Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[CH2:9][CH2:10][C:11]1[N:12]([CH2:22][C:23](O)=[O:24])[C:13]2[C:18]([C:19](=[O:21])[N:20]=1)=[CH:17][CH:16]=[CH:15][CH:14]=2.[CH3:26][C:27]([N:34]1[CH2:39][CH2:38][CH:37]([NH:40][CH2:41][C:42]2[CH:47]=[CH:46][C:45]([C:48]3[CH:53]=[CH:52][C:51]([C:54]([F:57])([F:56])[F:55])=[CH:50][CH:49]=3)=[CH:44][CH:43]=2)[CH2:36][CH2:35]1)([CH3:33])[C:28]([O:30][CH2:31][CH3:32])=[O:29].CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[CH2:9][CH2:10][C:11]1[N:12]([CH2:22][C:23]([N:40]([CH2:41][C:42]2[CH:47]=[CH:46][C:45]([C:48]3[CH:49]=[CH:50][C:51]([C:54]([F:56])([F:55])[F:57])=[CH:52][CH:53]=3)=[CH:44][CH:43]=2)[CH:37]2[CH2:36][CH2:35][N:34]([C:27]([CH3:26])([CH3:33])[C:28]([O:30][CH2:31][CH3:32])=[O:29])[CH2:39][CH2:38]2)=[O:24])[C:13]2[C:18]([C:19](=[O:21])[N:20]=1)=[CH:17][CH:16]=[CH:15][CH:14]=2
Reactant: O=C(O)Cn1c(CCc2ccc(F)cc2F)nc(=O)c2ccccc21
Reactant: CCOC(=O)C(C)(C)N1CCC(NCc2ccc(-c3ccc(C(F)(F)F)cc3)cc2)CC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCOC(=O)C(C)(C)N1CCC(N(Cc2ccc(-c3ccc(C(F)(F)F)cc3)cc2)C(=O)Cn2c(CCc3ccc(F)cc3F)nc(=O)c3ccccc32)CC1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 64.1 %

Procedure:
A mixture of [2-[2-(2,4-difluorophenyl)ethyl]-4-oxo-1(4H)-quinazolinyl]acetic acid (Int. C3) (120 mg, 1 equiv), ethyl 2-methyl-2-[4-({[4′-(trifluoromethyl)-4-biphenylyl]methyl}-amino)-1-piperidinyl]propanoate (Int. B2) (204 mg, 1.3 equiv), DMF (1.4 ml) and DIPEA (0.183 ml, 3 equiv) was shaken at room temperature, then HATU (206 mg, 1.5 equiv) was added with vigorous agitation and shaking continued for 1.5 h. A further portion of Intermediate D5 (12 mg, 0.1 equiv) was added then shaking was continued for 2 days. Reverse phase HPLC (Preparative Method B) gave ethyl 2-[4-({[2-[2-(2,4-difluorophenyl)ethyl]-4-oxo-1(4H)-quinazolinyl]acetyl} {[4′-(trifluoromethyl)-4-biphenylyl]methyl}amino)-1-piperidinyl]-2-methylpropanoate as a white solid (173 mg).
Reaction SMILES: [CH3:1][N:2]([CH3:18])[C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH:9]=[C:8]([C:13]([O:15][CH3:16])=[O:14])[CH:7]=[C:6]2[OH:17].[C:19]1([C:25]([C:29]2[CH:34]=[CH:33][C:32]([N:35]3[CH2:40][CH2:39][CH2:38][CH2:37][CH2:36]3)=[CH:31][CH:30]=2)(O)[C:26]#[CH:27])[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>C1(C)C=CC=CC=1>[CH3:18][N:2]([CH3:1])[C:3]1[CH:4]=[C:5]2[C:10]([CH:9]=[C:8]([C:13]([O:15][CH3:16])=[O:14])[C:7]3[CH:27]=[CH:26][C:25]([C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=4)([C:29]4[CH:34]=[CH:33][C:32]([N:35]5[CH2:40][CH2:39][CH2:38][CH2:37][CH2:36]5)=[CH:31][CH:30]=4)[O:17][C:6]=32)=[CH:11][CH:12]=1
Reactant: COC(=O)c1cc(O)c2cc(N(C)C)ccc2c1
Reactant: C#CC(O)(c1ccccc1)c1ccc(N2CCCCC2)cc1
Solvent: Cc1ccccc1
Product: COC(=O)c1cc2ccc(N(C)C)cc2c2c1C=CC(c1ccccc1)(c1ccc(N3CCCCC3)cc1)O2

