 %

Procedure:
A reaction mixture containing 5 g (0.045 mole) of cadmium metal dissolved in 100 g of mercury and 100 ml of acetonitrile was brought to reflux and 10.8 g (0.04 mole) of 2,4-dichloro-2-fluoro-5,5-dimethoxy-4-methylpentanenitrile and 0.05 mole of dimethylformamidehydrochloride in 50 ml of acetonitrile were added dropwise. After the addition was complete refluxing was maintained for an additional 5 hours. The salts and Hg were removed by filtration and the solvent was removed in vacuo. The residue was distilled through a Kuglerohr apparatus to afford 30 g of crude 4-chloro-2-fluoro-5,5-dimethoxy-4-methylpentanenitrile which was distilled through a spinning band column. Fractions boiling between 52°-55° C., 0.3 mm Hg, were collected and were shown to be essentially pure diasteromeric 4 -chloro-2-fluoro-5,5-dimethoxy-4-methylpentanenitriles, 'Hnmr (Acetone d6TMS) δ 1.5-1.75 (m, 3H, --CH3); δ 2.60 (dm, 2H, -- CH2 --), JHF 20.76 z; δ 3.58 ##STR7## δ 5.8 (dt, 1H, --CHF--); JH2F 46.6 Hz. IR NaCl neat 2260 cm-1 ; 1070 cm-1.
Reaction SMILES: [H-].[Na+].[NH:3]1[CH:7]=[N:6][CH:5]=[N:4]1.I[CH2:9][Si:10]1([C:15]2[CH:20]=[CH:19][C:18]([O:21][CH2:22][CH3:23])=[CH:17][CH:16]=2)[CH2:14][CH2:13][CH2:12][CH2:11]1.[NH4+].[Cl-]>CN(C=O)C>[CH2:22]([O:21][C:18]1[CH:17]=[CH:16][C:15]([Si:10]2([CH2:9][N:3]3[CH:7]=[N:6][CH:5]=[N:4]3)[CH2:14][CH2:13][CH2:12][CH2:11]2)=[CH:20][CH:19]=1)[CH3:23]
Reactant: c1nc[nH]n1
Reactant: CCOc1ccc([Si]2(CI)CCCC2)cc1
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: CN(C)C=O
Product: CCOc1ccc([Si]2(Cn3cncn3)CCCC2)cc1
Reaction time: 0.25 h
Yield: 81.2 %

Procedure:
To a 100 ml, round bottomed flask equipped with a condenser and a dropping funnel were added 0.29 g of NaH (0.01 mol, 80% dispersion in mineral oil) and 2 ml of DMF. After resolving 0.78 g (0.011 mol) of 1,2,4-triazole in 2 ml of dried DMF, the solution was added through the dropping funnel and the mixture was stirred for 15 min. 3.00 g (0.009 mol) of 1-iodomethyl-1-(4-ethoxyphenyl)-1-silacyclopentane as prepared in Example 9 was diluted with 3 ml of DMF to be dropwisely added to the flask, and the mixture was stirred at 45° C. for 4 and half hrs. After confirming by GC that all the reactants were participated with the reaction, the aqueous saturated NH4Cl solution was added therein, and the organic material was extracted three times 30 ml of diethylether. The extract was dried on anhydrous MgSO4, and filtered to remove the solvent The residue was separated by silica gel column (eluent: ether) to obtain 2.1 g of 1-(4-ethoxyphenyl)-1-(1H-1,2,4-triazole-1-yl) methyl-1-silacyclopentane.
Reaction SMILES: [Cl:1][CH2:2][C@@H:3]([OH:15])[CH2:4][CH:5]([CH2:13]O)[C:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7].C(N(CC)CC)C.[S:23](Cl)([CH3:26])(=[O:25])=[O:24]>C(Cl)Cl>[Cl:1][CH2:2][C@@H:3]([O:15][S:23]([CH3:26])(=[O:25])=[O:24])[CH2:4][C:5](=[CH2:13])[C:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7]
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)(C)OC(=O)C(CO)C[C@H](O)CCl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C=C(C[C@@H](CCl)OS(C)(=O)=O)C(=O)OC(C)(C)C
Reaction time: 0.33 h
Yield: 88.7 %

