Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[CH2:11][CH2:10][CH:4]([C:5]([O:7][CH2:8][CH3:9])=[O:6])[CH2:3][CH2:2]1.C(N(CC)CC)C.[C:19]1([C:25](Cl)([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>C(Cl)(Cl)Cl>[NH:1]1[CH2:2][CH2:3][CH:4]([C:5]([O:7][CH:8]([C:25]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)([C:32]2[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=2)[C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=2)[CH3:9])=[O:6])[CH2:10][CH2:11]1
Reactant: CCOC(=O)C1CCNCC1
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: CC(OC(=O)C1CCNCC1)C(c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a stirred, ice-cooled, solution of ethyl isonipecotate (78.5 g, 0.50 mole) and triethylamine (200 ml, 1.4 mole) in CHCl3 (1000 ml), triphenylmethyl chloride (15.33 g, 0.55 mole) was added. After stirring overnight at room temperature, the reaction mixture was washed with H2O, dried (Na2SO4) and the solvent evaporated. The oily residue was crystallized from MeOH-CHCl3, yielding 108.19 (96 percent) of 4-piperidine carboxylic acid, 1-(triphenylmethyl)ethyl ester as a white solid; mp 154°-155° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([OH:8])[CH:5]=[CH:6][CH:7]=1.F[C:10]1[CH:17]=[CH:16][C:13]([CH:14]=[O:15])=[CH:12][CH:11]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.C(OCC)(=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([CH:5]=[CH:6][CH:7]=1)[O:8][C:10]1[CH:17]=[CH:16][C:13]([CH:14]=[O:15])=[CH:12][CH:11]=1
Reactant: O=Cc1ccc(F)cc1
Reactant: Oc1cccc(Cl)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: O=Cc1ccc(Oc2cccc(Cl)c2)cc1
Yield: 95 %

Procedure:
3-Chlorophenol (0.52 g, 4 mmol), 4-fluorobenzaldehyde (0.50 g, 4 mmol), and potassium carbonate (0.56 g, 4 mmol) were stirred in DMF (5 mL) at 80° C. for 48 hours. The reaction mixture was diluted with ethyl acetate and washed with water and brine, dried over Na2SO4, filtered and evaporated to give the title compound in 95% yield. 1H NMR (CDCl3, 300 MHz) δ 6.95-7.40 (m, 9H), 7.85-8.31 (m, 4H), 9.94 (s, 1H). MS m/e 233 (M+H)+.
Reaction SMILES: [CH2:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][CH:2]1[C:11]([OH:13])=O.S(Cl)([Cl:16])=O>C1(C)C=CC=CC=1>[CH2:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][CH:2]1[C:11]([Cl:16])=[O:13]
Reactant: O=C(O)C1CCc2ccccc2C1
Reactant: O=S(Cl)Cl
Solvent: Cc1ccccc1
Product: O=C(Cl)C1CCc2ccccc2C1
Temperature: 60 °C

Procedure:
6.5 mmol (1.15 g) 1,2,3,4-Tetrahydro-naphthalene-2-carboxylic acid is dissolved in 20 mL toluene, 20 mL of thionylchloride are added, the mixture is heated to 60° C. in an oil bath for 2 hours. Then the mixture is concentrated in vacuum. Toluene is added to the residue and evaporated again. The crude product is obtained in almost quantitative yield.
Reaction SMILES: [NH2:1][CH:2]1[CH2:7][CH2:6][CH2:5][CH2:4][CH:3]1[N:8]1[CH:17]([C:18]2[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][C:19]=2[Cl:25])[CH:16]([C:26]([NH:28][O:29][CH2:30][C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)=[O:27])[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:9]1=[O:37].[N+]([NH:41][C:42](N)=[O:43])([O-])=O>C(O)C>[CH2:30]([O:29][NH:28][C:26]([CH:16]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:9](=[O:37])[N:8]([CH:3]2[CH2:4][CH2:5][CH2:6][CH2:7][CH:2]2[NH:1][C:42](=[O:43])[NH2:41])[CH:17]1[C:18]1[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][C:19]=1[Cl:25])=[O:27])[C:31]1[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=1
Reactant: NC(=O)N[N+](=O)[O-]
Reactant: NC1CCCCC1N1C(=O)c2ccccc2C(C(=O)NOCc2ccccc2)C1c1ccc(Cl)cc1Cl
Solvent: CCO
Product: NC(=O)NC1CCCCC1N1C(=O)c2ccccc2C(C(=O)NOCc2ccccc2)C1c1ccc(Cl)cc1Cl
Yield: 53.4 %