Procedure:
A solution of methyl 6-dimethylamino-4-hydroxy-2-naphthoate (5 mmol) and 1-phenyl-1-(4-piperidinophenyl)prop-2-yn-1-ol (5 mmol) in toluene (60 cm3) containing acidic alumina (Brockrmann 1) (5 g) was refluxed for 90 minutes. The cooled solution was filtered and the alumina residue washed well with ethyl acetate (5×40 cm3). Removal of the dried solvent gave a brown gum which was flash chromatographed using 30% ethyl acetate in hexane as the eluent to give an off-white solid. Recrystallisation from ethyl acetate and hexane gave the title compound (m.p. =155-156.5° C.).
Reaction SMILES: [Br:1][C:2]1[CH:9]=[C:8]([OH:10])[CH:7]=[C:6]([OH:11])[C:3]=1[CH:4]=[O:5].[CH2:12]1[CH2:17][O:16][CH:15]=[CH:14][CH2:13]1>ClCCl.CC1C=CC(S([O-])(=O)=O)=CC=1.C1C=C[NH+]=CC=1>[Br:1][C:2]1[CH:9]=[C:8]([O:10][CH:15]2[CH2:14][CH2:13][CH2:12][CH2:17][O:16]2)[CH:7]=[C:6]([OH:11])[C:3]=1[CH:4]=[O:5]
Reactant: O=Cc1c(O)cc(O)cc1Br
Reactant: C1=COCCC1
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Product: O=Cc1c(O)cc(OC2CCCCO2)cc1Br
Yield: 91.2 %

Procedure:
A solution of 2-bromo-4,6-dihydroxy-benzaldehyde (4.69 g, 21.7 mmol) in dichloromethane (100 mL) was treated with DHP (3.94 mL, 43.4 mmol) and PPTS (200 mg) at room temperature for 1 h. The reaction mixture was concentrated to dryness. The residue purified by flash column chromatography (silica, hexanes/ethyl acetate=4:1) to give the title compound (5.96 g, 92%) as a colorless oil. 1H NMR (300 MHz, CDCl3) δ 12.2 (s, 1H), 10.1 (s, 1H), 6.88 (d, J=2.1 Hz, 1H), 6.58 (d, J=2.1 Hz, 1H), 5.56 (s, 1H), 3.84-3.81 (m, 1H), 3.68-3.62 (m, 1H), 1.96-1.54 (m, 6H).
Reaction SMILES: [C:1]([OH:6])(=[O:5])[C:2]([OH:4])=[O:3].[CH3:7][C:8]1[O:32][C:11]2=[C:12]3[O:17][CH:16]([CH2:18][NH:19][CH2:20][CH2:21][CH2:22][NH:23][C:24]4[N:29]=[CH:28][CH:27]=[CH:26][N:25]=4)[CH2:15][CH2:14][C:13]3=[CH:30][CH:31]=[C:10]2[C:9]=1[CH3:33].C(O)(=O)C(O)=O>C(Cl)Cl.CO>[C:1]([OH:6])(=[O:5])[C:2]([OH:4])=[O:3].[N:25]1[CH:26]=[CH:27][CH:28]=[N:29][C:24]=1[NH:23][CH2:22][CH2:21][CH2:20][NH:19][CH2:18][CH:16]1[CH2:15][CH2:14][C:13]2=[CH:30][CH:31]=[C:10]3[CH:9]([CH3:33])[CH:8]([CH3:7])[O:32][C:11]3=[C:12]2[O:17]1
Reactant: Cc1oc2c3c(ccc2c1C)CCC(CNCCCNc1ncccn1)O3
Agent: O=C(O)C(=O)O
Solvent: CO
Solvent: ClCCl
Product: CC1Oc2c(ccc3c2OC(CNCCCNc2ncccn2)CC3)C1C
Yield: 3.3 %