Procedure:
To a stirred solution of tert-butyl (4S)-5-chloro-4-hydroxy-2-hydroxymethylpentanoate (10.0 g) and triethylamine (12.7 g) in methylene chloride (100 ml), mesyl chloride (11.5 g) was added dropwise under ice-cooling and the mixture was stirred for 20 minutes. The mixture was concentrated in vacuo. Water was added to the residue and extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium bicarbonate solution, water and saturated aqueous sodium chloride solution. The organic layer was dried over anhydrous magnesium sulfate and concentrated in vacuo. The oily residue was dissolved in benzene (130 ml) and 1,8-diazabicyclo[5.4.0]undec-7-ene (7.0 g) was added to the solution. The mixture was stirred for 2 hours at room temperature. Water was added to the mixture and extracted with ethyl acetate. The organic layer was washed with water and saturated sodium chloride solution, dried over anhydrous magnesium sulfate and concentrated in vacuo. The oily residue was purified by a silica gel column chromatography to give 11.1 g (89%) of tert-butyl (4S)-5-chloro-4-mesyloxy-2-methylenepentanoate.
Reaction SMILES: C(N(CC)C(C)C)(C)C.Cl.Cl.[CH3:12][Si:13]([CH3:40])([CH3:39])[CH2:14][CH2:15][O:16][CH2:17][N:18]1[C:22]2[N:23]=[CH:24][N:25]=[C:26]([C:27]3[CH:28]=[N:29][N:30]([C:32]4([CH2:36][C:37]#[N:38])[CH2:35][NH:34][CH2:33]4)[CH:31]=3)[C:21]=2[CH:20]=[CH:19]1.Cl[C:42]1[N:43]=[CH:44][C:45]([C:48]([NH:50][C@@H:51]([CH3:56])[C:52]([F:55])([F:54])[F:53])=[O:49])=[N:46][CH:47]=1.C([O-])(O)=O.[Na+]>CN1C(=O)CCC1>[C:37]([CH2:36][C:32]1([N:30]2[CH:31]=[C:27]([C:26]3[C:21]4[CH:20]=[CH:19][N:18]([CH2:17][O:16][CH2:15][CH2:14][Si:13]([CH3:39])([CH3:12])[CH3:40])[C:22]=4[N:23]=[CH:24][N:25]=3)[CH:28]=[N:29]2)[CH2:33][N:34]([C:42]2[N:43]=[CH:44][C:45]([C:48]([NH:50][C@@H:51]([CH3:56])[C:52]([F:55])([F:54])[F:53])=[O:49])=[N:46][CH:47]=2)[CH2:35]1)#[N:38]
Reactant: C[Si](C)(C)CCOCn1ccc2c(-c3cnn(C4(CC#N)CNC4)c3)ncnc21
Reactant: C[C@H](NC(=O)c1cnc(Cl)cn1)C(F)(F)F
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: CN1CCCC1=O
Product: C[C@H](NC(=O)c1cnc(N2CC(CC#N)(n3cc(-c4ncnc5c4ccn5COCC[Si](C)(C)C)cn3)C2)cn1)C(F)(F)F
Temperature: 120 °C
Reaction time: 2 h
Yield: 76 %

Procedure:
N,N-Diisopropylethylamine (0.11 mL, 0.62 mmol) was added to a mixture of {3-[4-(7-{[2-(trimethylsilyl)ethoxy]methyl}-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-3-yl}acetonitrile dihydrochloride (110 mg, 0.22 mmol) and 5-chloro-N-[(1S)-2,2,2-trifluoro-1-methylethyl]pyrazine-2-carboxamide (52 mg, 0.21 mmol) in NMP (3.0 mL). The reaction mixture was stirred at 120° C. for 2 h. The reaction mixture was worked up with saturated aqueous NaHCO3, and extracted with dichloromethylene (3×20 mL). The combined organic layers were washed with brine, dried over MgSO4, filtered and concentrated under reduced pressure. The residue was purified by flash chromatography on a silica gel column with ethyl acetate in dichloromethylene (0-65%) to afford the desired product (100 mg, 73%). LCMS (M+H)+: m/z=627.2.
Reaction SMILES: C(OC(C1C=C(C2C=CC(C[S:19][CH2:20][CH2:21][OH:22])=CC=2)C=CC=1)=O)C.[CH2:23]([O:25][C:26]([C:28]1[CH:33]=[CH:32][C:31]([C:34]2[CH:39]=[CH:38][CH:37]=[C:36]([CH2:40]Br)[CH:35]=2)=[CH:30][CH:29]=1)=[O:27])[CH3:24].SCCO.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[CH2:23]([O:25][C:26]([C:28]1[CH:33]=[CH:32][C:31]([C:34]2[CH:39]=[CH:38][CH:37]=[C:36]([CH2:40][S:19][CH2:20][CH2:21][OH:22])[CH:35]=2)=[CH:30][CH:29]=1)=[O:27])[CH3:24]
Reactant: CCOC(=O)c1cccc(-c2ccc(CSCCO)cc2)c1
Reactant: CCOC(=O)c1ccc(-c2cccc(CBr)c2)cc1
Agent: O=C([O-])[O-]
Agent: OCCS
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1ccc(-c2cccc(CSCCO)c2)cc1

