Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].[F:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[C:10]1[NH:11][C:12](=[O:23])[N:13]([CH3:22])[C:14]=1[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[F:21].[CH3:24][O:25][C:26](=[O:35])[CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33]Br>CN(C=O)C>[CH3:24][O:25][C:26](=[O:35])[CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][N:11]1[C:10]([C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[F:3])=[C:14]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[F:21])[N:13]([CH3:22])[C:12]1=[O:23]
Reactant: COC(=O)CCCCCCCBr
Reactant: Cn1c(-c2ccccc2F)c(-c2ccccc2F)[nH]c1=O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)CCCCCCCn1c(-c2ccccc2F)c(-c2ccccc2F)n(C)c1=O

Procedure:
The product is produced as described in example 1 from 0.63 of NaH (80% suspension in mineral oil), 5.9 g of 4.5-bis-(2-fluorophenyl)-1-methyl-4-imidazolin-2-one, 40 cc. of DMF, 5.0 g of 8-bromo caprylic methyl ester and 0.63 g of NaJ.
Reaction SMILES: [SH:1][CH2:2][CH2:3][CH2:4][C:5]([OH:7])=[O:6].[H-].[Na+].Br[CH2:11][CH2:12][Cl:13].S(Cl)(Cl)=O.[CH:18](O)(C)C>>[Cl:13][CH2:12][CH2:11][S:1][CH2:2][CH2:3][CH2:4][C:5]([O:7][CH3:18])=[O:6]
Reactant: ClCCBr
Reactant: O=C(O)CCCS
Reactant: CC(C)O
Agent: [H-]
Agent: [Na+]
Solvent: O=S(Cl)Cl
Product: COC(=O)CCCSCCCl
Temperature: 25 °C
Reaction time: 48 h

Procedure:
A 0° C. isopropanol (70 mL) solution of 4-mercaptobutyric acid (3.85 g, 20 mmol) was treated with sodium hydride in four portions (95%, 1.56 g total, 65 mmol) over 20 minutes and allowed to warm to room temperature. 1-Bromo-2-chloroethane (11 mL, 128 mmol) was added rapidly with the resulting suspension stirred vigorously for 2 days, then the volatiles were removed, and the residue was partitioned between 5% aqueous acetic acid and ethyl acetate. The combined organic extracts were washed with brine and stored over sodium sulfate. The extract was filtered and the volatiles were removed under vacuum. The residue was dissolved in methanol (60 mL) and cooled to 0° C. under argon atmosphere. Thionyl chloride (5 mL, 69 mmol) was added dropwise and the solution was stirred at room temperature. After 2-3 hours, the volatiles were removed, toluene was added, and the volatiles were removed again. Chromatography yielded (2.93 g, 14 mmol) of methyl 4-[(2-chloroethyl)thio]butanoate as a colorless oil: MS (NH3) m/z 199 (M+1+ with 37Cl), 197 (M+1+ with 35Cl).
Reaction SMILES: [Br:1][C:2]1[N:7]=[CH:6][C:5](I)=[CH:4][N:3]=1.[C:9]([Si:11]([CH3:14])([CH3:13])[CH3:12])#[CH:10].C(N(CC)CC)C>C1COCC1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.Cl[Pd]Cl.[Cu]I>[Br:1][C:2]1[N:7]=[CH:6][C:5]([C:10]#[C:9][Si:11]([CH3:14])([CH3:13])[CH3:12])=[CH:4][N:3]=1
Reactant: C#C[Si](C)(C)C
Reactant: Brc1ncc(I)cn1
Agent: Cl[Pd]Cl
Agent: [Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: C[Si](C)(C)C#Cc1cnc(Br)nc1
Temperature: 50 °C
Reaction time: 4 h
Yield: 70 %