Procedure:
CH2Cl2 /CH3OH 85/15). The desired fractions were collected and the solvent was evaporated. The residue (1.8 g) was dissolved in ethanol and converted into the ethanedioic acid salt (1:2) with ethanedioic acid (0.010 mol). The precipitate was filtered off and dried, yielding 1.1 g (3.3%) (±)-N-2-pyrimidinyl-N'-[(3,6,7,8-tetrahydro-2,3-dimethyl-2H-furo[3,2-h][1]benzopyran-8-yl)methyl]-1,3-propanediamine ethanedioate(1:2); mp. 171.2° C. (comp. 8-a).
Reaction SMILES: [Cl-].[CH2:2]([Al+:6][CH2:7][CH:8]([CH3:10])[CH3:9])[CH:3]([CH3:5])[CH3:4].[CH3:11][N:12]([CH3:24])[C:13]1[CH:14]=[CH:15][CH:16]=[C:17]2[C:22]=1[C:21]([Li])=[CH:20][CH:19]=[CH:18]2>C(OCC)C>[CH3:11][N:12]([CH3:24])[C:13]1[CH:14]=[CH:15][CH:16]=[C:17]2[C:22]=1[C:21]([Al:6]([CH2:7][CH:8]([CH3:10])[CH3:9])[CH2:2][CH:3]([CH3:5])[CH3:4])=[CH:20][CH:19]=[CH:18]2
Reactant: [Li]c1cccc2cccc(N(C)C)c12
Reactant: CC(C)C[Al+]CC(C)C
Agent: [Cl-]
Solvent: CCOCC
Product: CC(C)C[Al](CC(C)C)c1cccc2cccc(N(C)C)c12
Temperature: 25 °C
Reaction time: 24 h
Yield: 70907.1 %

Procedure:
9.5 g (0.048 mmol) of diisobutylaluminium chloride were added dropwise to a suspension, cooled to −40° C., of 12.1 g (0.048 mmol) of [8-(dimethylamino)naphth-1-yl]lithium etherate and 100 ml of diethyl ether in an inert nitrogen atmosphere. After slow warming to room temperature, the mixture was stirred for a further 24 hours in order to complete the reaction. Filtration through a D4 frit and removal of the solvent by distillation gave 10.6 g of [8-(dimethylamino)naphth-1-yl]diisobutylaluminium (71%) as a colourless, oily liquid by fractional distillation from the residue.
Reaction SMILES: [F:1][CH:2]([F:11])[O:3][C:4]1[C:5]([NH2:10])=[N:6][CH:7]=[CH:8][CH:9]=1.[Br:12]N1C(=O)CCC1=O>C(#N)C>[Br:12][C:8]1[CH:9]=[C:4]([O:3][CH:2]([F:1])[F:11])[C:5]([NH2:10])=[N:6][CH:7]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: Nc1ncccc1OC(F)F
Solvent: CC#N
Product: Nc1ncc(Br)cc1OC(F)F
Reaction time: 0.33 h
Yield: 93.2 %

Procedure:
To a solution of 3-(difluoromethoxy)pyridin-2-amine (2.3 g, 14.36 mmol) in acetonitrile (15 mL) was added N-bromosuccinimide (2.61 g, 14.65 mmol) over 3 min at 0° C. The reaction mixture was stirred at the same temperature for another 20 min and subsequently concentrated to dryness in vacuo. The resulting viscous mass was diluted with water and extracted with ethyl acetate (3×60 mL). The combined organic layers were dried over sodium sulfate and concentrated to dryness in vacuo. The resulting residue was purified by column chromatography (silica gel, 100-200 mesh, 20% ethyl acetate in hexane) affording 5-bromo-3-(difluoromethoxy)pyridin-2-amine (3.2 g, 93%): 1H NMR (400 MHz, DMSO-d6) δ 7.89 (s, 1H), 7.51 (s, 1H), 7.16 (t, J=73.6 Hz, 1H), 6.34 (s, 2H).
Reaction SMILES: [NH2:1][C:2]1[C:3]([F:23])=[C:4]([C:10]([C:12]2[CH:13]=[C:14]3[C:19](=[CH:20][CH:21]=2)[N:18]=[CH:17][C:16]([Cl:22])=[N:15]3)=[O:11])[C:5]([F:9])=[C:6]([F:8])[CH:7]=1.[CH2:24]([S:27](Cl)(=[O:29])=[O:28])[CH2:25][CH3:26]>C(Cl)Cl>[Cl:22][C:16]1[CH:17]=[N:18][C:19]2[C:14]([N:15]=1)=[CH:13][C:12]([C:10]([C:4]1[C:3]([F:23])=[C:2]([N:1]([S:27]([CH2:24][CH2:25][CH3:26])(=[O:29])=[O:28])[S:27]([CH2:24][CH2:25][CH3:26])(=[O:29])=[O:28])[CH:7]=[C:6]([F:8])[C:5]=1[F:9])=[O:11])=[CH:21][CH:20]=2
Reactant: Nc1cc(F)c(F)c(C(=O)c2ccc3ncc(Cl)nc3c2)c1F
Reactant: CCCS(=O)(=O)Cl
Solvent: ClCCl
Product: CCCS(=O)(=O)N(c1cc(F)c(F)c(C(=O)c2ccc3ncc(Cl)nc3c2)c1F)S(=O)(=O)CCC
Temperature: 25 °C
Reaction time: 1 h
Yield: 89.1 %