Procedure:
3′-(2-Hydroxy-ethylsulfanylmethyl)-biphenyl-4-carboxylic acid ethyl ester was synthesized as described for 4′-(2-hydroxy-ethylsulfanylmethyl)-biphenyl-3-carboxylic acid ethyl ester. 3′-Bromomethyl-biphenyl-4-carboxylic acid ethyl ester (4.98 g, 15.6 mmol, 1 eq) in anhydrous DMF was treated with 2-mercaptoethanol (2.44 g, 31.20 mmol, 2 eq.) and potassium carbonate (6.47 g, 46.80 mmol, 3 eq.). When complete, the reaction was worked up as described leaving a yellow oil.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[C:9]([O:11][CH3:12])[CH:8]=[C:7]([O:13][CH3:14])[C:3]=1[C:4]([NH2:6])=[O:5].[Br:15][C:16]1[N:21]=[C:20]([CH:22]=O)[CH:19]=[CH:18][CH:17]=1.OS([O-])=O.[Na+].O.C1(C)C=CC(S(O)(=O)=O)=CC=1>CN(C)C(=O)C>[Br:15][C:16]1[N:21]=[C:20]([C:22]2[NH:6][C:4](=[O:5])[C:3]3[C:2](=[CH:10][C:9]([O:11][CH3:12])=[CH:8][C:7]=3[O:13][CH3:14])[N:1]=2)[CH:19]=[CH:18][CH:17]=1
Reactant: COc1cc(N)c(C(N)=O)c(OC)c1
Reactant: O=Cc1cccc(Br)n1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=S([O-])O
Agent: [Na+]
Solvent: CC(=O)N(C)C
Solvent: O
Product: COc1cc(OC)c2c(=O)[nH]c(-c3cccc(Br)n3)nc2c1
Temperature: 120 °C
Yield: 47.9 %

Procedure:
To a solution of 2-amino-4,6-dimethoxybenzamide (0.40 g, 2.04 mmol) and 6-bromopyridine-2-carbaldehyde (0.379 g, 2.04 mmol) in N,N-dimethylacetamide (24 mL) was added NaHSO3 (0.544 g, 3.06 mmol) and p-toluenesulfonic acid monohydrate (0.078 g, 0.408 mmol) at rt. The reaction mixture was heated at 120° C. for 6 h. After that time the reaction was cooled to rt, concentrated under reduced pressure and diluted with water (10 mL). The precipitated solids were collected by filtration, washed with water and dried. The product was purified by flash column chromatography (silica gel, 95:5 dichloromethane/methanol) to give 2-(6-bromopyridin-2-yl)-5,7-dimethoxyquinazolin-4(3H)-one (0.354 g, 48%) as a light yellow solid: 1H NMR (400 MHz, DMSO-d6) δ 11.25 (br s, 1H), 8.36 (d, J=7.81 Hz, 1H), 7.87-8.04 (m, 2H), 6.81 (s, 1H), 6.62 (s, 1H), 3.91 (s, 3H), 3.87 (s, 3H); ESI MS m/z 362 [M+H]+.
Reaction SMILES: Cl[C:2]1[S:3][CH:4]=[CH:5][C:6]=1[N+:7]([O-])=O.C([Sn](CCCC)(CCCC)[C:15]1[N:16]=[CH:17][S:18][CH:19]=1)CCC>>[S:18]1[CH:19]=[C:15]([C:2]2[S:3][CH:4]=[CH:5][C:6]=2[NH2:7])[N:16]=[CH:17]1
Reactant: O=[N+]([O-])c1ccsc1Cl
Reactant: CCCC[Sn](CCCC)(CCCC)c1cscn1
Product: Nc1ccsc1-c1cscn1

