Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([C:3]1[CH:8]=[CH:7][N:6]=[CH:5][CH:4]=1)=[CH2:2].[Cl-].[NH4+:10]>CO>[N:6]1[CH:7]=[CH:8][C:3]([CH2:1][CH2:2][NH:10][CH2:2][CH2:1][C:3]2[CH:8]=[CH:7][N:6]=[CH:5][CH:4]=2)=[CH:4][CH:5]=1
Reactant: C=Cc1ccncc1
Reactant: [NH4+]
Agent: [Cl-]
Solvent: CO
Product: c1cc(CCNCCc2ccncc2)ccn1
Yield: 37 %

Procedure:
A mixture or 4-vinyl pyridine (10.0 g, 95.1 mmol) and ammonium chloride (5.1 g, 95.1 mmol) was heated to reflux in MeOH (90 ml) under argon for 27 h. The resulting precipitate was filtered and the filtrate was concentrated on rotavap. The resulting residue was dissolved in H2O (200 ml) and basified with 2N NaOH to pH 10.5 and extracted with CH2Cl2 (3×100 ml). The Combined organic extracts were dried (anhydrous MgSO4) and concentrated to a yellow oil which was purified by column chromatography on silica gel (10% MeOH/CH2Cl2) to yield the title compound (4.0 g, 18.5%) as a yellow solid: 1H NMR (400 MHz, DMSO-d6) δ 8.50 (d, 4H), 7.10 (d, 4H), 2.93 (t, 4H), 2.80 (t, 4H), 1.81 (br. 1H); MS (ES) m/e 228.2 [M+H)+.
Reaction SMILES: [C:1]12([C:11]3[CH:30]=[CH:29][C:14]([O:15][CH2:16][C:17]([NH:19][C:20]4[CH:21]=[C:22]([CH:26]=[CH:27][N:28]=4)[C:23]([OH:25])=O)=[O:18])=[CH:13][CH:12]=3)[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.[NH2:31][CH2:32][CH2:33][C:34]1[CH:39]=[CH:38][N:37]=[CH:36][CH:35]=1.C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.CO>CN(C1C=CN=CC=1)C.CN(C=O)C>[C:1]12([C:11]3[CH:30]=[CH:29][C:14]([O:15][CH2:16][C:17]([NH:19][C:20]4[CH:21]=[C:22]([CH:26]=[CH:27][N:28]=4)[C:23]([NH:31][CH2:32][CH2:33][C:34]4[CH:39]=[CH:38][N:37]=[CH:36][CH:35]=4)=[O:25])=[O:18])=[CH:13][CH:12]=3)[CH2:8][CH:7]3[CH2:9][CH:3]([CH2:4][CH:5]([CH2:6]3)[CH2:10]1)[CH2:2]2
Reactant: NCCc1ccncc1
Reactant: O=C(COc1ccc(C23CC4CC(CC(C4)C2)C3)cc1)Nc1cc(C(=O)O)ccn1
Agent: CN(C)c1ccncc1
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: CN(C)C=O
Solvent: CO
Product: O=C(COc1ccc(C23CC4CC(CC(C4)C2)C3)cc1)Nc1cc(C(=O)NCCc2ccncc2)ccn1
Yield: 85.3 %

Procedure:
To solution of 2-[2-(4-adamantan-1-yl-phenoxy)-acetylamino]-isonicotinic acid (40 mg, 0.098 mmol), 4-(2-aminoethyl)pyridine (24.06 mg, 0.196 mmol) and DMAP (24.06 mg, 0.196 mmol) in DMF was added PyBOP (102.4 mg, 0.196 mmol) at room temperature, and stirred. Reaction mixture was poured onto ice cold water, diluted by methanol/MC mixture (10%). The organic phase was separated, sequentially washed with aqueous sodium bicarbonate, brine and water, dried over anhydrous MgSO4, and concentrated. The resultant crude product was purified by PLC (MeOH:MC=1:9) to afford 2-[2-(4-adamantan-1-yl-phenoxy)acetylamino]-N-(2-pyridine-4-yl-ethyl)-isonicotinamide as a colorless solid (42.7 mg, 84% yield).
Reaction SMILES: [N:1]([C:4]1[CH:24]=[CH:23][C:7]([O:8][C:9]2[C:14]([C:15]3[CH:20]=[CH:19][N:18]=[C:17]([S:21][CH3:22])[N:16]=3)=[CH:13][CH:12]=[CH:11][N:10]=2)=[CH:6][CH:5]=1)=[C:2]=S.C1CCC(N=C=NC2CCCCC2)CC1.[F:40][C:41]1[CH:42]=[C:43]([NH2:49])[C:44]([NH2:48])=[CH:45][C:46]=1[F:47].C1COCC1>C(Cl)Cl>[F:40][C:41]1[C:46]([F:47])=[CH:45][C:44]2[NH:48][C:2]([NH:1][C:4]3[CH:24]=[CH:23][C:7]([O:8][C:9]4[C:14]([C:15]5[CH:20]=[CH:19][N:18]=[C:17]([S:21][CH3:22])[N:16]=5)=[CH:13][CH:12]=[CH:11][N:10]=4)=[CH:6][CH:5]=3)=[N:49][C:43]=2[CH:42]=1
Reactant: Nc1cc(F)c(F)cc1N
Reactant: CSc1nccc(-c2cccnc2Oc2ccc(N=C=S)cc2)n1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: ClCCl
Solvent: C1CCOC1
Product: CSc1nccc(-c2cccnc2Oc2ccc(Nc3nc4cc(F)c(F)cc4[nH]3)cc2)n1
Temperature: 70 °C
Reaction time: 4 h