Procedure:
To a mixed liquid of 269 mg of (3RS,4RS)-2-[(1SR,2SR)-2-aminocyclohexyl]-N-(benzyloxy)-3-(2,4-dichlorophenyl)-1-oxo-1,2,3,4-tetrahydroisoquinoline-4-carboxamide and 20 ml of ethanol was added 53 mg of nitrourea, followed by heating under reflux for 1 hour. The reaction solution was cooled and then concentrated, and the residue was purified by silica gel column chromatography (eluent: chloroform-methanol), then crystallized with acetonitrile, and collected by filtration to obtain 155 mg of (3RS,4RS)—N-(benzyloxy)-2-[(1SR,2SR)-2-(carbamoylamino)cyclohexyl]-3-(2,4-dichlorophenyl)-1-oxo-1,2,3,4-tetrahydroisoquinoline-4-carboxamide as a white crystal.
Reaction SMILES: Cl.[CH2:2]([O:9][C@@H]1[C@H](OCC2C=CC=CC=2)CN(CC2CC2)[C@]1(C)OCC1C=CC=CC=1)[C:3]1C=CC=CC=1.[CH2:36]([O:43][C@H:44]1[C@H:48]([O:49][CH2:50][C:51]2[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=2)[CH2:47][NH:46][C@@H:45]1[CH2:57][O:58][CH2:59][C:60]1[CH:65]=[CH:64][CH:63]=[CH:62][CH:61]=1)[C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1.ClCCO>>[CH2:36]([O:43][C@H:44]1[C@H:48]([O:49][CH2:50][C:51]2[CH:52]=[CH:53][CH:54]=[CH:55][CH:56]=2)[CH2:47][N:46]([CH2:3][CH2:2][OH:9])[C@@H:45]1[CH2:57][O:58][CH2:59][C:60]1[CH:65]=[CH:64][CH:63]=[CH:62][CH:61]=1)[C:37]1[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=1
Reactant: C[C@@]1(OCc2ccccc2)[C@H](OCc2ccccc2)[C@H](OCc2ccccc2)CN1CC1CC1
Reactant: c1ccc(COC[C@H]2NC[C@@H](OCc3ccccc3)[C@@H]2OCc2ccccc2)cc1
Agent: Cl
Agent: OCCCl
Product: OCCN1C[C@@H](OCc2ccccc2)[C@H](OCc2ccccc2)[C@H]1COCc1ccccc1

Procedure:
The title compound was prepared as described for compound 8 using (2R,3R,4R)-3,4-dibenzyloxy-2-benzyloxymethylpyrrolidine (Compound 1) (0.51 g, 1.27 mmol) and 2-chloroethanol (0.1 ml, 1.49 mmol) as starting material. (2R,3R,4R)-3,4-Dibenzyloxy-2-benzyloxymethyl-1-(2-hydroxyethyl)pyrrolidine was obtained as a golden oil (0.48 g, yield: 85%).
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]([CH3:11])[C:5]([C:6]([OH:8])=O)=[CH:4][N:3]=1.Cl.[CH:13]1([C:16]2[C:17]([N:23]3[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]3)=[N:18][CH:19]=[C:20]([CH3:22])[CH:21]=2)[CH2:15][CH2:14]1>>[CH:13]1([C:16]2[C:17]([N:23]3[CH2:28][CH2:27][N:26]([C:6]([C:5]4[CH:4]=[N:3][C:2]([F:1])=[CH:10][C:9]=4[CH3:11])=[O:8])[CH2:25][CH2:24]3)=[N:18][CH:19]=[C:20]([CH3:22])[CH:21]=2)[CH2:14][CH2:15]1
Reactant: Cc1cc(F)ncc1C(=O)O
Reactant: Cc1cnc(N2CCNCC2)c(C2CC2)c1
Agent: Cl
Product: Cc1cnc(N2CCN(C(=O)c3cnc(F)cc3C)CC2)c(C2CC2)c1
Yield: 61.4 %