Procedure:
2-Bromo-5-iodopyrimidine (1.2 g, 4.2 mmol) was dissolved under nitrogen in 25 ml THF. Bis-(triphenylphosphine)-palladium(II)dichloride (300 mg, 420 μmol, 0.1 equiv.), ethynyltrimethylsilane (540 mg, 0.77 ml, 5.48 mmol, 1.3 equiv.), triethylamine (0.85 g, 1.17 ml, 8.4 mmol, 2 equiv.) and copper(I)iodide (40 mg, 210 μmol, 0.05 equiv.) were added and the mixture was stirred for 4 hours at 50° C. The reaction mixture was cooled and evaporated to dryness. The crude product was purified by flash chromatography on silica gel, eluting with an ethyl acetate:heptane gradient 0:100 to 40:60. The desired 2-bromo-5-trimethylsilanylethynyl-pyrimidine (0.75 g, 70% yield) was obtained as a yellow solid, MS: m/e=255/257 (M+H+).
Reaction SMILES: [OH:1][CH2:2][C:3]([CH3:10])([CH3:9])[C:4]([O:6][CH2:7][CH3:8])=[O:5].C1CCN2C(=NCCC2)CC1.[C:22](=[S:24])=[S:23].[CH3:25]I>CN(C=O)C>[CH3:9][C:3]([CH3:10])([CH2:2][O:1][C:22]([S:24][CH3:25])=[S:23])[C:4]([O:6][CH2:7][CH3:8])=[O:5]
Reactant: CI
Reactant: S=C=S
Reactant: CCOC(=O)C(C)(C)CO
Solvent: CN(C)C=O
Solvent: C1CCC2=NCCCN2CC1
Product: CCOC(=O)C(C)(C)COC(=S)SC
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 61.9 %

Procedure:
To a stirred solution of ethyl 3-hydroxy-2,2-dimethylpropanoate (3.0 g, 20.52 mmol) in DMF (15 mL) was added DBU (3.10 g, 20.52 mmol) at RT followed by slow addition of CS2 (3.12 g, 41.0 mmol) over a period of 10 minutes. The reaction mixture was stirred at RT for 30 min, and then cooled to 10° C. prior to addition of MeI (6.58 mL, 103 mmol). The reaction mixture was stirred for 2 h at RT after which it was quenched with ice water and extracted with diethyl ether (2×25 mL). The combined organic layer was dried over Na2SO4, filtered and the filtrate evaporated to afford Intermediate 212A as a pale yellow liquid (3.0 g, 62%). 1H NMR (300 MHz, chloroform-d) δ ppm 4.59 (s, 2H), 4.19 (q, J=7.05 Hz, 2H), 2.55 (s, 3H), 1.23-1.29 (m, 9H).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([N:8]2[CH2:32][CH2:31][C:11]3([CH2:15][N:14]([C:16]([O:18][CH2:19][C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)=[O:17])[C@H:13]([C:26]([O:28][CH2:29][CH3:30])=[O:27])[CH2:12]3)[CH2:10][CH2:9]2)[CH:5]=[C:4](Cl)[N:3]=1.[N:34]1([C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][C:41]=2[CH2:46][NH2:47])[CH2:39][CH2:38][CH2:37][CH2:36][CH2:35]1.C(N(C(C)C)CC)(C)C>CC(O)C>[NH2:1][C:2]1[N:7]=[C:6]([N:8]2[CH2:32][CH2:31][C:11]3([CH2:15][N:14]([C:16]([O:18][CH2:19][C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)=[O:17])[C@H:13]([C:26]([O:28][CH2:29][CH3:30])=[O:27])[CH2:12]3)[CH2:10][CH2:9]2)[CH:5]=[C:4]([NH:47][CH2:46][C:41]2[CH:42]=[CH:43][CH:44]=[CH:45][C:40]=2[N:34]2[CH2:39][CH2:38][CH2:37][CH2:36][CH2:35]2)[N:3]=1
Reactant: NCc1ccccc1N1CCCCC1
Reactant: CCOC(=O)[C@@H]1CC2(CCN(c3cc(Cl)nc(N)n3)CC2)CN1C(=O)OCc1ccccc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(C)O
Product: CCOC(=O)[C@@H]1CC2(CCN(c3cc(NCc4ccccc4N4CCCCC4)nc(N)n3)CC2)CN1C(=O)OCc1ccccc1
Temperature: 120 °C