Procedure:
This amine was prepared from 2-chloro-3-nitrothiophene using Protocols E and F except that 4-(tributylstannyl)thiazole was used. Method[1], MS(ESI) 183.0 [M+H], Retention time=0.518 min.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[C:9]([I:11])[CH:8]=[CH:7][C:3]=1[C:4](O)=[O:5].CC[N:14]=C=NCCCN(C)C.ON1C2C=CC=CC=2N=N1.CCN(C(C)C)C(C)C.N>CN(C=O)C.O>[NH2:1][C:2]1[CH:10]=[C:9]([I:11])[CH:8]=[CH:7][C:3]=1[C:4]([NH2:14])=[O:5]
Reactant: CCN=C=NCCCN(C)C
Reactant: Nc1cc(I)ccc1C(=O)O
Agent: N
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: NC(=O)c1ccc(I)cc1N
Temperature: 25 °C
Reaction time: 8 h
Yield: 52.2 %

Procedure:
To a solution of 2-amino-4-iodobenzoic acid (2.5 g, 9.50 mmol) in DMF (10 mL) at rt under argon were added EDCI (2.18 g, 11.40 mmol), 1-hydroxybenzotriazole (1.54 g, 11.40 mmol), DIEA (1.98 mL, 11.40 mmol), and ammonia (7.0 N solution in MeOH; 1.90 mL, 13.30 mmol). The dark solution was stirred at rt overnight and diluted with H2O until precipitate formed. The precipitate was separated by filtration, washed with H2O, and dried under high vacuum for several hours to afford 2-amino-4-iodobenzamide as a tan solid (1.3 g, 52%). LC-MS (ESI) m/z 263 (M+H)+.
Reaction SMILES: [C@H:1]([O:5][C:6]1[CH:7]=[C:8]([CH:12]=[C:13]([O:15][C:16]2[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=2)[CH:14]=1)[C:9]([OH:11])=O)([CH2:3][CH3:4])[CH3:2].[CH2:23]([O:25][C:26](=[O:35])[CH2:27][S:28][C:29]1[S:33][C:32]([NH2:34])=[N:31][CH:30]=1)[CH3:24]>>[CH2:23]([O:25][C:26](=[O:35])[CH2:27][S:28][C:29]1[S:33][C:32]([NH:34][C:9](=[O:11])[C:8]2[CH:12]=[C:13]([O:15][C:16]3[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=3)[CH:14]=[C:6]([O:5][C@@H:1]([CH2:3][CH3:4])[CH3:2])[CH:7]=2)=[N:31][CH:30]=1)[CH3:24]
Reactant: CC[C@@H](C)Oc1cc(Oc2ccc(F)cc2)cc(C(=O)O)c1
Reactant: CCOC(=O)CSc1cnc(N)s1
Product: CCOC(=O)CSc1cnc(NC(=O)c2cc(Oc3ccc(F)cc3)cc(O[C@H](C)CC)c2)s1

Procedure:
The title compound was prepared from 3-((R)-sec-butoxy)-5-(4-fluoro-phenoxy)benzoic acid and (2-amino-thiazol-5-ylsulfanyl)-acetic acid ethyl ester following general procedure A
Reaction SMILES: [CH2:1]([NH:3][S:4](=[O:7])(=[O:6])[NH2:5])[CH3:2].Cl[C:9]1[C:14]([O:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[O:22][CH3:23])=[C:13]([Cl:24])[N:12]=[C:11]([C:25]2[CH:30]=[CH:29][N:28]=[CH:27][CH:26]=2)[N:10]=1>>[Cl:24][C:13]1[N:12]=[C:11]([C:25]2[CH:30]=[CH:29][N:28]=[CH:27][CH:26]=2)[N:10]=[C:9]([NH:5][S:4](=[O:7])(=[O:6])[NH:3][C:1]2[CH:2]=[CH:13][CH:14]=[CH:9][N:10]=2)[C:14]=1[O:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[O:22][CH3:23]
Reactant: COc1ccccc1Oc1c(Cl)nc(-c2ccncc2)nc1Cl
Reactant: CCNS(N)(=O)=O
Product: COc1ccccc1Oc1c(Cl)nc(-c2ccncc2)nc1NS(=O)(=O)Nc1ccccn1
Yield: 100.5 %