Procedure:
Using 6-fluoro-4-methylnicotinic acid (139 mg) and a free form (210 mg) of 1-(3-cyclopropyl-5-methylpyridin-2-yl)piperazine hydrochloride described in Preparation Example 85 with a base and by the reaction and treatment in the same manner as in Preparation Example 119, the title compound (180 mg) was obtained.
Reaction SMILES: Cl[C:2]1[N:3]([CH2:25][CH:26]2[CH2:30][CH2:29][O:28][CH2:27]2)[C:4]2[C:9]([N:10]=1)=[C:8]([N:11]1[CH2:16][CH2:15][O:14][CH2:13][CH2:12]1)[N:7]=[C:6]([C:17]1[CH:18]=[N:19][C:20]([NH:23][CH3:24])=[N:21][CH:22]=1)[N:5]=2.[CH3:31][S:32]([N:35]1[CH2:40][CH2:39][NH:38][CH2:37][CH2:36]1)(=[O:34])=[O:33]>CS(C)=O>[CH3:24][NH:23][C:20]1[N:19]=[CH:18][C:17]([C:6]2[N:5]=[C:4]3[C:9]([N:10]=[C:2]([N:38]4[CH2:39][CH2:40][N:35]([S:32]([CH3:31])(=[O:34])=[O:33])[CH2:36][CH2:37]4)[N:3]3[CH2:25][CH:26]3[CH2:30][CH2:29][O:28][CH2:27]3)=[C:8]([N:11]3[CH2:16][CH2:15][O:14][CH2:13][CH2:12]3)[N:7]=2)=[CH:22][N:21]=1
Reactant: CNc1ncc(-c2nc(N3CCOCC3)c3nc(Cl)n(CC4CCOC4)c3n2)cn1
Reactant: CS(=O)(=O)N1CCNCC1
Solvent: CS(C)=O
Product: CNc1ncc(-c2nc(N3CCOCC3)c3nc(N4CCN(S(C)(=O)=O)CC4)n(CC4CCOC4)c3n2)cn1
Temperature: 150 °C
Reaction time: 4 h
Yield: 24.9 %

Procedure:
A mixture of 5-[8-chloro-6-morpholin-4-yl-9-(tetrahydrofuran-3-ylmethyl)-9H-purin-2-yl]-N-methylpyrimidin-2-amine (100 mg, 0.23 mmol), N-methanesulfonylpiperazine (114 mg, 0.70 mmol), and dimethyl sulfoxide (1 ml) was stirred at 150° C. for 4 hours. The mixture was purified by preparative HPLC (column, NOMURA Develosil Combi-RP-5; mobile phase, acetonitrile/water/formic acid) to give the title compound (32 mg, 25%) as a light brown solid.
Reaction SMILES: [C:1](=[O:18])([O:12][CH:13]1[CH2:17][CH2:16][O:15][CH2:14]1)OC1C=CC([N+]([O-])=O)=CC=1.Cl.[CH3:20][N:21]1[CH2:26][CH2:25][N:24]([C:27]2[CH:32]=[C:31]([C:33]3[CH:42]=[C:41]4[C:36]([CH2:37][CH2:38][NH:39][CH2:40]4)=[CH:35][CH:34]=3)[N:30]=[C:29]([NH2:43])[N:28]=2)[CH2:23][CH2:22]1>>[NH2:43][C:29]1[N:30]=[C:31]([C:33]2[CH:42]=[C:41]3[C:36]([CH2:37][CH2:38][N:39]([C:1]([O:12][CH:13]4[CH2:17][CH2:16][O:15][CH2:14]4)=[O:18])[CH2:40]3)=[CH:35][CH:34]=2)[CH:32]=[C:27]([N:24]2[CH2:23][CH2:22][N:21]([CH3:20])[CH2:26][CH2:25]2)[N:28]=1
Reactant: CN1CCN(c2cc(-c3ccc4c(c3)CNCC4)nc(N)n2)CC1
Reactant: O=C(Oc1ccc([N+](=O)[O-])cc1)OC1CCOC1
Agent: Cl
Product: CN1CCN(c2cc(-c3ccc4c(c3)CN(C(=O)OC3CCOC3)CC4)nc(N)n2)CC1

Procedure:
This compound was prepared by using procedures analogous to those described for the synthesis of Example 67, Step 2 starting from 4-nitrophenyl tetrahydrofuran-3-yl carbonate and 4-(4-methylpiperazin-1-yl)-6-(1,2,3,4-tetrahydroisoquinolin-7-yl)pyrimidin-2-amine HCl salt. Analytic LCMS (M+H)+: m/z=439.4.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][CH:3]=1.CN(C=O)C.[Br:17][CH2:18][C:19](Br)=[O:20]>O1CCOCC1>[Br:17][CH2:18][C:19]([NH:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:10][CH:11]=1)=[O:20]
Reactant: O=C(Br)CBr
Reactant: COC(=O)c1ccc(N)cc1
Solvent: C1COCCO1
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(NC(=O)CBr)cc1
Temperature: 0 °C
Reaction time: 8 h
Yield: 76.1 %