Procedure:
To a solution of (S)-2-benzyl 3-ethyl 8-(2-amino-6-chloropyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-2,3-dicarboxylate (200 mg, 0.6 mmol) and [2-(1-piperidinyl)phenyl]methanamine (CAS#: 72752-54-6) (105 mg, 0.8 mmol) in i-PrOH (2 mL) was added diisopropylethyl amine (0.5 mL). The reaction was heated to 120° C. for 2 h followed by heating to 140° C. for 1 h under microwave conditions, then cooled to RT and concentrated in vacuo. Purification by normal phase silica gel column (EtOAc/heptane) provided (S)-2-benzyl 3-ethyl 8-(2-amino-6-((2-(piperidin-1-yl)benzyl)amino)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-2,3-dicarboxylate as a white solid.
Reaction SMILES: [F:1][C:2]([F:6])([F:5])[CH2:3][OH:4].[H-].[Na+].Br[CH2:10][C:11]1[CH:18]=[C:17]([F:19])[CH:16]=[CH:15][C:12]=1[C:13]#[N:14].O>CN(C)C=O>[F:19][C:17]1[CH:16]=[CH:15][C:12]([C:13]#[N:14])=[C:11]([CH2:10][O:4][CH2:3][C:2]([F:6])([F:5])[F:1])[CH:18]=1
Reactant: OCC(F)(F)F
Reactant: N#Cc1ccc(F)cc1CBr
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: N#Cc1ccc(F)cc1COCC(F)(F)F
Temperature: 25 °C
Reaction time: 1 h

Procedure:
336 μl 2,2,2-Trifluoroethanol were dissolved in 10 ml dimethylformamide. 243 mg sodium hydride were added and the mixture stirred at room temperature for one hour. Then 1.0 g 2-Bromomethyl-4-fluoro-benzonitrile were added in one portion and the reaction mixture was stirred at room temperature for three hours. The reaction mixture was poured on 50 ml water and extracted five times with portion of 25 ml ethyl acetate. The combined organic layers were dried over MgSO4, the solvent removed in vacuo and the resulting residue purified on silica gel with the eluent heptane=>n-heptane:ethyl acetate=4:1 to obtain 750 mg 4-Fluoro-2-(2,2,2-trifluoro-ethoxymethyl)-benzonitrile.
Reaction SMILES: [CH3:1][Mg]Cl.[CH3:4][O:5][C:6](=[O:17])[C:7](=[C:12]([CH2:15][CH3:16])[CH2:13][CH3:14])[C:8]([O:10][CH3:11])=[O:9].[NH4+].[Cl-]>O1CCCC1.[Cu]I>[CH3:11][O:10][C:8](=[O:9])[CH:7]([C:12]([CH2:15][CH3:16])([CH3:1])[CH2:13][CH3:14])[C:6]([O:5][CH3:4])=[O:17]
Reactant: CCC(CC)=C(C(=O)OC)C(=O)OC
Reactant: C[Mg]Cl
Agent: [Cu]I
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CCC(C)(CC)C(C(=O)OC)C(=O)OC
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 92.5 %