Procedure:
According to the procedure described in referential Example 1e), ethyl-sulfamic acid amide (40 mg, Referential Example 22) was reacted with 4,6-dichloro-5-(o-methoxyphenoxy)-2-(4-pyridyl)-pyrimidine (100 mg, Referential Example 1d)) to give pyridine-2-sulfamic acid-[6-chloro-5-(o-methoxyphenoxy)-2-(4-pyridyl)-4-pyrimidinyl]-amide (70 mg). tR=4.40 min (LC); [M−H]+=434.28 (ES−);
Reaction SMILES: [ClH:1].C(OCC)(=O)C.C(OC([N:15]1[CH2:20][CH2:19][CH:18]([CH2:21][N:22]2[CH2:27][CH2:26][N:25]([CH2:28][CH:29]3[CH2:34][CH2:33][N:32](C(OC(C)(C)C)=O)[CH2:31][CH2:30]3)[CH2:24][CH2:23]2)[CH2:17][CH2:16]1)=O)(C)(C)C>C(Cl)Cl>[ClH:1].[ClH:1].[ClH:1].[ClH:1].[NH:32]1[CH2:33][CH2:34][CH:29]([CH2:28][N:25]2[CH2:24][CH2:23][N:22]([CH2:21][CH:18]3[CH2:17][CH2:16][NH:15][CH2:20][CH2:19]3)[CH2:27][CH2:26]2)[CH2:30][CH2:31]1
Reactant: CC(C)(C)OC(=O)N1CCC(CN2CCN(CC3CCN(C(=O)OC(C)(C)C)CC3)CC2)CC1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: C1CC(CN2CCN(CC3CCNCC3)CC2)CCN1
Reaction time: 0.5 h
Yield: 84 %

Procedure:
A 4N hydrogen chloride in ethyl acetate (4 ml; 16 mmol) was added to a solution in methylene chloride (2 ml) of 1,4-bis[(1-tert-butoxycarbonyl-4-piperidinyl)methyl]piperazine (195 mg; 0.40 mmol) synthesized by the above process under ice cooling, and the mixture was stirred for 30 minutes. The ice bath was removed, and the mixture was stirred at room temperature for 12 hours. The reaction mixture was concentrated under reduced pressure, and the resultant crude crystals were recrystallized from methylene chloride-methanol-diethyl ether, thereby obtaining 154 mg (yield: 84%) of the title compound as a colorless crystalline powder (melting point: 280° C. or higher).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:18]=[C:17]2[C:12]([C:13]([NH:22][CH2:23][CH:24]3[CH2:29][CH2:28][O:27][CH2:26][CH2:25]3)=[C:14]([N+:19]([O-])=O)[CH:15]=[N:16]2)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H][H]>[Pt].C(#N)C>[CH2:1]([O:8][C:9]1[CH:18]=[C:17]2[C:12]([C:13]([NH:22][CH2:23][CH:24]3[CH2:29][CH2:28][O:27][CH2:26][CH2:25]3)=[C:14]([NH2:19])[CH:15]=[N:16]2)=[CH:11][CH:10]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: [H][H]
Reactant: O=[N+]([O-])c1cnc2cc(OCc3ccccc3)ccc2c1NCC1CCOCC1
Agent: [Pt]
Solvent: CC#N
Product: Nc1cnc2cc(OCc3ccccc3)ccc2c1NCC1CCOCC1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A 2 L glass parr vessel was charged with of 7-(benzyloxy)-3-nitro-N-(tetrahydro-2H-pyran-4-ylmethyl)quinolin-4-amine (59.34 g, 0.151 mol), platinum on carbon (5%, 6.6 g) and acetonitrile (600 mL) to provide a black mixture. The vessel was placed on a shaker and pressurized with hydrogen gas (−50 psi, 3.4×105 Pa). After shaking for 18 hours at ambient temperature, the mixture was filtered through CELITE filter agent, and the filter cake washed with acetonitrile. The filtrate was concentrated under reduced pressure to provide 7-(benzyloxy)-N4-(tetrahydro-2H-pyran-4-ylmethyl)quinoline-3,4-diamine
Reaction SMILES: [Br:1][C:2]1[C:14]([F:15])=[CH:13][C:12]([C:16](O)=[O:17])=[C:11]2[C:3]=1[C:4]1[CH2:5][CH2:6][CH:7]([C:19]([O:21][CH2:22][CH3:23])=[O:20])[CH2:8][C:9]=1[NH:10]2.C(Cl)CCl.C1C=CC2N(O)N=[N:34]C=2C=1.[OH-].[NH4+]>C1COCC1.C(Cl)Cl.CCOC(C)=O>[Br:1][C:2]1[C:14]([F:15])=[CH:13][C:12]([C:16](=[O:17])[NH2:34])=[C:11]2[C:3]=1[C:4]1[CH2:5][CH2:6][CH:7]([C:19]([O:21][CH2:22][CH3:23])=[O:20])[CH2:8][C:9]=1[NH:10]2
Reactant: CCOC(=O)C1CCc2c([nH]c3c(C(=O)O)cc(F)c(Br)c23)C1
Reactant: On1nnc2ccccc21
Agent: [NH4+]
Agent: [OH-]
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: ClCCCl
Product: CCOC(=O)C1CCc2c([nH]c3c(C(N)=O)cc(F)c(Br)c23)C1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 84.1 %

