Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:17]3([CH2:21][O:20][C:19]([N:22](C(OC(C)(C)C)=O)C(OC(C)(C)C)=O)=[N:18]3)[C:13]3([CH2:16][O:15][CH2:14]3)[C:9]3([CH2:12][CH2:11][CH2:10]3)[O:8][C:5]2=[CH:6][CH:7]=1.[F:37][C:38]1[CH:43]=[CH:42][C:41]([O:44][CH3:45])=[CH:40][C:39]=1B(O)O.C([O-])([O-])=O.[Na+].[Na+]>O1CCOCC1.C1(C)C=CC=CC=1.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>[F:37][C:38]1[CH:43]=[CH:42][C:41]([O:44][CH3:45])=[CH:40][C:39]=1[C:2]1[CH:3]=[C:4]2[C:17]3([CH2:21][O:20][C:19]([NH2:22])=[N:18]3)[C:13]3([CH2:16][O:15][CH2:14]3)[C:9]3([CH2:10][CH2:11][CH2:12]3)[O:8][C:5]2=[CH:6][CH:7]=1
Reactant: COc1ccc(F)c(B(O)O)c1
Reactant: CC(C)(C)OC(=O)N(C(=O)OC(C)(C)C)C1=NC2(CO1)c1cc(Br)ccc1OC1(CCC1)C21COC1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: Cc1ccccc1
Product: COc1ccc(F)c(-c2ccc3c(c2)C2(COC(N)=N2)C2(COC2)C2(CCC2)O3)c1
Temperature: 100 °C
Reaction time: 2 h
Yield: 14.7 %

Procedure:
A mixture of di-tert-butyl (6′-bromotrispiro[cyclobutane-1,2′-chromene-4′,4″-[1,3]oxazole-3′,3′″-oxetan]-2″-yl)imidodicarbonate (14.1 mg), 2-fluoro-5-methoxyphenylboronic acid (12.7 mg), PdCl2(PPh3)2 (5.3 mg) and 1M aqueous Na2CO3 (0.1 mL) in dioxane (0.4 mL) was stirred for 2 hours at 100° C. The mixture was filtered by using Chem Elut cartridges (Agilent Technologies) and washed with CHCl3. The filtrate was evaporated to give a brown oil. The oil was dissolved in toluene (0.5 mL) and to the mixture was added silicagel (neutral; 50 mg). The mixture was stirred for 1 hour at 100° C. The mixture was filtered and washed with CHCl3. The filtrate was evaporated. The residue was purified with HPLC (Column: Waters SunFire™ Prep C18 OBD™ 5 micrometer, 19×100 mm; MeOH/0.1% aqueous HCOOH 11/89 to 95/5(v/v)) and afforded 6′-(2-fluoro-5-methoxyphenyl)trispiro[cyclobutane-1,2′-chromene-4′,4″-[1,3]oxazole-3′,3′″-oxetan]-2″-amine (1.5 mg).
Reaction SMILES: Cl.[C:2]([C:5]1[CH:6]=[CH:7][C:8]([O:29][CH2:30][C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)=[C:9]([CH2:11][C:12]([NH:14][C:15]2[CH:20]=[CH:19][C:18]([C:21]([N:23]3[CH2:27][CH2:26][CH2:25][CH2:24]3)=[O:22])=[C:17]([CH3:28])[CH:16]=2)=[O:13])[CH:10]=1)(=[NH:4])[NH2:3].C(N(CC)CC)C.[N+](C1C=CC([C:53]2[CH:61]=[CH:60][CH:59]=[CH:58][C:54]=2[C:55]([O-])=[O:56])=CC=1)([O-])=O>C(Cl)Cl>[C:55]([NH:4][C:2]([C:5]1[CH:6]=[CH:7][C:8]([O:29][CH2:30][C:31]2[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=2)=[C:9]([CH2:11][C:12]([NH:14][C:15]2[CH:20]=[CH:19][C:18]([C:21]([N:23]3[CH2:27][CH2:26][CH2:25][CH2:24]3)=[O:22])=[C:17]([CH3:28])[CH:16]=2)=[O:13])[CH:10]=1)=[NH:3])(=[O:56])[C:54]1[CH:58]=[CH:59][CH:60]=[CH:61][CH:53]=1
Reactant: Cc1cc(NC(=O)Cc2cc(C(=N)N)ccc2OCc2ccccc2)ccc1C(=O)N1CCCC1
Reactant: O=C([O-])c1ccccc1-c1ccc([N+](=O)[O-])cc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1cc(NC(=O)Cc2cc(C(=N)NC(=O)c3ccccc3)ccc2OCc2ccccc2)ccc1C(=O)N1CCCC1