Procedure:
A resealable pressure vial, under nitrogen, was charged with 4-(2-(4-isothiocyanatophenoxy)pyridin-3-yl)-2-(methylthio)pyrimidine (1.12 g, 3.18 mmol), PS-DCC (1.27 mmol/g polymer supported cyclohexyl carbodiimide) (7.50 g, 9.53 mmol), 4,5-difluorobenzene-1,2-diamine (0.69 g, 4.77 mmol), and THF (45 ml, 0.07 M). The vessel was sealed and the reaction mixture stirred at 70° C. for 4 h. The reaction mixture was cooled to RT, diluted with DCM, and filtered over celite. The filtrate was concentrated to afford yellow residue, which was triturated with DCM, filtered, and dried under high vacuum to afford 5,6-difluoro-N-(4-(3-(2-(methylthio)pyrimidin-4-yl)pyridin-2-yloxy)phenyl)-1H-benzo[d]imidazol-2-amine as a tan solid. MS m/z=463.1 [M+H]+. Calc'd for C23H16F2N6OS: 462.48.
Reaction SMILES: CN(C)C[CH2:4][NH:5][C:6]([C@@H:8]([NH:20][C:21]([C:23]1[CH:42]=[CH:41][C:26]2[N:27]([CH:35]3[CH2:40][CH2:39][CH2:38][CH2:37][CH2:36]3)[C:28]([C:30]3[CH:34]=[CH:33][O:32][CH:31]=3)=[N:29][C:25]=2[CH:24]=1)=[O:22])[CH2:9][C:10]1[C:18]2[C:13](=[CH:14][CH:15]=[C:16]([OH:19])[CH:17]=2)[NH:12][CH:11]=1)=[O:7].[CH3:44][N:45]([CH2:47][CH2:48]CN)[CH3:46]>>[CH3:44][N:45]([CH3:46])[CH2:47][CH2:48][CH2:4][NH:5][C:6]([C@@H:8]([NH:20][C:21]([C:23]1[CH:42]=[CH:41][C:26]2[N:27]([CH:35]3[CH2:36][CH2:37][CH2:38][CH2:39][CH2:40]3)[C:28]([C:30]3[CH:34]=[CH:33][O:32][CH:31]=3)=[N:29][C:25]=2[CH:24]=1)=[O:22])[CH2:9][C:10]1[C:18]2[C:13](=[CH:14][CH:15]=[C:16]([OH:19])[CH:17]=2)[NH:12][CH:11]=1)=[O:7]
Reactant: CN(C)CCNC(=O)[C@H](Cc1c[nH]c2ccc(O)cc12)NC(=O)c1ccc2c(c1)nc(-c1ccoc1)n2C1CCCCC1
Reactant: CN(C)CCCN
Product: CN(C)CCCNC(=O)[C@H](Cc1c[nH]c2ccc(O)cc12)NC(=O)c1ccc2c(c1)nc(-c1ccoc1)n2C1CCCCC1