Procedure:
Step A To a suspension of CuI (5.7 g, 30 mmol) in anhydrous tetrahydrofuran (100 mL) at −50° C. was added methylmagnesium chloride (3 M, 20 mL, 60 mmol) during a period of 15 min. After the addition was finished, the reaction mixture was gradually warmed room temperature and stirred for 20 min. Then the temperature of the mixture was lowered to −50° C., a tetrahydrofuran solution (20 mL) of 2-(1-ethyl-propylidene)-malonic acid dimethyl ester (3 g, 15 mmol) prepared in Example 106a Step A was added. The reaction mixture was allowed to slowly warmed to room temperature and stirred for 1 h. Aqueous saturated NH4Cl solution was added to quench the reaction. The mixture was filtered, and the filtrate was concentrated to remove most of tetrahydrofuran. The residue was extracted with ethyl acetate twice. The organic layers were combined, concentrated. The residue was purified by chromatography (EtOAc:hexanes=1:30) to give 2-(1-ethyl-1-methyl-propyl)-malonic acid dimethyl ester as a colorless oil (3 g, 93%).
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]([C:8]2[CH:9]=[CH:10][C:11]([O:14][CH2:15][CH2:16][CH2:17][O:18][C:19]3[CH:20]=[C:21]4[C:25](=[CH:26][CH:27]=3)[C@H:24]([CH2:28][C:29]([O:31]CC)=[O:30])[CH2:23][CH2:22]4)=[N:12][CH:13]=2)[S:5][C:6]=1[CH3:7].[Li+].[OH-]>C1COCC1.CO.O>[CH3:1][C:2]1[N:3]=[C:4]([C:8]2[CH:9]=[CH:10][C:11]([O:14][CH2:15][CH2:16][CH2:17][O:18][C:19]3[CH:20]=[C:21]4[C:25](=[CH:26][CH:27]=3)[C@H:24]([CH2:28][C:29]([OH:31])=[O:30])[CH2:23][CH2:22]4)=[N:12][CH:13]=2)[S:5][C:6]=1[CH3:7]
Reactant: CCOC(=O)C[C@@H]1CCc2cc(OCCCOc3ccc(-c4nc(C)c(C)s4)cn3)ccc21
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: Cc1nc(-c2ccc(OCCCOc3ccc4c(c3)CC[C@H]4CC(=O)O)nc2)sc1C
Temperature: 25 °C
Reaction time: 18 h
Yield: 89.9 %

Procedure:
To a solution of ethyl [(1S)-5-(3-{[5-(4,5-dimethyl-1,3-thiazol-2-yl)-2-pyridinyl]oxy}propoxy)-2,3-dihydro-1H-inden-1-yl]acetate (Example 260) (80 mg, 0.17 mmol) in THF (2 mL), methanol (2 mL) and water (1 mL) was added LiOH (40 mg, 1.74 mmol). The reaction mixture was stirred at rt for 18 h, and then concentrated under reduced pressure. The residue was taken up in water and acidified with a 5% aqueous solution of H3PO4, and extracted with EtOAc. The combined organic layers were dried (Na2SO4) and concentrated under reduced pressure to give the product (67 mg, 89%). 1H NMR (400 MHz, CD2Cl2) δ 8.57 (d, 1H), 8.06 (dd, 1H), 7.09 (d, 1H), 6.85 (d, 1H), 6.80 (d, 1H), 6.71 (dd, 1H), 4.53 (t, 2H), 4.15 (t, 2H), 3.49 (qt, 1H), 2.92-2.75 (m, 2H), 2.71 (dd, 1H), 2.45-2.28 (m, 8H), 2.32-2.22 (m, 2H), 1.82-1.70 (m, 1H); LC-MS: RT=3.41 min, (M+H)+ 439.0.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([N:8]2[CH2:13][CH2:12][N:11]([CH:14](O)[CH2:15][CH3:16])[CH2:10][CH2:9]2)[CH:5]=[N:4][CH:3]=1.[F:18][C:19]1[CH:24]=[CH:23][C:22]([CH:25](Br)[C:26]2[CH:31]=[CH:30][C:29]([F:32])=[CH:28][CH:27]=2)=[CH:21][CH:20]=1.C(=O)(O)[O-:35].[Na+]>CN(C)C=O>[F:18][C:19]1[CH:24]=[CH:23][C:22]([CH:25]([C:26]2[CH:31]=[CH:30][C:29]([F:32])=[CH:28][CH:27]=2)[O:35][CH2:16][CH2:15][CH2:14][N:11]2[CH2:12][CH2:13][N:8]([C:6]3[CH:5]=[N:4][CH:3]=[C:2]([Cl:1])[N:7]=3)[CH2:9][CH2:10]2)=[CH:21][CH:20]=1
Reactant: CCC(O)N1CCN(c2cncc(Cl)n2)CC1
Reactant: Fc1ccc(C(Br)c2ccc(F)cc2)cc1
Reactant: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Product: Fc1ccc(C(OCCCN2CCN(c3cncc(Cl)n3)CC2)c2ccc(F)cc2)cc1