Procedure:
To a solution of (3-amino-2,5,6-trifluorophenyl)(3-chloroquinoxalin-6-yl)methanone (700 mg, 2.0 mmol, 1 eq.) in DCM (35 mL) was added TEA (5.6 mL, 400 mmol, 22 eq.) and propane-1-sulfonyl chloride (2.1 mL, 20 mmol, 10 eq.). The resulting mixture was stirred at rt for 1 h, washed with water and extracted with DCM (20 mL×3). The combined organic layers were dried over Na2SO4, filtered and concentrated. The resulting residue was purified by flash column chromatography (PE/EA=2/1, v/v) to afford N-(3-(3-chloroquinoxaline-6-carbonyl)-2,4,5-trifluorophenyl)-N-(propylsulfonyl)propane-1-sulfonamide (980 mg, 90%).
Reaction SMILES: C([O:5][C:6](=[O:40])[CH2:7][CH2:8][N:9]1[CH2:18][CH2:17][C:16]2[C:11](=[CH:12][CH:13]=[C:14]([C:19]3[O:23][N:22]=[C:21]([C:24]4[CH:29]=[CH:28][C:27]([C:30]5[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=5)=[C:26]([C:36]([F:39])([F:38])[F:37])[CH:25]=4)[N:20]=3)[CH:15]=2)[CH2:10]1)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[F:39][C:36]([F:37])([F:38])[C:26]1[CH:25]=[C:24]([C:21]2[N:20]=[C:19]([C:14]3[CH:15]=[C:16]4[C:11](=[CH:12][CH:13]=3)[CH2:10][N:9]([CH2:8][CH2:7][C:6]([OH:40])=[O:5])[CH2:18][CH2:17]4)[O:23][N:22]=2)[CH:29]=[CH:28][C:27]=1[C:30]1[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=1
Reactant: CC(C)(C)OC(=O)CCN1CCc2cc(-c3nc(-c4ccc(-c5ccccc5)c(C(F)(F)F)c4)no3)ccc2C1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(O)CCN1CCc2cc(-c3nc(-c4ccc(-c5ccccc5)c(C(F)(F)F)c4)no3)ccc2C1
Temperature: 25 °C

Procedure:
To a solution of crude 3-{6-[3-(2-trifluoromethyl-biphenyl-4-yl)-[1,2,4]oxadiazol-5-yl]-3,4-dihydro-1H-isoquinolin-2-yl}-propionic acid tert-butyl ester in CH2Cl2 (1 mL) is added TFA(1 mL). The mixture is stirred at room temperature for an hour. All the solvents are evaporated. The mixture is purified by reverse phase preparative LC/MS to give 3-{6-[3-(2-Trifluoromethyl-biphenyl-4-yl)-[1,2,4]oxadiazol-5-yl]-3,4-dihydro-1H-isoquinolin-2-yl}-propionic acid: 1H NMR (DMSO, 400 MHz) δ 8.52 (s, 1H), 8.38 (d, 1H), 8.15 (s, 1H), 8.10 (d, 1H), 7.68 (d, 1H), 7.50 (m, 4H), 7.38 (m, 2H), 3.20-3.50 (m, 8H), 2.92 (t, 2H), MS (ES+): (494.10, M+1)+.
Reaction SMILES: [CH3:1][N:2]1[CH:7]2[CH2:8][CH2:9][CH:3]1[CH:4]([C:10]#[N:11])[CH2:5][CH2:6]2.[H-].[Al+3].[Li+].[H-].[H-].[H-].O>O1CCCC1>[NH2:11][CH2:10][CH:4]1[CH2:5][CH2:6][CH:7]2[N:2]([CH3:1])[CH:3]1[CH2:9][CH2:8]2
Reactant: CN1C2CCC(C#N)C1CC2
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: CN1C2CCC(CN)C1CC2
Reaction time: 3 h