Procedure:
The carboxylic acid of example 133 was coupled to dimethylaminopropylamine under standard TBTU conditions to yield the title compound of example 136.
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][C:7]([C@H:12]([OH:15])[CH2:13][Cl:14])=[CH:8][C:9]=2[Cl:11])[CH2:4][CH2:3]1.C1(Cl)C(Cl)=C(Cl)C(=O)C(=O)C=1Cl>COC(C)(C)C>[Cl:14][CH2:13][C@H:12]([C:7]1[CH:6]=[C:5]2[C:10](=[C:9]([Cl:11])[CH:8]=1)[N:2]([CH3:1])[CH:3]=[CH:4]2)[OH:15]
Reactant: CN1CCc2cc([C@H](O)CCl)cc(Cl)c21
Agent: O=C1C(=O)C(Cl)=C(Cl)C(Cl)=C1Cl
Solvent: COC(C)(C)C
Product: Cn1ccc2cc([C@H](O)CCl)cc(Cl)c21

Procedure:
A solution (S)-N-Methyl-5-(2-chloro-1-hydroxylethyl)-7-chloro-indoline (0.10 mmol) in 100 mL of t-butyl methyl ether is treated with o-chloroanil (0.10 mmol) at ambient temperature. The solution is concentrated and the residue chromatographed over silica gel (1:1 hexane/ethyl acetate) to provide the corresponding indole.
Reaction SMILES: [CH2:1]([O:3][CH2:4][CH2:5][CH2:6][NH:7][CH2:8][C:9]1[CH:14]=[CH:13][C:12]([CH:15]([CH3:17])[CH3:16])=[CH:11][CH:10]=1)[CH3:2].[OH:18][C:19]1[CH:24]=[CH:23][C:22]([CH2:25][CH2:26][C:27](O)=[O:28])=[CH:21][CH:20]=1.F[B-](F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.C(N(C(C)C)CC)(C)C>CN(C=O)C.CCOC(C)=O>[CH2:1]([O:3][CH2:4][CH2:5][CH2:6][N:7]([CH2:8][C:9]1[CH:14]=[CH:13][C:12]([CH:15]([CH3:16])[CH3:17])=[CH:11][CH:10]=1)[C:27](=[O:28])[CH2:26][CH2:25][C:22]1[CH:23]=[CH:24][C:19]([OH:18])=[CH:20][CH:21]=1)[CH3:2]
Reactant: CCOCCCNCc1ccc(C(C)C)cc1
Reactant: O=C(O)CCc1ccc(O)cc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCOCCCN(Cc1ccc(C(C)C)cc1)C(=O)CCc1ccc(O)cc1
Temperature: 0 °C
Reaction time: 8 h
Yield: 108.2 %

Procedure:
N-(3-ethoxypropyl)-N-(4-isopropylbenzyl)amine (0.62 g, 2.65 mmol) was dissolved in DMF (10 ml), 3-(4-hydroxyphenyl)propanoic acid (0.4 g, 2.41 mmol), was added and the mixture was cooled to 0° C. N-[(1H-1,2,3-benzotriazol-1-yloxy)(dimethylamino)-methylene]-N-methylmethanaminium tetrafluoroborate (0.85 g, 2.65 mmol) and diisopropylethylamine (0.65 g, 5.05 mmol) was added. The mixture was allowed to warm to room temperature and stirred overnight. EtOAc (15 ml) was added and the organic phase was washed with two portions of sodium hydrogencarbonate (aq, 10 ml). EtOAc was removed by evaporation and the crude was purified by preparative HPLC (started with acetonitrile/buffer 60/40 and then the acetonitrile concentration was increased to 100%, the buffer was a mixture of acetonitrile/water 10/90 and ammonium acetate (0.1 M, column KR-100-7-C8, 50 mm×250 mm, flow 40 ml/min). The product containing fractions were pooled and the acetonitrile was removed by evaporation. EtOAc (10 ml) was added and the organic phase was washed with two portions of brine and dried (MgSO4). The solvent was removed by evaporation and gave 1.0 gram of N-(3-ethoxypropyl)-3-(4-hydroxyphenyl)-N-(4-isopropylbenzyl)propanamide (yield 75.8%).
Reaction SMILES: [CH3:1][C@@:2]1([NH:24][C:25]([C@H:27]2[CH:42]=[C:41]3[C@@H:30]([CH2:31][C:32]4[C:40]5[C:35](=[CH:36][CH:37]=[CH:38][C:39]=53)[NH:34][CH:33]=4)[N:29]([CH3:43])[CH2:28]2)=[O:26])[O:15][C@:14]2([OH:16])[N:5]([C@@H:6]([CH2:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[C:7]([N:9]3[C@H:13]2[CH2:12][CH2:11][CH2:10]3)=[O:8])[C:3]1=[O:4].[CH3:44][S:45]([OH:48])(=[O:47])=[O:46].C(OCC)C>C(O)C>[CH3:1][C@@:2]1([NH:24][C:25]([C@@H:27]2[CH:42]=[C:41]3[C@H:30]([CH2:31][C:32]4[C:40]5[C:35](=[CH:36][CH:37]=[CH:38][C:39]=53)[NH:34][CH:33]=4)[N:29]([CH3:43])[CH2:28]2)=[O:26])[O:15][C@:14]2([OH:16])[N:5]([C@@H:6]([CH2:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[C:7]([N:9]3[C@H:13]2[CH2:12][CH2:11][CH2:10]3)=[O:8])[C:3]1=[O:4].[CH3:44][S:45]([OH:48])(=[O:47])=[O:46]
Reactant: CN1C[C@@H](C(=O)N[C@]2(C)O[C@@]3(O)[C@@H]4CCCN4C(=O)[C@H](Cc4ccccc4)N3C2=O)C=C2c3cccc4[nH]cc(c34)C[C@H]21
Agent: CS(=O)(=O)O
Solvent: CCO
Solvent: CCOCC
Product: CN1C[C@H](C(=O)N[C@]2(C)O[C@@]3(O)[C@@H]4CCCN4C(=O)[C@H](Cc4ccccc4)N3C2=O)C=C2c3cccc4[nH]cc(c34)C[C@@H]21