Procedure:
To a stirred solution of 1-(6-chloro-2-pyrazinyl)-4-piperazinyl propanol 3 g. (0.013 mol) in 50 ml. of dimethylformamide was added 3.3 g. (0.017 mol) of bis(4-fluorophenyl)methylbromide and 2.6 g. (0.034 mol) of sodium bicarbonate. The reaction mixture was refluxed overnight, dimethylformamide was evaporated under vacuum and the residue was extracted with methylene chloride (3×400 ml.). The methylene chloride extracts were collected, washed with water and dried (anhydrous Na2SO4). Evaporation of the methylene chloride afforded the title compound as a brown oil. HPLC purification afforded 2 g. (37% yield) of the pure product. It was converted to the (1:1) fumarate salt and recovered as the hemihydrate; m.p. 165°-167° C.
Reaction SMILES: C[CH:2](C)/[CH:3]=[CH:4]/[C:5](O)=[O:6].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH3:33][C:34]1[CH:43]=[C:42]([NH:44][CH2:45][CH2:46][NH2:47])[C:41]2[C:36](=[CH:37][CH:38]=[CH:39][CH:40]=2)[N:35]=1.C(N(CC)CC)C>C(#N)C>[CH3:33][C:34]1[CH:43]=[C:42]([NH:44][CH2:45][CH2:46][NH:47][C:5](=[O:6])/[CH:4]=[CH:3]/[CH3:2])[C:41]2[C:36](=[CH:37][CH:38]=[CH:39][CH:40]=2)[N:35]=1
Reactant: CC(C)/C=C/C(=O)O
Reactant: Cc1cc(NCCN)c2ccccc2n1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: CC#N
Product: C/C=C/C(=O)NCCNc1cc(C)nc2ccccc12
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 68.3 %

Procedure:
(E)-4-Methylpent-2-enoic acid (190 mg, 1.3 mmol) was mixed together with HBTU (470 mg, 1.3 mmol) and N-(2-methyl-4-quinolyl)ethane-1,2-diamine (250 mg, 1.2 mmol) in acetonitrile (5 ml). Triethylamine (1 mll) was added with stirring at 0° C. over 15 minutes and the resulting mixture was stirred at room temperature overnight. The volatiles were removed under reduced pressure, the residue was dissolved in DCM and washed with a saturated solution of sodium bicarbonate. The combined aqueous solutions were extracted three times with DCM. The organic layers were combined, dried over sodium sulfate, the solvent was removed under reduced pressure to give 245 mg of a yellow solid (0.82 mmol, 66%). MS (APCI) m/z=298.2 [M+1]+.
Reaction SMILES: [NH2:1][C:2]([CH3:21])([CH3:20])[CH2:3][C:4]1[CH:19]=[CH:18][C:7]([O:8][C:9]2[CH:17]=[CH:16][C:12]([C:13]([NH2:15])=[O:14])=[CH:11][N:10]=2)=[CH:6][CH:5]=1.[CH2:22](Br)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>>[CH2:22]([NH:1][C:2]([CH3:21])([CH3:20])[CH2:3][C:4]1[CH:5]=[CH:6][C:7]([O:8][C:9]2[CH:17]=[CH:16][C:12]([C:13]([NH2:15])=[O:14])=[CH:11][N:10]=2)=[CH:18][CH:19]=1)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: BrCc1ccccc1
Reactant: CC(C)(N)Cc1ccc(Oc2ccc(C(N)=O)cn2)cc1
Product: CC(C)(Cc1ccc(Oc2ccc(C(N)=O)cn2)cc1)NCc1ccccc1