Procedure:
A solution of methyl 4-aminobenzoate (5.0 g, 33 mmol) in a mixture of anhydrous DMF (30 mL) and anhydrous dioxane (30 mL) in a 250 mL 3-necked round-bottomed flask equipped with a constant addition funnel (60 mL) was cooled to 0° C. using an ice-bath. Bromoacetyl bromide (6.66 g, 2.9 mL, 33 mmol) was added dropwise, keeping the internal temperature between 0° to 5° C. over a 1/2 h period. After the addition the bromoacetyl bromide was completed, the solution was warmed to rt, stirred overnight, and then the solution was slowly poured into 500 mL of ice-water, causing a solid to precipitate. The precipitate was filtered, washed with water, and then dried in a vacuum dessicator overnight to afford 6.83 g (76%) of the title compound as a pale brown solid; mp 153°-155° C.: 1H NMR (DMSO-d6) δ10.72 (s, 1H), 7.93 (d, J=8.8, 3H), 7.72 (d, J=8.8, 2H), 4.07 (s, 2H), 3.82 (s, 3H) 13C NMR (DMSO-d6) δ165.69, 165.36, 124.91, 130.26, 124.49, 118.64, 51.92, 30.25; MS (EI, m/z) 271 (M+ ).
Reaction SMILES: [I:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]([CH3:13])=[C:11]([C:14]([OH:16])=O)[CH:10]=[N:9]2)=[CH:4][CH:3]=1.[NH2:17][C:18]1[CH:19]=[CH:20][C:21]([N:26]2[CH2:31][CH2:30][CH:29]([N:32]3[CH2:37][CH2:36][O:35][CH2:34][CH2:33]3)[CH2:28][CH2:27]2)=[C:22]([CH:25]=1)[C:23]#[N:24]>>[C:23]([C:22]1[CH:25]=[C:18]([NH:17][C:14]([C:11]2[CH:10]=[N:9][N:8]([C:5]3[CH:4]=[CH:3][C:2]([I:1])=[CH:7][CH:6]=3)[C:12]=2[CH3:13])=[O:16])[CH:19]=[CH:20][C:21]=1[N:26]1[CH2:31][CH2:30][CH:29]([N:32]2[CH2:33][CH2:34][O:35][CH2:36][CH2:37]2)[CH2:28][CH2:27]1)#[N:24]
Reactant: N#Cc1cc(N)ccc1N1CCC(N2CCOCC2)CC1
Reactant: Cc1c(C(=O)O)cnn1-c1ccc(I)cc1
Product: Cc1c(C(=O)Nc2ccc(N3CCC(N4CCOCC4)CC3)c(C#N)c2)cnn1-c1ccc(I)cc1
Yield: 48 %

Procedure:
By the reaction and treatment in the same manner as in Example 64 using 1-(4-iodophenyl)-5-methylpyrazole-4-carboxylic acid (1.2 g) and 5-amino-2-(4-morpholinopiperidin-1-yl)benzonitrile (1 g), the title compound (1.0 g) was obtained, melting point: 280° C.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]#[N:9])=[CH:6][N:5]=[C:4]2[CH:10]=[CH:11][S:12][C:3]=12.[Cl:13][C:14]1[CH:19]=[C:18]([Cl:20])[CH:17]=[CH:16][C:15]=1[SH:21]>CN(C)C=O>[Cl:13][C:14]1[CH:19]=[C:18]([Cl:20])[CH:17]=[CH:16][C:15]=1[S:21][C:2]1[C:7]([C:8]#[N:9])=[CH:6][N:5]=[C:4]2[CH:10]=[CH:11][S:12][C:3]=12
Reactant: N#Cc1cnc2ccsc2c1Cl
Reactant: Sc1ccc(Cl)cc1Cl
Solvent: CN(C)C=O
Product: N#Cc1cnc2ccsc2c1Sc1ccc(Cl)cc1Cl
Temperature: 25 °C
Reaction time: 1 h
Yield: 71.7 %