Procedure:
The nitrile (1.1 g) in tetrahydrofuran (20 ml) was added to lithium aluminium hydride (0.5 g) in tetrahydrofuran (30 ml) and the mixture stirred for three hours. Water (0.5 ml) sodium hydroxide solution (10%) (0.75 ml) and water (1.25 ml) were added successively and the mixture filtered. The filtrate was dried (K2CO3) and evaporated to give crude (D31) (1 g) as an oil.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([N:8]2[CH2:22][CH2:21][C:11]3([CH2:15][NH:14][C@H:13]([C:16]([O:18]CC)=[O:17])[CH2:12]3)[CH2:10][CH2:9]2)[CH:5]=[C:4]([O:23][C@H:24]([C:29]2[CH:34]=[CH:33][C:32]([C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=3)=[CH:31][C:30]=2[N:41]2[CH:45]=[CH:44][C:43]([CH3:46])=[N:42]2)[C:25]([F:28])([F:27])[F:26])[N:3]=1.O.[OH-].[Li+].Cl>C1COCC1.O>[NH2:1][C:2]1[N:7]=[C:6]([N:8]2[CH2:9][CH2:10][C:11]3([CH2:15][NH:14][C@H:13]([C:16]([OH:18])=[O:17])[CH2:12]3)[CH2:21][CH2:22]2)[CH:5]=[C:4]([O:23][C@H:24]([C:29]2[CH:34]=[CH:33][C:32]([C:35]3[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=3)=[CH:31][C:30]=2[N:41]2[CH:45]=[CH:44][C:43]([CH3:46])=[N:42]2)[C:25]([F:28])([F:27])[F:26])[N:3]=1
Reactant: CCOC(=O)[C@@H]1CC2(CCN(c3cc(O[C@H](c4ccc(-c5ccccc5)cc4-n4ccc(C)n4)C(F)(F)F)nc(N)n3)CC2)CN1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: Cc1ccn(-c2cc(-c3ccccc3)ccc2[C@@H](Oc2cc(N3CCC4(CC3)CN[C@H](C(=O)O)C4)nc(N)n2)C(F)(F)F)n1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of (S)-ethyl 8-(2-amino-6-((R)-2,2,2-trifluoro-1-(3-(3-methyl-1H-pyrazol-1-yl)-[1,1′-biphenyl]-4-yl)ethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylate (50 mg, 0.08 mmol) from Step 4 in THF (2.0 mL) and water (0.2 mL), was added lithium hydroxide monohydrate (58 mg, 0.05 mmol). The reaction mixture was stirred at RT for 2 h, then the solution was neutralized with 1 N HCl, and concentrated in vacuo. Purification by normal phase silica gel column (EtOAc/heptane) provided the title compound as an off-white solid as the zwitterionic form.
Reaction SMILES: Br[CH2:2][CH2:3][S:4]([O-:7])(=[O:6])=[O:5].[Na+].[NH2:9][C:10]1[CH:20]=[CH:19][C:13]([C:14]([O:16][CH2:17][CH3:18])=[O:15])=[CH:12][CH:11]=1.Cl>CN(C)P(N(C)C)(N(C)C)=O>[S:4]([CH2:3][CH2:2][NH:9][C:10]1[CH:11]=[CH:12][C:13]([C:14]([O:16][CH2:17][CH3:18])=[O:15])=[CH:19][CH:20]=1)([OH:7])(=[O:6])=[O:5]
Reactant: CCOC(=O)c1ccc(N)cc1
Reactant: O=S(=O)([O-])CCBr
Agent: Cl
Agent: [Na+]
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: CCOC(=O)c1ccc(NCCS(=O)(=O)O)cc1