Procedure:
Using a method similar to example 2, using 6-[4-(2-amino-2-methyl-propyl)phenoxy]-nicotinamide and benzyl bromide gives the title product: HPLC (30/70 to 90/10 ACN/(0.1% TFA in water) Zorbax SB-Phenyl Column 4.6 mm×15 cm×5 micron: Retention time: 3.96 minutes, Purity: 100%; mass spectrum (ion spray): m/z=376.2 (M+1).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:17]2[CH:22]=[CH:21][C:20](Br)=[CH:19][CH:18]=2)([C:13]([F:16])([F:15])[F:14])[C:9]([F:12])([F:11])[F:10])=[CH:4][CH:3]=1.C([Li])CCC.C(=O)=O.CC(C)=O.Cl[Si:37]([CH3:40])([CH3:39])[CH3:38]>O1CCCC1.CCCCCC>[CH3:38][Si:37]([CH3:40])([CH3:39])[C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:17]2[CH:22]=[CH:21][C:20]([Si:37]([CH3:40])([CH3:39])[CH3:38])=[CH:19][CH:18]=2)([C:13]([F:16])([F:15])[F:14])[C:9]([F:12])([F:11])[F:10])=[CH:4][CH:3]=1
Reactant: C[Si](C)(C)Cl
Reactant: FC(F)(F)C(c1ccc(Br)cc1)(c1ccc(Br)cc1)C(F)(F)F
Agent: O=C=O
Agent: [Li]CCCC
Solvent: CC(C)=O
Solvent: CCCCCC
Solvent: C1CCOC1
Product: C[Si](C)(C)c1ccc(C(c2ccc([Si](C)(C)C)cc2)(C(F)(F)F)C(F)(F)F)cc1
Temperature: -78 °C
Reaction time: 16 h

Procedure:
To a solution of 4.62 g (0.1 mole) 2,2-bis(4-bromophenyl)hexafluoropropane in 75 ml of anhydrous tetrahydrofuran was added dropwise 28 ml (0.4 moles) of a 1.4 molar solution of n-butyllithium in hexane while the reaction mixture was cooled in a dry ice-acetone slush. The reaction mixture was stirred for one half hour at -78° C. A dropwise addition of chlorotrimethylsilane (5 ml, 0.04 moles) was then made to the reaction mixture at -78° C. The stirring slurry was allowed to come to ambient temperature over 16 hours. To the reaction mixture was added 100 ml hexane. The organic layer was washed with 2×150 ml saturated sodium chloride solution and 2×150 ml water. The organic layer was dried, filtered, and concentrated to yield the white crystalline product 2,2-bis(4-trimethylsilylphenyl)hexafluoropropane.
Reaction SMILES: I.[C@H:2]1([NH:11][C:12]2[CH:21]=[CH:20][C:19]3[C:14](=[CH:15][CH:16]=[C:17]([NH:22][C:23](=[NH:26])SC)[CH:18]=3)[N:13]=2)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3]1.[CH3:27][N:28]1[CH2:33][CH2:32][CH:31]([NH2:34])[CH2:30][CH2:29]1>>[C@H:2]1([NH:11][C:12]2[CH:21]=[CH:20][C:19]3[C:14](=[CH:15][CH:16]=[C:17]([NH:22][C:23]([NH:34][CH:31]4[CH2:32][CH2:33][N:28]([CH3:27])[CH2:29][CH2:30]4)=[NH:26])[CH:18]=3)[N:13]=2)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3]1
Reactant: CSC(=N)Nc1ccc2nc(N[C@@H]3CCc4ccccc43)ccc2c1
Reactant: CN1CCC(N)CC1
Agent: I
Product: CN1CCC(NC(=N)Nc2ccc3nc(N[C@@H]4CCc5ccccc54)ccc3c2)CC1

Procedure:
The title compound was prepared in accordance with the general method 16 described in example 151 from 1-[2-((R)-indan-1-ylamino)-quinolin-6-yl]-2-methyl-isothiourea hydroiodide and 1-methylpiperidine-4-amine; MS: m/e=415.3 (M+H+).
Reaction SMILES: P(Cl)(Cl)(Cl)=O.[NH:6]1[C:14]2[C:9](=[CH:10][C:11]([CH2:15][NH:16][C:17](=[O:19])[CH3:18])=[CH:12][CH:13]=2)[CH:8]=[CH:7]1.[C:20](OCC)(=[O:22])C>CN(C)C=O>[CH:20]([C:8]1[C:9]2[C:14](=[CH:13][CH:12]=[C:11]([CH2:15][NH:16][C:17](=[O:19])[CH3:18])[CH:10]=2)[NH:6][CH:7]=1)=[O:22]
Reactant: CC(=O)NCc1ccc2[nH]ccc2c1
Reactant: CCOC(C)=O
Solvent: O=P(Cl)(Cl)Cl
Solvent: CN(C)C=O
Product: CC(=O)NCc1ccc2[nH]cc(C=O)c2c1
Reaction time: 0.25 h
Yield: 17 %