Procedure:
350 mg (0.69 mmol) of 2-(5-carbamimidoyl-2-benzyloxy-phenyl)-N-[3-methyl-4-(pyrrolidin-1-yl-carbonyl)-phenyl]-acetamide-hydrochloride are suspended in 40 ml of methylene chloride and combined with 1.0 ml of triethylamine and 300 mg (1.3 mmol) of 4-nitrophenylbenzoate. The reaction mixture is refluxed for 4 hours. After the addition of 100 ml of saline solution the aqueous phase is extracted 3× with methylene chloride. The combined organic phases are dried over sodium sulphate and concentrated by evaporation.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([C:8]2[CH:16]=[C:15]3[C:11]([C:12]([NH:17]C(=O)C)=[N:13][NH:14]3)=[CH:10][CH:9]=2)[CH:5]=[C:4]([O:21][CH3:22])[N:3]=1.Cl>CO>[NH2:1][C:2]1[N:7]=[C:6]([C:8]2[CH:16]=[C:15]3[C:11]([C:12]([NH2:17])=[N:13][NH:14]3)=[CH:10][CH:9]=2)[CH:5]=[C:4]([O:21][CH3:22])[N:3]=1
Reactant: COc1cc(-c2ccc3c(NC(C)=O)n[nH]c3c2)nc(N)n1
Agent: Cl
Solvent: CO
Product: COc1cc(-c2ccc3c(N)n[nH]c3c2)nc(N)n1
Temperature: 60 °C
Reaction time: 12 h
Yield: 26.9 %

Procedure:
To N-{6-[2-amino-6-(methyloxy)-4-pyrimidinyl]-1H-indazol-3-yl}acetamide (115 mg, 0.218 mmol) in CH3OH (20 mL) was added HCl (0.21 mL, 2.5 mmol, 12 M), and the reaction mixture was stirred for 12 hours at 60° C. The reaction was cooled to room temperature and stirred over the weekend. The mixture was concentrated, and the resulting yellow solid was purified on a Gilson RPHPLC(CH3CN/H2O w/0.1% TFA). The fractions containing the desired product were combined and concentrated. The resulting yellow solid was dissolved in water and treated with NaOH (1M). The resulting pink solid was filtered to afford the title compound (15 mg, 25%). LC-MS (ES) m/z=257 [M+H]+. 1H NMR (400 MHz, DMSO-d6): δ 3.86 (s, 3H), 5.40 (s, 2H), 6.58 (s, 1H), 6.64 (s, 2H), 7.54 (dd, J=8.6, 1.0 Hz, 1H), 7.72 (d, J=8.3 Hz, 1H), 7.95 (s, 1H), 11.57 (s, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:25]=[CH:24][C:5]2[CH:6]([C:16]3[C:17](=[O:23])[NH:18][C:19](=[O:22])[NH:20][CH:21]=3)[C:7]3[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][C:8]=3[CH:9]=[CH:10][C:4]=2[CH:3]=1.[CH2:26]([O:28][C:29]([C:31]1[O:32][C:33]([CH2:36]Br)=[CH:34][CH:35]=1)=[O:30])[CH3:27]>>[Cl:15][C:12]1[CH:13]=[CH:14][C:7]2[CH:6]([C:16]3[C:17](=[O:23])[NH:18][C:19](=[O:22])[N:20]([CH2:36][C:33]4[O:32][C:31]([C:29]([O:28][CH2:26][CH3:27])=[O:30])=[CH:35][CH:34]=4)[CH:21]=3)[C:5]3[CH:24]=[CH:25][C:2]([Cl:1])=[CH:3][C:4]=3[CH:10]=[CH:9][C:8]=2[CH:11]=1
Reactant: O=c1[nH]cc(C2c3ccc(Cl)cc3C=Cc3cc(Cl)ccc32)c(=O)[nH]1
Reactant: CCOC(=O)c1ccc(CBr)o1
Product: CCOC(=O)c1ccc(Cn2cc(C3c4ccc(Cl)cc4C=Cc4cc(Cl)ccc43)c(=O)[nH]c2=O)o1