Procedure:
A mixture of 7-chlorothieno[3,2-b]pyridine-6-carbonitrile (200 mg, 1.03 mmol) and 2,4-dichlorothiophenol (202.9 mg, 1.13 mmol) in 5 mL of N,N-dimethylformamide is stirred at room temperature for 1 hour, and then concentrated in vacuo. The resulting residue is treated with water and stirred for 1 hour. The precipitate is filtered, washed with water, air dried, and then purified by flash column chromatography eluting with a gradient of 5% ethyl acetate in hexane to 20% ethyl acetate in hexane to provide 249.0 mg of 7-[(2,4-dichlorophenyl)thio]thieno[3,2-b]pyridine-6-carbonitrile as a white solid, mp 126–128° C.; 1H NMR (DMSO-d6) δ 7.47 (dd, J=6,2 Hz, 1H), 7.54 (d, J=6 Hz, 1H), 7.73 (d, J=4 Hz, 1H), 7.88 (d, J=2 Hz, 1 H), 8.43 (d, J=4 Hz, 1H), 9.09 (s, 1H); MS 336.9, 339.0 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:12]=[CH:11][C:10]([N:13]2[C:18](=[O:19])[C:17]3[CH2:20][CH2:21][CH2:22][C:16]=3[N:15]([CH3:23])[C:14]2=[O:24])=[CH:9][C:3]=1[C:4]([O:6][CH2:7][CH3:8])=[O:5].[Na].Cl[C:27]1C=CC(N2C(=O)C3CCCCC=3N(C)C2=O)=CC=1C(O)=O.C(Br)(C)C>>[Cl:1][C:2]1[CH:12]=[CH:11][C:10]([N:13]2[C:18](=[O:19])[C:17]3[CH2:20][CH2:21][CH2:22][C:16]=3[N:15]([CH3:23])[C:14]2=[O:24])=[CH:9][C:3]=1[C:4]([O:6][CH:7]([CH3:27])[CH3:8])=[O:5]
Reactant: CCOC(=O)c1cc(-n2c(=O)c3c(n(C)c2=O)CCC3)ccc1Cl
Reactant: Cn1c2c(c(=O)n(-c3ccc(Cl)c(C(=O)O)c3)c1=O)CCCC2
Agent: [Na]
Solvent: CC(C)Br
Product: CC(C)OC(=O)c1cc(-n2c(=O)c3c(n(C)c2=O)CCC3)ccc1Cl

Procedure:
using ethyl 2-chloro-5-(1,2,4,5,6,7-hexahydro-1-methyl-2,4-dioxo-3H-cyclopenta[d]pyrimidin-3-yl)-benzoate via the sodium salt of the corresponding carboxylic acid and isopropyl bromide there is obtained isopropyl 2-chloro-5-(1,2,4,5,6,7-hexahydro-1-methyl-2,4-dioxo-3H-cyclopenta[d]pyrimidin-3-yl)-benzoate, m.p 148°-150° C.
Reaction SMILES: C(C1CCCCC1=O)=O.[C:10]1([C:16]2([CH2:25][CH2:26][C:27]#[N:28])[CH2:21][CH2:20][CH2:19][CH:18](C=O)[C:17]2=[O:24])[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.C1(C)C=CC(S([N:38]=[N+:39]=[N-])(=O)=O)=CC=1.CNC.C(NCC)C>C(OCC)C>[C:10]1([C:16]2([CH2:25][CH2:26][C:27]#[N:28])[CH2:21][CH2:20][CH2:19][C:18](=[N+:38]=[N-:39])[C:17]2=[O:24])[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: Cc1ccc(S(=O)(=O)N=[N+]=[N-])cc1
Reactant: N#CCCC1(c2ccccc2)CCCC(C=O)C1=O
Agent: CNC
Agent: O=CC1CCCCC1=O
Solvent: CCOCC
Solvent: CCNCC
Product: N#CCCC1(c2ccccc2)CCCC(=[N+]=[N-])C1=O

Procedure:
Reaction of a formyl cyclohexanone derivative with para-toluenesulfonylazide effects displacement of the formyl group by a diazo moiety to provide a diazocyclohexanone derivative. For example, a formyl cyclohexanone derivative such as 2-phenyl-2-(2-cyanoethyl)-6-formylcyclohexanone can be reacted with about an equimolar quantity of para-toluene-sulfonylazide in the presence of dimethylamine or diethylamine, in an organic solvent such as diethyl ether, to provide, for instance, 2-phenyl-2-(2-cyanoethyl)-6-diazocyclohexanone.
Reaction SMILES: C(OC(=O)[NH:7][CH:8]1[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][N:16]2[C:25]3[C:20](=[CH:21][CH:22]=[C:23]([F:26])[CH:24]=3)[C:19](=[O:27])[N:18]([CH3:28])[C:17]2=[O:29])[CH2:10][CH2:9]1)(C)(C)C.FC(F)(F)C(O)=O.NC1CCN(CCN2C3C=C(OC)C=CC=3COC2=O)CC1>>[NH2:7][CH:8]1[CH2:9][CH2:10][N:11]([CH2:14][CH2:15][N:16]2[C:25]3[C:20](=[CH:21][CH:22]=[C:23]([F:26])[CH:24]=3)[C:19](=[O:27])[N:18]([CH3:28])[C:17]2=[O:29])[CH2:12][CH2:13]1
Reactant: Cn1c(=O)c2ccc(F)cc2n(CCN2CCC(NC(=O)OC(C)(C)C)CC2)c1=O
Agent: COc1ccc2c(c1)N(CCN1CCC(N)CC1)C(=O)OC2
Solvent: O=C(O)C(F)(F)F
Product: Cn1c(=O)c2ccc(F)cc2n(CCN2CCC(N)CC2)c1=O