Procedure:
A solution of 4.1 g. of sodium 2-bromoethanesulfonate and 7.9 g. of ethyl 4-aminobenzoate in 110 ml. of hexamethylphosphoramide is stirred at 125° for 18 hours and then poured into dilute hydrochloric acid. The solid is collected by filtration, dried and recrystallized from acetonitrile to yield ethyl 4-(2-sulfoethylamino)benzoate as a white solid.
Reaction SMILES: [CH2:1]([OH:12])[C@H:2]([C@H:4]([C@@H:6]([C@@H:8]([CH2:10][OH:11])[OH:9])[OH:7])[OH:5])[OH:3].CO[C:15]1[CH:34]=[CH:33][C:18]([C:19](Cl)([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[CH:17][CH:16]=1.C(Cl)Cl>N1C=CC=CC=1>[C:19]([O:11][CH2:10][C@H:8]([C@H:6]([C@@H:4]([C@@H:2]([CH2:1][O:12][C:19]([C:18]1[CH:33]=[CH:34][CH:15]=[CH:16][CH:17]=1)([C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1)[C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1)[OH:3])[OH:5])[OH:7])[OH:9])([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[C:18]1[CH:33]=[CH:34][CH:15]=[CH:16][CH:17]=1
Reactant: COc1ccc(C(Cl)(c2ccccc2)c2ccccc2)cc1
Reactant: OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO
Solvent: c1ccncc1
Solvent: ClCCl
Product: O[C@@H]([C@H](O)[C@H](O)COC(c1ccccc1)(c1ccccc1)c1ccccc1)[C@H](O)COC(c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Yield: 87.4 %

Procedure:
To a flask containing 1 g of D-mannitol (5.49 mmols) and 3.73 g of 4-methoxytrityl chloride (12.07 mmols) were added 26.7 mL anhydrous DCM. Once all material dissolved 13.35 mL of pyridine was added. The reaction mixture was refluxed for 5 hours then allowed to cool to RT overnight. The reaction was quenched with 25 mL of water then extracted 3 times with 7 mL of DCM buffered with 0.1% triethylamine. The organic fractions were combined then washed 3 times with 7 mL of brine. The DCM layers were dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The resulting residue was dissolved in a minimum amount of DCM and subjected to silica gel column chromatographic purification (EtOAc/hexanes) to obtain 3.2 g of the desired product (80% yield). 1H-NMR (500 MHz, CDCl3): δ 7.34 (m, 6H, aromatic), 7.24 (m, 24H, aromatic), 6.71 (m, 4H, aromatic), 3.83 (s, 1H, —OH), 3.72 (s, 6H, CH3), 3.687 (broad peak, 4H, CH2), 3.24 (m, 4H, —CH—), 2.88 (s, 1H, —OH), 2.62 (s, 1H, —OH). Mass spec analysis (MALDI-TOF): exact mass: 726.32, obtained: 749.86 [M+Na]+.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1.[Cl:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[N:15]([CH3:22])[C:16](=[O:21])[CH2:17][CH2:18][C:19]#[CH:20]>>[Cl:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[N:15]([CH3:22])[C:16](=[O:21])[CH2:17][CH2:18][C:19]#[C:20][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1
Reactant: Brc1ccccn1
Reactant: C#CCCC(=O)N(C)c1ccccc1Cl
Product: CN(C(=O)CCC#Cc1ccccn1)c1ccccc1Cl
Yield: 6600 %

Procedure:
The title compound was prepared in accordance with the general method of Example 1, from 2-bromopyridine (157 mg, 1.00 mmol) and pent-4-ynoic acid (2-chloro-phenyl)-methyl-amide (220 mg, 1.00 mmol). The crude residue was purified by flash chromatography (DCM/MeOH 98:2) to yield 20 mg (66 mmol, 7%) of N-(2-chlorophenyl)-N-methyl-5-(pyridin-2-yl)pent-4-ynamide as a brown liquid.
Reaction SMILES: [C:1]([NH:9][CH2:10][C:11]([C:13]1[CH:17]=[CH:16][S:15][CH:14]=1)=[O:12])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].Br[CH2:21][C:22]([O:24][CH2:25][CH3:26])=[O:23]>>[C:1]([NH:9][CH:10]([C:11]([C:13]1[CH:17]=[CH:16][S:15][CH:14]=1)=[O:12])[CH2:21][C:22]([O:24][CH2:25][CH3:26])=[O:23])(=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(CNC(=O)c1ccccc1)c1ccsc1
Reactant: CCOC(=O)CBr
Agent: [H-]
Agent: [Na+]
Product: CCOC(=O)CC(NC(=O)c1ccccc1)C(=O)c1ccsc1
Yield: 66.1 %