Procedure:
The synthesis was performed with reference to the known literature (International Patent Publication WO2000/75139). N,N-Dimethylformamide (2.0 mL) cooled to 0° C. was added dropwise with phosphorus oxychloride (0.54 g, 3.5 mmol), and then the mixture was stirred for 15 minutes. Then, the mixture was added with a solution of N-[(1H-indol-5-yl)methyl]acetamide (0.60 g, 3.2 mmol) in N,N-dimethylformamide (4.0 mL), and then the mixture was stirred overnight at room temperature. The reaction mixture was added with ethyl acetate, and then the organic layer was washed successively with water and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and then the residue was subjected to silica gel column chromatography (eluted with chloroform/methanol (90:10)) to obtain a solid containing the objective substance. This solid was washed with ethyl acetate to obtain N-[(3-formyl-1H-indol-5-yl)methyl]acetamide (0.12 g, 17%).
Reaction SMILES: CO.C1C[O:6][CH2:5]C1.[H-].[Na+].Cl[C:11]1[N:16]=[C:15]([C:17]2[CH:22]=[CH:21][N:20]=[CH:19][CH:18]=2)[N:14]=[C:13]([NH:23][S:24](=[O:36])(=[O:35])[NH:25][C:26]2[CH:31]=[CH:30][C:29]([CH:32]([CH3:34])[CH3:33])=[CH:28][CH:27]=2)[C:12]=1[O:37][C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][C:39]=1[O:44][CH3:45]>CN(C=O)C>[CH3:5][O:6][C:11]1[N:16]=[C:15]([C:17]2[CH:22]=[CH:21][N:20]=[CH:19][CH:18]=2)[N:14]=[C:13]([NH:23][S:24](=[O:36])(=[O:35])[NH:25][C:26]2[CH:31]=[CH:30][C:29]([CH:32]([CH3:34])[CH3:33])=[CH:28][CH:27]=2)[C:12]=1[O:37][C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][C:39]=1[O:44][CH3:45]
Reactant: COc1ccccc1Oc1c(Cl)nc(-c2ccncc2)nc1NS(=O)(=O)Nc1ccc(C(C)C)cc1
Reactant: C1CCOC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CO
Product: COc1ccccc1Oc1c(NS(=O)(=O)Nc2ccc(C(C)C)cc2)nc(-c2ccncc2)nc1OC
Temperature: 80 °C

Procedure:
To a mixture of methanol (1 ml) and THF (2 ml) was added sodium hydride (100 mg, 60% dispersion in mineral oil) followed by the addition of 4-i-propyl-phenyl sulfamic acid-[6-chloro-5-(o-methoxyphenoxy)-2-(4-pyridyl)-pyrimidin-4-yl]-amide (100 mg, Referential Example 1e)). DMF (0.5 ml) was added and the reaction mixture was heated to 80° C. for 20 h. The solvents were evaporated, water (14 ml) and a 10% solution of citric acid was added until the pH was 3. The precipitate was filtered off and washed with water to give 4-i-propyl-phenyl sulfamic acid-[6-methoxy-5-(o-methoxyphenoxy)-2-(4-pyridyl)-pyrimidin-4-yl]-amide (100 mg). tR=5.08 min, (LC); [M+H]+=522.45 (ES+).
Reaction SMILES: [F:1][C:2]([F:28])([F:27])[C:3]1[CH:8]=[CH:7][C:6]([N:9]2[CH2:14][CH2:13][N:12]([S:15]([C:18]3[CH:19]=[C:20]4[C:24](=[CH:25][CH:26]=3)[NH:23][CH2:22][CH2:21]4)(=[O:17])=[O:16])[CH2:11][CH2:10]2)=[CH:5][CH:4]=1.C(C1C(=O)C(Cl)=C(Cl)C(=O)C=1C#N)#N>ClCCl>[F:27][C:2]([F:1])([F:28])[C:3]1[CH:8]=[CH:7][C:6]([N:9]2[CH2:10][CH2:11][N:12]([S:15]([C:18]3[CH:19]=[C:20]4[C:24](=[CH:25][CH:26]=3)[NH:23][CH:22]=[CH:21]4)(=[O:17])=[O:16])[CH2:13][CH2:14]2)=[CH:5][CH:4]=1
Reactant: O=S(=O)(c1ccc2c(c1)CCN2)N1CCN(c2ccc(C(F)(F)F)cc2)CC1
Agent: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Solvent: ClCCl
Product: O=S(=O)(c1ccc2[nH]ccc2c1)N1CCN(c2ccc(C(F)(F)F)cc2)CC1
Temperature: 25 °C
Reaction time: 4 h
Yield: 70 %