Procedure:
tert-Butyl{1-[2-(7-fluoro-3-methyl-2,4-dioxo-3,4-dihydroquinazolin-1(2H)-yl)ethyl]piperidin-4-yl}carbamate (Intermediate 135) (200 mg, 0.476 mmol) was reacted as described for Intermediate 106. The crude trifluoro acetate of the title compound was used without further purification for the next step (quantitative).
Reaction SMILES: [CH2:1]([C:3]([C:12]1[CH:25]=[CH:24][C:15]([O:16][CH2:17][CH:18]([OH:23])[C:19]([CH3:22])([CH3:21])[CH3:20])=[C:14]([CH3:26])[CH:13]=1)([C:6]1[S:7][CH:8]=[C:9]([CH3:11])[CH:10]=1)[CH2:4][CH3:5])[CH3:2].CC1C=CC=C(C)N=1.FC(F)(F)S(O[Si:41]([C:44]([CH3:47])([CH3:46])[CH3:45])([CH3:43])[CH3:42])(=O)=O>ClCCl>[CH2:1]([C:3]([C:12]1[CH:25]=[CH:24][C:15]([O:16][CH2:17][CH:18]([O:23][Si:41]([C:44]([CH3:47])([CH3:46])[CH3:45])([CH3:43])[CH3:42])[C:19]([CH3:21])([CH3:20])[CH3:22])=[C:14]([CH3:26])[CH:13]=1)([C:6]1[S:7][CH:8]=[C:9]([CH3:11])[CH:10]=1)[CH2:4][CH3:5])[CH3:2]
Reactant: CC(C)(C)[Si](C)(C)OS(=O)(=O)C(F)(F)F
Reactant: CCC(CC)(c1ccc(OCC(O)C(C)(C)C)c(C)c1)c1cc(C)cs1
Solvent: Cc1cccc(C)n1
Solvent: ClCCl
Product: CCC(CC)(c1ccc(OCC(O[Si](C)(C)C(C)(C)C)C(C)(C)C)c(C)c1)c1cc(C)cs1
Temperature: 25 °C
Reaction time: 2 h
Yield: 97.2 %

Procedure:
To a solution of 1-{4-[1-ethyl-1-(4-methyl-thiophen-2-yl)-propyl]-2-methyl-phenoxy}-3,3-dimethyl-butan-2-ol (7.5 g, 20 mmol) in dichloromethane (100 ml) at −78° C. is added 2,6-dimethylpyridine (5.8 ml, 50 mmol) followed by tert-butyldimethylsilyl trifluoromethanesulfonate (6.0 ml, 26 mmol). After stirring at RT for 2 h, the reaction diluted with dichoromethane and washed successively with 1N HCl followed by satd NaHCO3. The organic layer is dried over MgSO4 and concentrated to give the title product (9.5 g, 97%).
Reaction SMILES: Br[CH2:2][C:3]1[CH:4]=[C:5]([B:9]([OH:11])[OH:10])[CH:6]=[CH:7][CH:8]=1.[CH3:12][NH:13][S:14]([CH3:17])(=[O:16])=[O:15].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O.ClCCl>[CH3:12][N:13]([CH2:2][C:3]1[CH:4]=[C:5]([B:9]([OH:11])[OH:10])[CH:6]=[CH:7][CH:8]=1)[S:14]([CH3:17])(=[O:16])=[O:15]
Reactant: OB(O)c1cccc(CBr)c1
Reactant: CNS(C)(=O)=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: CC(C)=O
Product: CN(Cc1cccc(B(O)O)c1)S(C)(=O)=O
Temperature: 25 °C
Reaction time: 6 h