Procedure:
A mixture of 5-bromo-2-(ethoxycarbonyl)-6-fluoro-2,3,4,9-tetrahydro-1H-carbazole-8-carboxylic acid (0.513 g, 1.34 mmol), EDC (0.384 g, 2.00 mmol), and HOBT (0.307 g, 2.00 mmol) in THF (10 mL) and DCM (1.65 mL) was stirred at room temperature for 20 min. Ammonium hydroxide (0.078 mL, 2.00 mmol) was added, and the mixture was stirred at room temperature for 60 min. The mixture was diluted with EtOAc and washed twice with saturated aqueous of NaHCO3, then with brine. The aqueous layers were extracted with EtOAc, and the combined organic layers were dried and concentrated. The residue was triturated in MeOH with sonication to provide ethyl 5-bromo-8-carbamoyl-6-fluoro-2,3,4,9-tetrahydro-1H-carbazole-2-carboxylate as a yellow solid (0.432 g, 84% yield). Mass spectrum m/z 383, 385 (M+H)+.
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[C:7]([NH2:10])[CH:8]=[CH:9][C:4]=2[N:3]=[CH:2]1.[F:11][C:12]([F:19])([F:18])[CH:13]=[CH:14][C:15]([OH:17])=[O:16].C1(O)C=CC(O)=CC=1>C1(C)C=CC=CC=1>[S:1]1[C:5]2[CH:6]=[C:7]([NH:10][CH:13]([C:12]([F:19])([F:18])[F:11])[CH2:14][C:15]([OH:17])=[O:16])[CH:8]=[CH:9][C:4]=2[N:3]=[CH:2]1
Reactant: O=C(O)C=CC(F)(F)F
Reactant: Nc1ccc2ncsc2c1
Agent: Oc1ccc(O)cc1
Solvent: Cc1ccccc1
Product: O=C(O)CC(Nc1ccc2ncsc2c1)C(F)(F)F
Yield: 58.6 %

Procedure:
Benzothiazol-6-ylamine (1 g, 0.006 mol) was reacted with 4,4,4-trifluoro-but-2-enoic acid (1.39 g, 0.009 mol), benzene-1,4-diol (0.05 g, 0.00046 mol) and toluene (50 mL) to afford the crude product. Purification by column chromatography on silica gel (15% ethyl acetate in hexane) afforded 1.02 g of the product (53.68% yield).
Reaction SMILES: Br[CH2:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[N:9]([CH3:13])[C:8](=[O:14])[CH:7]=[CH:6]2.[CH2:15]([C:17]1([C:23]2[CH:28]=[CH:27][CH:26]=[C:25]([OH:29])[CH:24]=2)[CH2:22][CH2:21][O:20][CH2:19][CH2:18]1)[CH3:16]>>[CH2:15]([C:17]1([C:23]2[CH:28]=[CH:27][CH:26]=[C:25]([O:29][CH2:2][C:3]3[CH:4]=[C:5]4[C:10](=[CH:11][CH:12]=3)[N:9]([CH3:13])[C:8](=[O:14])[CH:7]=[CH:6]4)[CH:24]=2)[CH2:18][CH2:19][O:20][CH2:21][CH2:22]1)[CH3:16]
Reactant: Cn1c(=O)ccc2cc(CBr)ccc21
Reactant: CCC1(c2cccc(O)c2)CCOCC1
Product: CCC1(c2cccc(OCc3ccc4c(ccc(=O)n4C)c3)c2)CCOCC1
Yield: 63 %

Procedure:
Using a similar procedure to that described in Example 14, 6-bromomethyl-1-methyl-1,2-dihydroquinolin-2-one was reacted with 4-ethyl-4-(3-hydroxyphenyl)tetrahydropyran to give 4-ethyl-4-[3-(1-methyl-2-oxo-1,2-dihydroquinolin-6-ylmethoxy)phenyl]tetrahydropyran in 63% yield, m.p. 139° C.