Procedure:
Ergotaminine (1.25 g; 2.15 mmoles) was dissolved in absolute ethanol (53 ml), containing methanesulfonic acid (0.16 ml; 2.46 mmoles). The clear solution was poured into absolute diethylether (430 ml). The precipitated salt was filtered off and dried in vacuo. Ergotaminine methanesulfonate (1.3 g; 99.2% of the theory) with a melting point of 184°-187° C. was obtained.
Reaction SMILES: [OH:1][CH:2]([CH2:29][OH:30])[CH2:3][NH:4][C:5]1[CH:12]=[C:11]([N:13]2[C:21]3[CH2:20][C:19]([CH3:23])([CH3:22])[CH2:18][C:17](=[O:24])[C:16]=3[C:15]([C:25]([F:28])([F:27])[F:26])=[N:14]2)[CH:10]=[CH:9][C:6]=1[C:7]#[N:8].[OH-:31].[Na+].OO>CCO.O>[OH:1][CH:2]([CH2:29][OH:30])[CH2:3][NH:4][C:5]1[CH:12]=[C:11]([N:13]2[C:21]3[CH2:20][C:19]([CH3:22])([CH3:23])[CH2:18][C:17](=[O:24])[C:16]=3[C:15]([C:25]([F:27])([F:28])[F:26])=[N:14]2)[CH:10]=[CH:9][C:6]=1[C:7]([NH2:8])=[O:31]
Reactant: [OH-]
Reactant: CC1(C)CC(=O)c2c(C(F)(F)F)nn(-c3ccc(C#N)c(NCC(O)CO)c3)c2C1
Agent: OO
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: CC1(C)CC(=O)c2c(C(F)(F)F)nn(-c3ccc(C(N)=O)c(NCC(O)CO)c3)c2C1
Yield: 29.5 %

Procedure:
2-(2,3-Dihydroxy-propylamino)-4-(6,6-dimethyl-4-oxo-3-trifluoromethyl-4,5,6,7-tetrahydro-indazol-1-yl)-benzonitrile (1.7 g, 4 mmol, 1 eq), NaOH (806 mg, 20 mmol, 5 eq), and H2O2 (3 mL) were dissolved in EtOH-water (4:1) (40 mL). The mixture was microwaved at 120° C. for 15 min, then concentrated to dryness, and purified by flash chromatography, eluted by 10% MeOH in EtOAc to give pure 2-(2,3-Dihydroxy-propylamino)-4-(6,6-dimethyl-4-oxo-3-trifluoromethyl-4,5,6,7-tetrahydro-indazol-1-yl)-benzamide (0.52 g, 29% yield). LCMS (m/z): M+H=441.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([NH:15][C:16]2[C:17]3[CH:25]=[C:24]([C:26]4[O:30][C:29]([CH:31]=O)=[CH:28][CH:27]=4)[N:23]=[CH:22][C:18]=3[N:19]=[CH:20][N:21]=2)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:33][C:34]1[CH:35]=[N:36][CH:37]=[CH:38][CH:39]=1>>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([NH:15][C:16]2[C:17]3[CH:25]=[C:24]([C:26]4[O:30][C:29]([CH2:31][NH:33][C:34]5[CH:35]=[N:36][CH:37]=[CH:38][CH:39]=5)=[CH:28][CH:27]=4)[N:23]=[CH:22][C:18]=3[N:19]=[CH:20][N:21]=2)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Nc1cccnc1
Reactant: O=Cc1ccc(-c2cc3c(Nc4ccc(OCc5ccccc5)cc4)ncnc3cn2)o1
Product: c1ccc(COc2ccc(Nc3ncnc4cnc(-c5ccc(CNc6cccnc6)o5)cc34)cc2)cc1