Procedure:
175 a) A suspension of [3-(bromomethyl)phenyl]boronic acid (1.0 g, 4.6 mmol), N-methyl-methanesulfonamide (0.56 g, 5.1 mmol) and potassium carbonate (1.9 g, 14 mmol) in acetone (10 mL) was stirred for 6 hours at room temperature. The mixture was diluted with dichloromethane (50 mL), filtered through a plug of diatomaceous earth and evaporated under reduced pressure. Crude (3-{[methyl(methylsulfonyl)amino]methyl}phenyl)boronic acid was isolated as a yellow viscous oil (1.08 g, 88%). MS=266 (M+Na)+. 175 b) N-[3-(2-Chloro-[1,2,4]triazolo[1,5-a]pyridin-8-yl)-benzyl]-N-methyl-methanesulfonamide was prepared from 8-bromo-2-chloro-[1,2,4]triazolo[1,5-a]pyridine (500.0 mg, 2.151 mmol) and (3-{[methyl(methylsulfonyl)amino]methyl}phenyl)boronic acid (650.0 mg, 2.674 mmol) in a manner analogous to Example 2c. Product isolated as a pale yellow foam (0.331 g, 44%). 1H NMR (400 MHz, CDCl3, δ, ppm): 8.51 (d, J=6.8 Hz, 1H), 7.99-7.95 (m, 2H), 7.74 (d, J=7.4 Hz, 1H), 7.54 (t, J=7.6 Hz, 1H), 7.45 (d, J=7.6 Hz, 1H), 7.18 (t, J=7.1 Hz, 1H), 4.42 (s, 2H), 2.92 (s, 3H), 2.84 (s, 3H). MS=351 (MH)+. 175 c) N-Methyl-N-(3-{2-[4-(4-methyl-piperazin-1-yl)-phenylamino]-[1,2,4]triazolo[1,5-a]pyridin-8-yl}-benzyl)-methanesulfonamide was prepared from N-[3-(2-chloro-[1,2,4]triazolo[1,5-a]pyridin-8-yl)-benzyl]-N-methyl-methanesulfonamide (75.0 mg, 0.214 mmol) and 4-(4-methyl-piperazin-1-yl)-phenylamine (45.0 mg, 0.235 mmol) with 2,2′-bis-dicyclohexylphosphanyl-biphenyl (24.0 mg, 0.0439 mmol) as the ligand in a manner analogous to Example 2d. Product isolated as a yellow foam (0.007 g, 6%). 1H NMR (400 MHz, CDCl3, δ, ppm): 8.41 (d, J=6.7 Hz, 1H), 7.99 (d, J=7.7 Hz, 1H), 7.95 (s, 1H), 7.57 (d, J=7.4 Hz, 1H), 7.55-7.46 (m, 3H), 7.42 (d, J=7.4 Hz, 1H), 7.00-6.91 (m, 3H), 6.65 (s, 3H), 4.42 (s, 2H), 3.19-3.14 (m, 4H), 2.87 (s, 3H), 2.83 (s, 3H), 2.63-2.57 (m, 4H), 2.37 (s, 3H). MS=506 (MH)+.
Reaction SMILES: Cl([O-])=O.[Na+].[F:5][CH:6]([F:18])[O:7][C:8]1[CH:15]=[CH:14][C:11]([CH:12]=[O:13])=[CH:10][C:9]=1[O:16][CH3:17].S(=O)(=O)([OH:21])N.C(O)(=O)C>O>[F:5][CH:6]([F:18])[O:7][C:8]1[CH:15]=[CH:14][C:11]([C:12]([OH:21])=[O:13])=[CH:10][C:9]=1[O:16][CH3:17]
Reactant: COc1cc(C=O)ccc1OC(F)F
Reactant: NS(=O)(=O)O
Agent: [Na+]
Agent: [O-][Cl+][O-]
Solvent: CC(=O)O
Solvent: O
Product: COc1cc(C(=O)O)ccc1OC(F)F
Temperature: 0 °C
Reaction time: 1 h

Procedure:
A solution of 7.3 g of 80% strength sodium chlorite in 15 ml of water is added dropwise with continuous stirring to a mixture of 10.0 g of 4-difluoromethoxy-3-methoxybenzaldehyde, 6.5 g of sulphamic acid and 50 ml of glacial acetic acid. The internal temperature is kept between 30° and 35° C. by cooling with ice water. After dropwise addition is complete, the mixture is stirred for a further 1 h and then diluted with water. The precipitated 4-difluoromethoxy-3-methoxybenzoic acid is filtered off with suction, washed with water, dried in vacuo and crystallized from acetonitrile/petroleum ether (b.p. 40°) 2/8. Yield 7.1 g; m.p. 170° C.
Reaction SMILES: [OH:1][C:2]1[NH:3][C:4]2[C:9]([C:10]=1[C:11]1[C:20]3[C:15](=[CH:16][C:17]([O:21][CH2:22][CH2:23][O:24][CH3:25])=[CH:18][CH:19]=3)[N:14]=[CH:13][N:12]=1)=[CH:8][C:7]([C:26]([O:28]C)=[O:27])=[CH:6][CH:5]=2.CO.[OH-].[Na+]>O>[OH:1][C:2]1[NH:3][C:4]2[C:9]([C:10]=1[C:11]1[C:20]3[C:15](=[CH:16][C:17]([O:21][CH2:22][CH2:23][O:24][CH3:25])=[CH:18][CH:19]=3)[N:14]=[CH:13][N:12]=1)=[CH:8][C:7]([C:26]([OH:28])=[O:27])=[CH:6][CH:5]=2
Reactant: COCCOc1ccc2c(-c3c(O)[nH]c4ccc(C(=O)OC)cc34)ncnc2c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: COCCOc1ccc2c(-c3c(O)[nH]c4ccc(C(=O)O)cc34)ncnc2c1
Temperature: 40 °C
Yield: 85.1 %