Procedure:
The subtitle compound was prepared from the product of step (vi) (0.54 g) and 5-bromomethyl-2-furancarboxylic acid ethyl ester (J. Chem. Soc. Perkin Trans. 1, 1981, 1125, Bull. Chem. Soc. Jpn. 1987, 60, 1807)(0.34 g) according to the method of example 1 step (iv). Purification was by chromatography eluting with 30% ethyl acetate in isohexane. Yield 0.55 g.
Reaction SMILES: Cl.[N:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]([CH2:32][CH2:33][C:34]([O:36][CH2:37][CH3:38])=[O:35])[C:9]([C:11]1[CH:31]=[CH:30][C:14]2[N:15]([CH3:29])[C:16]([CH2:18][CH2:19][C:20]3[CH:25]=[CH:24][C:23]([C:26](=[NH:28])[NH2:27])=[CH:22][CH:21]=3)=[N:17][C:13]=2[CH:12]=1)=[O:10].Cl[C:40]([O:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH3:48])=[O:41]>ClCCl.CO>[N:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]([CH2:32][CH2:33][C:34]([O:36][CH2:37][CH3:38])=[O:35])[C:9]([C:11]1[CH:31]=[CH:30][C:14]2[N:15]([CH3:29])[C:16]([CH2:18][CH2:19][C:20]3[CH:25]=[CH:24][C:23]([C:26](=[NH:27])[NH:28][C:40]([O:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH3:48])=[O:41])=[CH:22][CH:21]=3)=[N:17][C:13]=2[CH:12]=1)=[O:10]
Reactant: CCOC(=O)CCN(C(=O)c1ccc2c(c1)nc(CCc1ccc(C(=N)N)cc1)n2C)c1ccccn1
Reactant: CCCCCCOC(=O)Cl
Agent: Cl
Solvent: CO
Solvent: ClCCl
Product: CCCCCCOC(=O)NC(=N)c1ccc(CCc2nc3cc(C(=O)N(CCC(=O)OCC)c4ccccn4)ccc3n2C)cc1
Yield: 72 %

Procedure:
Prepared analogously to Example 90 from 1-methyl-2-[2-(4-amidinophenyl)ethyl]-benzimidazol-5-yl-carboxylic acid-N-(2-pyridyl)-N-(2-ethoxycarbonylethyl)-amide-hydrochloride and n-hexyl chloroformate. Yield: 72% of theory, C35H42N6O5 (626.8) Rf value: 0.54 (silica gel; dichloromethane/methanol=9:1) ##EQU95##
Reaction SMILES: [CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:15])=[C:11](F)[CH:12]=3)[C:7](=[O:16])[C:6]([C:17]([OH:19])=[O:18])=[CH:5]2)[CH2:3][CH2:2]1.[CH2:20]([N:22]1[CH2:27][CH2:26][NH:25][CH2:24][CH:23]1[CH3:28])[CH3:21]>>[CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:15])=[C:11]([N:25]4[CH2:26][CH2:27][N:22]([CH2:20][CH3:21])[CH:23]([CH3:28])[CH2:24]4)[CH:12]=3)[C:7](=[O:16])[C:6]([C:17]([OH:19])=[O:18])=[CH:5]2)[CH2:3][CH2:2]1
Reactant: O=C(O)c1cn(C2CC2)c2cc(F)c(F)cc2c1=O
Reactant: CCN1CCNCC1C
Product: CCN1CCN(c2cc3c(cc2F)c(=O)c(C(=O)O)cn3C2CC2)CC1C
Yield: 51 %

Procedure:
The condensation of 1-cyclopropyl-6,7-difluoro-1,4-dihydro-4-oxo-quinoline-3-carboxylic acid with 4-ethyl-3-methylpiperazine was carried out in a similar manner as described in example 1 gave the titled product. Yield 51%, m.p 200° C., C20H24FN3O3, m/z 374 (M+1).
Reaction SMILES: [BH4-].[Na+].COCCOCCOC.Br[CH:13]1[C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=2[CH2:17][O:16][C:15]2[CH:24]=[CH:25][C:26]([CH2:28][C:29]([O:31][CH3:32])=[O:30])=[CH:27][C:14]1=2>O>[CH:27]1[C:14]2[CH2:13][C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=3[CH2:17][O:16][C:15]=2[CH:24]=[CH:25][C:26]=1[CH2:28][C:29]([O:31][CH3:32])=[O:30]
Reactant: COC(=O)Cc1ccc2c(c1)C(Br)c1ccccc1CO2
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: COCCOCCOC
Product: COC(=O)Cc1ccc2c(c1)Cc1ccccc1CO2