Procedure:
4.7 g of N-benzoyl-N-[(3-thienylcarbonyl)methyl]amine, 1.1 g of 50% sodium hydride and 3.9 g of ethyl bromoacetate are treated in the same manner as described in Preparation 1-(4). 4.2 g of ethyl 3-benzoylamino-3-(3-thienylcarbonyl)propionate are thereby obtained.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[F:7][C:8]([F:23])([F:22])[O:9][C:10]1[CH:11]=[C:12]2[C:16](=[CH:17][CH:18]=1)[NH:15][C:14]([C:19](O)=[O:20])=[CH:13]2.[NH3:24]>C1COCC1.CN(C)C=O>[F:7][C:8]([F:23])([F:22])[O:9][C:10]1[CH:11]=[C:12]2[C:16](=[CH:17][CH:18]=1)[NH:15][C:14]([C:19]([NH2:24])=[O:20])=[CH:13]2
Reactant: O=C(O)c1cc2cc(OC(F)(F)F)ccc2[nH]1
Reactant: N
Agent: O=C(Cl)C(=O)Cl
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: NC(=O)c1cc2cc(OC(F)(F)F)ccc2[nH]1
Temperature: 2.5 °C
Reaction time: 0.5 h

Procedure:
Oxalyl chloride (2.63 ml, 30.6 mmol) was added dropwise at 0° C. within 45 min. to a suspension of 5-trifluoromethoxy-1H-indole-2-carboxylic acid (5 g, 20.4 mmol) in THF (20 ml) and N,N-dimethyl formamide (0.5 ml). Stirring was continued at 0-5° C. for 30 min. and thereafter for 3 h at room temperature. The resulting solution was cooled to 0-5° C. again and then added within 15 min. to 75 ml of a 25% aqueous solution of ammonia. After stirring for 30 min. the precipitated amide was collected, washed with water and dried at 40° C. in vacuo yielding 5-trifluoromethoxy-1H-indole-2-carboxylic acid amide as off white solid. Yield 5 g (100%)
Reaction SMILES: [C:1](#[N:4])[CH:2]=[CH2:3].[OH:5][C:6]1([C:16]2[CH:17]=[C:18]([CH3:22])[CH:19]=[CH:20][CH:21]=2)[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[NH:8][C:7]1=[O:15]>>[C:1]([CH2:2][CH2:3][N:8]1[C:9]2[C:14](=[CH:13][CH:12]=[CH:11][CH:10]=2)[C:6]([OH:5])([C:16]2[CH:17]=[C:18]([CH3:22])[CH:19]=[CH:20][CH:21]=2)[C:7]1=[O:15])#[N:4]
Reactant: Cc1cccc(C2(O)C(=O)Nc3ccccc32)c1
Reactant: C=CC#N
Product: Cc1cccc(C2(O)C(=O)N(CCC#N)c3ccccc32)c1

Procedure:
Reaction of acrylonitrile with 3-hydroxy-3-(m-tolyl)indolin- 2-one by a procedure analogous to that of Example 1 gives 1-(2-cyanoethyl)- 3-hydroxy-3-(m-tolyl)indole- 2-one. Hydrogenation of 1-(2-cyanoethyl)-3-hydroxy-3-(m-tolyl) indolin-2-one by a procedure analogous to that of Example 2 gives 1-(3-aminopropyl)-3-hydroxy-3-(m-tolyl)indolin- 2-one. Cyclodehydration of 1-(3-aminopropyl)-3-hydroxy-3-(m-tolyl) indolin -2-one by a procedure analogous to that of Example 3 gives 2,3,4,10-tetrahydro-10-(m-tolyl) pyrimido[ 1,2-a] indol-10-ol.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]#[N:9])[CH:5]=[CH:4][N:3]=1.[CH3:10][N:11]1[CH:15]=[C:14]([Sn](CCCC)(CCCC)CCCC)[N:13]=[CH:12]1>C1(C)C=CC=CC=1>[CH3:10][N:11]1[CH:15]=[C:14]([C:2]2[CH:7]=[C:6]([C:8]#[N:9])[CH:5]=[CH:4][N:3]=2)[N:13]=[CH:12]1
Reactant: CCCC[Sn](CCCC)(CCCC)c1cn(C)cn1
Reactant: N#Cc1ccnc(Cl)c1
Solvent: Cc1ccccc1
Product: Cn1cnc(-c2cc(C#N)ccn2)c1
Temperature: 120 °C
Yield: 62.8 %