Procedure:
To a mixture of methyl 2-hydroxy-3-[7-(2-methoxyethoxy)quinazolin-4-yl]-1H-indole-5-carboxylate (5.15 g, 13.1 mmol), methanol (100 mL) and water (50 mL) was added aqueous sodium hydroxide (92 mL, 1 M) and the reaction mixture was stirred at 40° C. over night. Methanol was removed in vacuo and the basic aqueous layer was acidified with 1 M hydrochloric acid and stirred for 30 min. The precipitate formed was filtered off, washed with hydrochloric acid (50 mL, 1 M) and water (2×50 mL) and dried in vacuo at 50° C. over night. The crude product was stirred in methanol at room temperature over night. The solid was filtered off to give 4.23 g (85% yield) of the title compound as an orange solid: MS (AP+) m/z 380.3 (M++1).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:7][N:8]1[C:16]2[C:11](=[CH:12][C:13]([OH:17])=[CH:14][CH:15]=2)[C:10]([CH3:19])([CH3:18])[CH2:9]1.[CH:20]1([N:26]=[C:27]=[O:28])[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1>>[CH:20]1([NH:26][C:27](=[O:28])[O:17][C:13]2[CH:12]=[C:11]3[C:16](=[CH:15][CH:14]=2)[N:8]([CH2:7][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=2)[CH2:9][C:10]3([CH3:19])[CH3:18])[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1
Reactant: CC1(C)CN(Cc2ccccn2)c2ccc(O)cc21
Reactant: O=C=NC1CCCCC1
Product: CC1(C)CN(Cc2ccccn2)c2ccc(OC(=O)NC3CCCCC3)cc21

Procedure:
The title compound was synthesized from 1-(2-pyridylmethyl)-3,3-dimethylindolin-5-ol (20.0 mg, 0.09 mmol) using the same procedure employed for Example 2 (2), but with cyclohexylisocyanate instead of 4-isopropylphenylisocyanate. The product was obtained as a white solid (15.4 mg, 52%) having the following characteristics.
Reaction SMILES: [C:1]([O:11][C:12]([C:15]([CH2:18][CH2:19]I)([F:17])[F:16])([F:14])[F:13])([C:4]([C:7]([F:10])([F:9])[F:8])([F:6])[F:5])([F:3])[F:2].CNC=[O:24].O>CCOCC>[C:1]([O:11][C:12]([C:15]([CH2:18][CH2:19][OH:24])([F:17])[F:16])([F:14])[F:13])([C:4]([C:7]([F:10])([F:9])[F:8])([F:6])[F:5])([F:3])[F:2]
Reactant: CNC=O
Reactant: FC(F)(F)C(F)(F)C(F)(F)OC(F)(F)C(F)(F)CCI
Solvent: O
Solvent: CCOCC
Product: OCCC(F)(F)C(F)(F)OC(F)(F)C(F)(F)C(F)(F)F
Temperature: 150 °C
Reaction time: 0.25 h
Yield: 85 %

Procedure:
A mixture of C3F7OCF2CF2CH2CH2I (300 g, 0.68 mol) and N-methyl-formamide (300 mL), was heated to 150° C. for 26 hours. Then the reaction was cooled to 100° C., followed by the addition of water to separate the crude ester. Ethyl alcohol (77 mL) and p-toluene sulfonic acid (2.59 g) were added to the crude ester, and the reaction was stirred at 70° C. for 15 minutes. Then ethyl formate and ethyl alcohol were distilled out to give a crude product. The crude product was dissolved in ether, washed with aqueous sodium sulfite, water, and brine in turn, then dried over magnesium sulfate. The product was then distilled to give 199 g of C3F7OCF2CF2CH2CH2OH in 85% yield. The boiling point is 71˜73° C. at 40 mmHg (5320 Pa).