Procedure:
5-[4-(4-Trifluoromethyl-phenyl)-piperazine-1-sulfonyl]-2,3-dihydro-1H-indole (180 mg, 0.44 mmol) was dissolved in dichloromethane (10 mL). DDQ (100 mg, 0.44 mmol) was added and stirred at room temperature for 4 h. The reaction was concentrated and purified by silica gel flash column chromatography (45% ethyl acetate in hexanes) to provide 5-[4-(4-trifluoromethyl-phenyl)-piperazine-1-sulfonyl]-1H-indole (70%) as a white solid. 1H NMR (400 MHz, DMSO-D6) δ 11.72 (s, 1H), 8.07 (s, 1H). 7.65 (d, 1H), 7.62-7.61 (m, 1H), 7.52-7.48 (m, 3H), 7.04 (d, 2H), 6.71 (m, 1H), 3.40-3.36 (m, 4H), 3.02-2.99 (m, 4H).
Reaction SMILES: [CH2:1]([OH:3])[CH3:2].C=[O:5].[NH2:6][C:7]1[CH:8]=[C:9](C=[CH:14][CH:15]=1)C(O)=O.O>CS(C)=O.CO>[CH:14]1[C:2]([C:1]([OH:5])=[O:3])=[CH:9][CH:8]=[C:7]([NH2:6])[CH:15]=1
Reactant: C=O
Reactant: CCO
Reactant: Nc1cccc(C(=O)O)c1
Solvent: CO
Solvent: CS(C)=O
Solvent: O
Product: Nc1ccc(C(=O)O)cc1

Procedure:
In 70 ml of dimethyl sulfoxide (DMSO) containing 20 percent of ethanol, 1.94 g (0.02 mole) of polymaleimide was dissolved. The resultant solution, with 2 ml of 37 percent formalin solution added thereto, was thermally refluxed at temperatures of 70° to 75° C. To the substance obtained by the thermal reflux was added a solution obtained by dissolving 2.74 g (0.02 mole) of m-aminobenzoic acid in 10 ml of a DMSO solution containing 20 percent of ethanol. This mixed solution was refluxed for two hours. Then, the reaction solution was cooled, and the cooled reaction solution was added to a mixed solution of water and methanol to precipitate insoluble components. The final precipitate was separated by filtration and dissolved in a DMSO solution. The resultant solution was purified by repeated addition of water and methanol in the manner just mentioned, and finally dried. A 2.46-g portion (0.01 mole) of poly-m-maleimidemethyl aminobenzoic acid thus obtained was dissolved in a mixed solution of water and tetrahydrofuran and cooled with water. Separately, 1 g (0.01 mole) of 2-aminothiazole was dissolved in 20 ml of 6 normal hydrochloric acid and cooled. A solution obtained by dissolving 0.74 g of sodium nitrite in a small amount of water was gradually added, while under ice cooling, to the 2-aminothiazole solution to effect diazotization. The resultant diazotized solution was added to the cooled poly-m-maleimidemethyl aminobenzoic acid solution, with the molar ratio of poly-m-maleimidemethyl aminobenzoic acid to the diazotized compound at 1:1, to effect diazo coupling. The precipitate which consequently occurred was separated by filtration and dissolved in dioxane. The resultant solution was poured in a mixed solution of water and methanol. The precipitate was again purified and dried to afford 3.37 g of PTAMMABC (m.p. 280° C.).