Procedure:
A mixture of 6.0 g. of sodium borohydride, 26 ml. of diglyme, 14 ml. of water, and 4.8 g. of methyl 6,11-dihydro-11-bromodibenz[b,e]oxepin-2-acetate is heated at 50° for one hour. Water is added and the mixture is extracted with ether. The ether extracts are dried with sodium sulfate, filtered, and concentrated in vacuo to provide methyl 6,11-dihydrodibenz[b,e]oxepin-2-acetate.
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([C:11]3[CH:16]=[CH:15][CH:14]=[C:13]([Cl:17])[CH:12]=3)=[CH:9][N:10]=2)[N:7]=1.[NH:18]1[CH2:23][CH2:22][CH2:21][C@H:20]([NH2:24])[CH2:19]1.C([O-])(O)=O.[Na+]>CN1C(=O)CCC1>[Cl:17][C:13]1[CH:12]=[C:11]([C:8]2[N:6]3[N:7]=[C:2]([N:18]4[CH2:23][CH2:22][CH2:21][C@H:20]([NH2:24])[CH2:19]4)[CH:3]=[CH:4][C:5]3=[N:10][CH:9]=2)[CH:16]=[CH:15][CH:14]=1
Reactant: Clc1cccc(-c2cnc3ccc(Cl)nn23)c1
Reactant: N[C@H]1CCCNC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN1CCCC1=O
Product: N[C@H]1CCCN(c2ccc3ncc(-c4cccc(Cl)c4)n3n2)C1
Temperature: 180 °C
Reaction time: 1 h
Yield: 12.6 %

Procedure:
To a solution of 6-chloro-3-(3-chlorophenyl)imidazo[1,2-b]pyridazine (200 mg, 0.78 mmol) and (S)-Piperidin-3-amine (290 mg, 2.12 mmol) in NMP (1.0 mL) was added NaHCO3 (118 mg, 1.52 mmol), the mixture was stirred at 180° C. for 60 mins under microwave irridation. The mixture was purified by flash chromatograph to give (S)-1-(3-(3-chlorophenyl)imidazo[1,2-b]pyridazin-6-yl)piperidin-3-amine (32 mg, 0.098 mmol, 13%) as a pale yellow solid.
Reaction SMILES: C([O:3][C:4]([C:6]1[N:7]=[CH:8][N:9]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([C:17]3[C:18]([O:25][CH3:26])=[N:19][C:20]([O:23][CH3:24])=[N:21][CH:22]=3)[CH:12]=2)[CH:10]=1)=[O:5])C.[OH-].[K+]>C(O)C>[CH3:24][O:23][C:20]1[N:19]=[C:18]([O:25][CH3:26])[C:17]([C:13]2[CH:12]=[C:11]([N:9]3[CH:10]=[C:6]([C:4]([OH:5])=[O:3])[N:7]=[CH:8]3)[CH:16]=[CH:15][CH:14]=2)=[CH:22][N:21]=1
Reactant: CCOC(=O)c1cn(-c2cccc(-c3cnc(OC)nc3OC)c2)cn1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: COc1ncc(-c2cccc(-n3cnc(C(=O)O)c3)c2)c(OC)n1

Procedure:
This compound is prepared by hydrolysis of 23m using a 1:1 mixture of aqueous potassium hydroxide (2M) and ethanol.
Reaction SMILES: [F:1][CH:2]([F:12])[C:3]1[C:4](I)=[CH:5][C:6]([O:9][CH3:10])=[N:7][CH:8]=1.[Cl:13][C:14]1[CH:15]=[CH:16][C:17]([C:23]#[N:24])=[C:18](B(O)O)[CH:19]=1>>[Cl:13][C:14]1[CH:15]=[CH:16][C:17]([C:23]#[N:24])=[C:18]([C:4]2[C:3]([CH:2]([F:12])[F:1])=[CH:8][N:7]=[C:6]([O:9][CH3:10])[CH:5]=2)[CH:19]=1
Reactant: N#Cc1ccc(Cl)cc1B(O)O
Reactant: COc1cc(I)c(C(F)F)cn1
Product: COc1cc(-c2cc(Cl)ccc2C#N)c(C(F)F)cn1