Procedure:
In an analogous manner to Example 1, 5-(4-(4-Benzyloxy-phenylamino)-pyrido[3,4-d]pyrimidin-6-yl)-furan-2-carbaldehyde and 3-aminopyridine were converted into the title compound; δH [2H6]-DMSO 10.42 (1H, b), 9.08 (1H, s), 8.69 (1H, s), 8.55 (1H, s), 8.09 (1H, d), 7.79 (1H, d), 7.70 (2H, d), 7.52−7.27 (5H, m), 7.16−6.99 (5H, m), 6.52 (2H, m), 5.11 (2H, s), 4.42 (2H, d); m/z 501 (M+1)+.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([CH2:25][C@@H:26]3[CH2:30][CH2:29][CH2:28][N:27]3[C:31](=[O:35])[CH2:32][C:33]#[N:34])[N:9]=[C:10]([C:11]3[CH:16]=[CH:15][C:14]([O:17][C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)=[CH:13][C:12]=3[F:24])[C:3]=12.N1CCCCC1.[CH3:42][C:43]([N:47]1[CH2:52][CH2:51][O:50][CH2:49][CH2:48]1)([CH3:46])[CH:44]=O>C(O)C>[NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([CH2:25][C@@H:26]3[CH2:30][CH2:29][CH2:28][N:27]3[C:31]([C:32](=[CH:42][C:43]([CH3:46])([N:47]3[CH2:52][CH2:51][O:50][CH2:49][CH2:48]3)[CH3:44])[C:33]#[N:34])=[O:35])[N:9]=[C:10]([C:11]3[CH:16]=[CH:15][C:14]([O:17][C:18]4[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=4)=[CH:13][C:12]=3[F:24])[C:3]=12
Reactant: CC(C)(C=O)N1CCOCC1
Reactant: N#CCC(=O)N1CCC[C@H]1Cn1nc(-c2ccc(Oc3ccccc3)cc2F)c2c(N)ncnc21
Solvent: C1CCNCC1
Solvent: CCO
Product: CC(C)(C=C(C#N)C(=O)N1CCC[C@H]1Cn1nc(-c2ccc(Oc3ccccc3)cc2F)c2c(N)ncnc21)N1CCOCC1
Temperature: 105 °C
Yield: 21 %

Procedure:
To a sealed tube was added 3-[(2S)-2-[[4-amino-3-(2-fluoro-4-phenoxy-phenyl)pyrazolo[3,4-d]pyrimidin-1-yl]methyl]pyrrolidin-1-yl]-3-oxo-propanenitrile (900 mg, 1.91 mmol), ethanol (12 mL), piperidine (0.23 mL, 2.29 mmol) and 2-methyl-2-morpholino-propanal (0.49 mL, 2.86 mmol). The tube was sealed and heated to 105° C. for 24 hrs. The mixture was then cooled, concentrated and then dissolved in ethyl acetate (100 mL) and washed with 5% citric acid (100 ml) and then brine. The organic layer was dried (MgSO4), filtered and concentrated. The crude material was purified by Isolera (column size 100 g. Solvent system 4%-8% MeOH/EtOAc) to obtain 245 mg (21% yield) of the title compound. MS (pos. ion) m/z: 611 (M+1).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([CH2:9][CH2:10][CH2:11][CH3:12])=[C:7]([O:13][CH2:14][O:15][CH3:16])[C:6]([O:17][CH3:18])=[C:5]([CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][C:24]2[C:29]([O:30][CH2:31][O:32][CH3:33])=[C:28]([O:34][CH3:35])[CH:27]=[C:26]([O:36][CH2:37][O:38][CH3:39])[C:25]=2[O:40][CH3:41])[C:4]=1[O:42][CH2:43][O:44][CH3:45].Cl[C:47]([O:49][CH2:50][CH3:51])=[O:48]>>[CH3:1][O:2][C:3]1[C:8]([CH2:9][CH2:10][CH2:11][CH3:12])=[C:7]([O:13][CH2:14][O:15][CH3:16])[C:6]([O:17][CH3:18])=[C:5]([CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][C:24]2[C:29]([O:30][CH2:31][O:32][CH3:33])=[C:28]([O:34][CH3:35])[C:27]([C:47]([O:49][CH2:50][CH3:51])=[O:48])=[C:26]([O:36][CH2:37][O:38][CH3:39])[C:25]=2[O:40][CH3:41])[C:4]=1[O:42][CH2:43][O:44][CH3:45]
Reactant: CCCCc1c(OC)c(OCOC)c(CCCCCc2c(OC)c(OCOC)cc(OC)c2OCOC)c(OC)c1OCOC
Reactant: CCOC(=O)Cl
Product: CCCCc1c(OC)c(OCOC)c(CCCCCc2c(OCOC)c(OC)c(C(=O)OCC)c(OCOC)c2OC)c(OC)c1OCOC