Procedure:
To a solution of 2-chloro-4-pyridinenitrile (300 mg, 2.16 mmol) in toluene (10 mL) was added N-methyl-4-(tributylstannyl)imidazole (964 mg, 2.6 mmol), followed by tetrakistriphenylphosphine palladium (0) (150 mg, 0.13 mmol). The reaction mixture was heated at 120° C. in a microwave initiator for 1 hr. The mixture was cooled down to r.t, solid filtered and dried to give 250 mg of 2-(1-methyl-1H-imidazol-4-yl)pyridine-4-carbonitrile as a white solid. Filtrate was purified by flash column chromatography (CH2Cl2/MeOH=20/1) to give additional 100 mg of the product (total 350 mg, 88%). 1H NMR (400 MHz, DMSO-d6): δ 3.73 (3H, s), 7.59 (1H, d, J=4.8 Hz), 7.82 (1H, s), 8.09 (1H, s), 8.72 (1H, d, J=5 Hz). [M+H] Calc'd for C10H8N4, 185. Found, 185.
Reaction SMILES: [C:1]([CH2:3][CH2:4][CH2:5][CH2:6][N:7]1[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[N:9]=[C:8]1[C:16]([CH:18]1[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]1)=[O:17])#[N:2].[C:24]([CH2:28][O:29][CH2:30][CH2:31]Br)([O:26][CH3:27])=[O:25].C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[C:1]([CH2:3][CH2:4][CH2:5][CH2:6][N:7]1[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[N:9]=[C:8]1[C:16]([CH:18]1[CH2:23][CH2:22][N:21]([CH:30]([O:29][CH2:28][C:24]([O:26][CH3:27])=[O:25])[CH3:31])[CH2:20][CH2:19]1)=[O:17])#[N:2]
Reactant: N#CCCCCn1c(C(=O)C2CCNCC2)nc2ccccc21
Reactant: COC(=O)COCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)COC(C)N1CCC(C(=O)c2nc3ccccc3n2CCCCC#N)CC1
Temperature: 90 °C

Procedure:
Mix 1-[(4-cyanobutyl)-1H-benzimidazol-2-yl][1-(4-piperidinyl)]methanone (4.0 g, 12.91 mmol), carbomethoxy methoxy ethylbromide (3.0 g, 15.3 mmol), potassium carbonate (5.29 g, 38.25 mmol) and dimethylformamide (100 mL). Stir and heat and at 90° C. overnight. Allow to cool to room temperature, dilute with water and extract with ethyl acetate (2×). Wash the combined organic phases with water (3×), then brine and dry (MgSO4). Evaporate the solvent in vacuo and purify by chromatography to give the title compound.
Reaction SMILES: N1C=CC=CC=1N.[F:8][C:9]1[CH:10]=[C:11]([NH:15][C:16]2[CH:21]=[C:20]([C:22]3[CH:27]=[CH:26][N:25]=[C:24](NCC(OC)C)[N:23]=3)[CH:19]=[CH:18][N:17]=2)[CH:12]=[CH:13][CH:14]=1.[Cl:34]C1N=C(Cl)C=CN=1>O1CCOCC1.[Cu](I)I.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>[Cl:34][C:24]1[N:23]=[C:22]([C:20]2[CH:19]=[CH:18][N:17]=[C:16]([NH:15][C:11]3[CH:12]=[CH:13][CH:14]=[C:9]([F:8])[CH:10]=3)[CH:21]=2)[CH:27]=[CH:26][N:25]=1
Reactant: COC(C)CNc1nccc(-c2ccnc(Nc3cccc(F)c3)c2)n1
Reactant: Clc1ccnc(Cl)n1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: I[Cu]I
Agent: Nc1ccccn1
Solvent: C1COCCO1
Product: Fc1cccc(Nc2cc(-c3ccnc(Cl)n3)ccn2)c1
Temperature: 25 °C

Procedure:
To a solution of N-(3-fluorophenyl)-4-trimethylstannyl)-2-pyridinamine (i.e., the product of Step B) (4.0 g, 11 mmol) in 1,4-dioxane (100 mL) under nitrogen was added 2,4-dichloropyrimidine (2.26 g, 15 mmol), copper iodide (216 mg, 1.1 mmol) and bis(triphenylphosphine)palladium(II) dichloride (400 mg, 0.57 mmol). The resulting mixture was stirred at reflux for 4 h. After cooling to room temperature, the solution was concentrated under reduced pressure. The resulting residue was purified using column chromatography on silica gel eluted with 25% ethyl acetate in hexanes to afford 2.3 g of title compound as a yellow solid.