Procedure:
616 mg (purity 83%, 1.79 mmol) of 5-(difluoromethyl)-4-iodo-2-methoxypyridine and 325 mg (1.79 mmol) of 5-chloro-2-cyanophenylboronic acid in the presence of [1,1-bis(diphenylphosphino)ferrocene]palladium(II) chloride/dichloromethane monoadduct were reacted according to General Method 2A. Yield: 223 mg (42% of theory)
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]3[CH:20]=[CH:19][C:18]([C:21]4[CH:22]=[C:23]([CH:27]=[CH:28][C:29]=4[CH3:30])[C:24](O)=[O:25])=[CH:17][C:11]=3[C:12]=2[C:13](=[O:16])[NH:14][CH3:15])=[CH:4][CH:3]=1.[N:31]1[CH:36]=[C:35]([C:37]2([NH2:40])[CH2:39][CH2:38]2)[CH:34]=[N:33][CH:32]=1.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl.C(N(C(C)C)CC)(C)C>C(Cl)Cl>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[O:9][C:10]3[CH:20]=[CH:19][C:18]([C:21]4[CH:22]=[C:23]([C:24](=[O:25])[NH:40][C:37]5([C:35]6[CH:36]=[N:31][CH:32]=[N:33][CH:34]=6)[CH2:39][CH2:38]5)[CH:27]=[CH:28][C:29]=4[CH3:30])=[CH:17][C:11]=3[C:12]=2[C:13]([NH:14][CH3:15])=[O:16])=[CH:6][CH:7]=1
Reactant: CNC(=O)c1c(-c2ccc(F)cc2)oc2ccc(-c3cc(C(=O)O)ccc3C)cc12
Reactant: NC1(c2cncnc2)CC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CNC(=O)c1c(-c2ccc(F)cc2)oc2ccc(-c3cc(C(=O)NC4(c5cncnc5)CC4)ccc3C)cc12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a mixture of 3-(2-(4-fluorophenyl)-3-(methylcarbamoyl)benzofuran-5-yl)-4-methylbenzoic acid (0.1 g, 0.25 mmol, 1 eq), 1-(pyrimidin-5-yl)cyclopropanamine (0.041 g, 0.3 mmol, 1.2 eq) (60% purity), HOBT (0.057 g, 0.42 mmol, 1.7 eq), EDC.HCl (0086 g, 0.44 mmol, 1.8 eq) in DCM at ambient temperature under nitrogen was added Diisopropylehtylamine (0.162 g, 1.2 mmol, 5.0 eq). The clear mixture was stirred at ambient temperature for overnight. The mixture was concentrated, diluted with water and extracted with EtOAc. The organic layer is further washed with water, dried over sodium sulphate and concentrated. The product obtained was further purified by column chromatography (neutral alumina) using 0.5% Methanol/DCM and finally it was purified by preparative HPLC. Yield: 0.02 g (20%). 1H NMR (400 MHz, DMSO-d6): δ 1.34-1.35 (m, 2H), 1.41-1.42 (m, 2H), 2.29 (s, 3H), 2.81-2.82 (d, 3H), J=4.56 Hz), 738-7.45 (m, 4H), 7.58 (d, 1H, J=0.96 Hz), 7.75 (d, 1H, J=8.4 Hz), 7.81 (s, 1H), 7.83 (m, 1H), 7.98-8.01 (m, 2H), 8.46-8.47 (d, 1H, J=4.6 Hz), 8.64 (s, 2H), 9.01 (s, 1H), 9.31 (s, 1H). LCMS: (ES+) m/z=521.2 (M+H). LCMS Method: Column-Ascentis Express C18 (5×2.1 mm-2.7 μm) Mphase A: 2% ACN-98% H2O-10 mM NH4COOH Mphase B: 98% ACN-2% H2O-10 mM NH4COOH Flow: 1 ML/Min
Reaction SMILES: [OH:1][C:2]1([CH2:15][CH:16]=O)[CH2:14][CH2:13][C:5]2([O:10][CH2:9][C:8]([CH3:12])([CH3:11])[CH2:7][O:6]2)[CH2:4][CH2:3]1.[C:18]1([C@@H:24]([NH2:27])[CH2:25][CH3:26])[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>>[CH3:11][C:8]1([CH3:12])[CH2:9][O:10][C:5]2([CH2:4][CH2:3][C:2]([CH2:15][CH2:16][NH:27][C@H:24]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[CH2:25][CH3:26])([OH:1])[CH2:14][CH2:13]2)[O:6][CH2:7]1
Reactant: CC[C@H](N)c1ccccc1
Reactant: CC1(C)COC2(CCC(O)(CC=O)CC2)OC1
Product: CC[C@H](NCCC1(O)CCC2(CC1)OCC(C)(C)CO2)c1ccccc1
Yield: 50 %

Procedure:
The title compound is prepared from (9-hydroxy-3,3-dimethyl-1,5-dioxa-spiro[5.5]undec-9-yl)-acetaldehyde and (S)-1-phenyl-propylamine following a procedure analogous to that described in Step 3 of Intermediate 2. Yield: 50% of theory; LC (method 8): tR=1.16 min; Mass spectrum (ESI+): m/z=362 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[C:7]([S:8](Cl)(=[O:10])=[O:9])=[CH:6][CH:5]=[CH:4][N:3]=1.[CH3:12][O:13][C:14]1[CH:15]=[CH:16][C:17]([NH2:22])=[N:18][C:19]=1[O:20][CH3:21].N1C=CC=CC=1>C(Cl)Cl>[Cl:1][C:2]1[C:7]([S:8]([NH:22][C:17]2[CH:16]=[CH:15][C:14]([O:13][CH3:12])=[C:19]([O:20][CH3:21])[N:18]=2)(=[O:10])=[O:9])=[CH:6][CH:5]=[CH:4][N:3]=1
Reactant: O=S(=O)(Cl)c1cccnc1Cl
Reactant: COc1ccc(N)nc1OC
Solvent: ClCCl
Solvent: c1ccncc1
Product: COc1ccc(NS(=O)(=O)c2cccnc2Cl)nc1OC
Yield: 66.4 %

Procedure:
The title compound (549 mg, 1.66 mmol) was prepared from 2-chloropyridine-3-sulfonyl chloride (530 mg, 2.5 mmol), 5,6-dimethoxypyridin-2-amine (424 mg, 2.8 mmol) and pyridine (0.6 mL, 7.5 mmol) in DCM (10 mL) using the methods of (IntC1).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:30])[CH2:4][C@H:5]1[C:9]2[CH:10]=[CH:11][C:12]([O:14][C@H:15]3[C:23]4[C:18](=[C:19]([CH2:28]Br)[C:20]([C:24]([F:27])([F:26])[F:25])=[CH:21][CH:22]=4)[CH2:17][CH2:16]3)=[CH:13][C:8]=2[O:7][CH2:6]1.[N:31]1[C:36]2[CH2:37][CH2:38][N:39](C[B-](F)(F)F)[CH2:40][C:35]=2[CH:34]=[N:33][CH:32]=1>>[CH3:1][O:2][C:3](=[O:30])[CH2:4][C@H:5]1[C:9]2[CH:10]=[CH:11][C:12]([O:14][C@H:15]3[C:23]4[C:18](=[C:19]([CH2:28][N:39]5[CH2:38][CH2:37][C:36]6[N:31]=[CH:32][N:33]=[CH:34][C:35]=6[CH2:40]5)[C:20]([C:24]([F:27])([F:26])[F:25])=[CH:21][CH:22]=4)[CH2:17][CH2:16]3)=[CH:13][C:8]=2[O:7][CH2:6]1
Reactant: COC(=O)C[C@@H]1COc2cc(O[C@@H]3CCc4c3ccc(C(F)(F)F)c4CBr)ccc21
Reactant: F[B-](F)(F)CN1CCc2ncncc2C1
Product: COC(=O)C[C@@H]1COc2cc(O[C@@H]3CCc4c3ccc(C(F)(F)F)c4CN3CCc4ncncc4C3)ccc21

Procedure:
The title compound is prepared from {(S)-6-[(R)-4-bromomethyl-5-trifluoromethyl-indan-1-yloxy]-2,3-dihydro-benzofuran-3-yl}-acetic acid methyl ester and (7,8-dihydro-pyrido[4,3-d]pyrimidin-6-yl)methyltrifluoroborate following a procedure analogous to that described for Intermediate 3. LC (method 1): tR=1.13 min; Mass spectrum (ESI+): m/z=540 [M+H]+.
Reaction SMILES: [Br:1]N1C(=O)CCC1=O.O.[C:10]1([N:16]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>>[C:23]1([N:16]([C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:17]2[CH:22]=[CH:21][C:20]([Br:1])=[CH:19][CH:18]=2)[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: c1ccc(N(c2ccccc2)c2ccccc2)cc1
Solvent: O
Product: Brc1ccc(N(c2ccccc2)c2ccccc2)cc1
Reaction time: 12 h
Yield: 59 %

Procedure:
In addition, 15 g of triphenylamine dissolved in 50 ml of N,N-dimethylformide is prepared. 11.4 g of N-bromosuccinimide is added into the N,N-dimethylformide solution and the solution is stirred for 12 hours. After 20 ml of water is added, a white crystal is obtained. The white crystal is filtered and dried to obtain 11.70 g of N,N-diphenyl-4-bromoaniline (60%). Next, 8.26 g of N,N-diphenyl-4-bromoaniline is dissolved in 100 ml of tetrahydrofuran. After cooling the solution to −78° C., 24 ml of n-butyl lithium is dropt into the cold solution slowly, then the solution is stirred for 2 hours and the temperature of solution is raised to 0° C. Then, the reacting solution is cooled to −78° C. again, and 5.2 ml of boric acid trimethyl ester is added into the solution slowly. After stirring the reacting solution for 12 hours, 20 ml of 2N HCl is added to terminate the reaction. 100 ml of ethyl ether is used to extract the solution, and the extracted solution is dehydrated by MgSO4. Then, the extracted solution is concentrated, and hexane is added to obtain a white crystal. This white crystal is filtered and dried to obtain 4.3 g of compound (B)(60%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:9]2[CH:14]=[CH:13][C:12]([CH2:15][C:16](O)=[O:17])=[C:11]([N+:19]([O-])=O)[CH:10]=2)[CH:6]=[CH:7][CH:8]=1>CO.[Pd]>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:9]2[CH:10]=[C:11]3[C:12]([CH2:15][C:16](=[O:17])[NH:19]3)=[CH:13][CH:14]=2)[CH:6]=[CH:7][CH:8]=1
Reactant: COc1cccc(-c2ccc(CC(=O)O)c([N+](=O)[O-])c2)c1
Agent: [Pd]
Solvent: CO
Product: COc1cccc(-c2ccc3c(c2)NC(=O)C3)c1
Yield: 69.3 %

Procedure:
3′-Methoxy-3-nitrobiphenyl-4-acetic acid (5.2 g) was dissolved in methanol and hydrogenated over 0.8 g of 10% palladium on carbon for 3 hours at room temperature. The catalyst was removed by filtration, washed with methanol and the filtrates combined and concentrated to give a brown solid. The solid was chromatographed on silica gel in ethyl acetate:hexane:acetic acid (33:66:1) to give 3.0 g of 6-(3-methoxypheny)-2-oxindole as a pink solid.
Reaction SMILES: [CH:1]1([CH2:4][S:5]([OH:7])=[O:6])[CH2:3][CH2:2]1.[CH2:8]=[C:9]([CH2:13][C:14]([N:16]1[CH2:21][CH2:20][O:19][CH2:18][CH2:17]1)=[O:15])[C:10]([OH:12])=[O:11]>C1(C)C=CC=CC=1.C(#N)C>[CH:1]1([CH2:4][S:5]([CH2:8][CH:9]([CH2:13][C:14]([N:16]2[CH2:17][CH2:18][O:19][CH2:20][CH2:21]2)=[O:15])[C:10]([OH:12])=[O:11])(=[O:7])=[O:6])[CH2:3][CH2:2]1
Reactant: O=S(O)CC1CC1
Reactant: C=C(CC(=O)N1CCOCC1)C(=O)O
Solvent: CC#N
Solvent: Cc1ccccc1
Product: O=C(O)C(CC(=O)N1CCOCC1)CS(=O)(=O)CC1CC1
Temperature: 85 °C
Reaction time: 4.5 h
Yield: 40.1 %

Procedure:
To a solution of cyclopropylmethylsulphinic acid (1.8 g, 15 mmol) in anhydrous toluene (45 mL) and anhydrous acetonitrile (9 mL) was added 2-Methylene4-morpholin-4-yl-4-oxo-butyric acid (2.98 g, 15 mmol). The resulting solution was warmed to 85° C. and stirred at this temperature for 4.5 h. The heterogeneous reaction mixture is then allowed to cool to room temperature then concentrated under reduced pressure. The residue is then purified by flash chromatography eluting with 7% methanol in dichloromethane to give 2-Cyclopropylmethanesulfonylmethyl-4-morpholin-4-yl-4-oxo-butyric acid (1.92 g) as viscous oil which was re crystallized from hot ethyl acetate to give a white solid.
Reaction SMILES: [F:1][C:2]1[CH:14]=[CH:13][C:5]([C:6](=[O:12])[NH:7][CH2:8][C:9]([OH:11])=O)=[CH:4][CH:3]=1.Cl.[S:16]1[C:20]([CH:21]([NH2:28])[C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[CH:19][CH:18]=[N:17]1>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([NH:7][CH2:8][C:9](=[O:11])[NH:28][CH:21]([C:20]2[S:16][N:17]=[CH:18][CH:19]=2)[C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[O:12])=[CH:13][CH:14]=1
Reactant: O=C(O)CNC(=O)c1ccc(F)cc1
Reactant: NC(c1ccccc1)c1ccns1
Agent: Cl
Product: O=C(CNC(=O)c1ccc(F)cc1)NC(c1ccccc1)c1ccns1

Procedure:
Prepared in analogy to example 1.1 from 4-fluoro-hippuric acid (CA [366-79-0]) and rac-C-isothiazol-5-yl-C-phenyl-methylamine hydrochloride (example 4.9).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:10]=[CH:9][C:8](=[O:11])[NH:7][C:6]=1[C:12](=[O:19])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[O:4].[CH2:20](Br)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>C1(C)C=CC=CC=1.C(=O)([O-])[O-].[Ag+2]>[CH3:1][O:2][C:3](=[O:4])[C:5]1[CH:10]=[CH:9][C:8]([O:11][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[N:7][C:6]=1[C:12](=[O:19])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: COC(=O)c1ccc(=O)[nH]c1C(=O)c1ccccc1
Reactant: BrCc1ccccc1
Agent: [Ag+2]
Agent: O=C([O-])[O-]
Solvent: Cc1ccccc1
Product: COC(=O)c1ccc(OCc2ccccc2)nc1C(=O)c1ccccc1
Reaction time: 24 h

Procedure:
A slurry of 2-benzoyl-6-oxo-1,6-dihydropyridine-3-carboxylic acid methyl ester (1.00 g), benzyl bromide (1.88 ml) and silver carbonate (1.64 g) in toluene (50 ml) was stirred at room temperature in the dark under nitrogen for 3 days. More silver carbonate (0.82 g) was added and the slurry was stirred as before for 24 h. A final portion of silver carbonate (0.82 g) was added, and the mixture was stirred as before for 3 days. The mixture was filtered, and the filtrate was concentrated in vacuo. The residue was purified by flash chromatography on silica gel, eluting with dichloromethane, yielding 2-benzoyl-6-benzyloxynicotinic acid methyl ester as a pale brown solid (1.14 g). 1H NMR (400 MHz, CDCl3) δ3.69 (3H, s), 5.39 (2H, s), 6.92 (1H, d, J=8.8 Hz), 7.30 (3H, m), 7.37 (2H, m), 7.45 (2H, t, J=7.7 Hz), 7.59 (1H, t, J=7.4 Hz), 7.78 (2H, d, J=7.8 Hz), 8.25 (1H, d, J=8.7 Hz); MS (ES+) m/e 348 [MH]+.
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([CH3:9])=[CH:5][C:4]=1[O:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.[C-:18]#[N:19].[Na+].O>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.C(Cl)Cl>[CH3:9][C:6]1[CH:7]=[CH:8][C:3]([CH2:2][C:18]#[N:19])=[C:4]([O:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:5]=1
Reactant: [C-]#N
Reactant: Cc1ccc(CBr)c(OCc2ccccc2)c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Product: Cc1ccc(CC#N)c(OCc2ccccc2)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 100 %

Procedure:
A two-phase mixture of crude 1-bromomethyl-4-methyl-2-phenylmethoxybenzene (21.84 g, 75 mmol), NaCN (11.0 g, 0.22 mol), tetrabutylammonium bromide (2.4 g, 7.5 mmol), water (25 ml) and CH2Cl2 (50 ml) was stirred at room temperature for 1 hour and the layers were separated. The organic layer was washed well with water to remove tetrabutylammonium salts and after drying (CaCl2) the solvent was removed to give (4-methyl-2-phenylmethoxyphenyl)acetonitrile (17.8 g, 100% crude yield) as an oil.