Procedure:
By using procedures similar to those described in Example 99, except that 1 g of 1,4-dimethoxy-2,5-bis(methoxymethoxy)-6-butyl-3-{5-[2,5-dimethoxy-3,6-bis(methoxymethoxy)phenyl]pentyl}benzene was reacted with 0.3 ml of ethyl chloroformate in place of oxygen gas, there was obtained 1.3 g of 1,4-dimethoxy-2,5-bis(methoxymethoxy)-6-butyl-3-{5-[2,5-dimethoxy-3,6-bis(methoxymethoxy)-4-(ethoxycarbonyl)phenyl]pentyl}benzene. Colorless oily substance.
Reaction SMILES: [O:1]=P12OP3(OP(OP(O3)(O1)=O)(=O)O2)=O.[C:15]([C:17]1(O)[CH2:22][CH2:21][CH2:20][C:19]([CH3:24])([CH3:23])[CH2:18]1)#[CH:16]>CC1C=CC=CC=1>[CH3:16][C:15]([C:17]1[CH2:18][C:19]([CH3:24])([CH3:23])[CH2:20][CH2:21][CH:22]=1)=[O:1]
Reactant: O=P12OP3(=O)OP(=O)(O1)OP(=O)(O2)O3
Reactant: C#CC1(O)CCCC(C)(C)C1
Solvent: Cc1ccccc1
Product: CC(=O)C1=CCCC(C)(C)C1
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 38.9 %

Procedure:
Phosphorus pentoxide (33.1 g, 233 mmol) was added to a solution of 1-ethynyl-3,3-dimethylcyclohexanol (152 g, 1.00 mol) in MePh (800 ml). The slurry was heated to reflux, and stirred at this temp. for 90 min. The reaction mixture was allowed to cool to room temp., and then poured into ice/water (1:1, 500 ml). The product was extracted with Et2O (2×500 ml), and the combined organic extracts were washed with water (500 ml) and brine (100 ml), dried (Na2SO4) and concentrated under reduced pressure. Silica-gel FC (pentane/Et2O, 9:1, Rf=0.70) provided 13.8 g (9%) of 1-(5′,5′-dimethylcyclohex-1′-enyl)ethanone.
Reaction SMILES: [C:1]1([CH:7]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH2:8][NH:9][C:10]2[N:18]=[C:17]([C:19]#[N:20])[N:16]=[C:15]3[C:11]=2[N:12]=[CH:13][N:14]3C2CCCCO2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl>C(O)C>[C:27]1([CH:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[CH2:8][NH:9][C:10]2[N:18]=[C:17]([C:19]#[N:20])[N:16]=[C:15]3[C:11]=2[N:12]=[CH:13][NH:14]3)[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=1
Reactant: N#Cc1nc(NCC(c2ccccc2)c2ccccc2)c2ncn(C3CCCCO3)c2n1
Agent: Cl
Solvent: CCO
Product: N#Cc1nc(NCC(c2ccccc2)c2ccccc2)c2nc[nH]c2n1
Temperature: 25 °C
Reaction time: 24 h
Yield: 104.8 %

Procedure:
A stirred solution of 6-[(2,2-diphenylethyl)amino]-9-tetrahydro-2H-pyran-2-yl-9H-purine-2-carbonitrile (preparation 9) (17 g, 40.1 mmol) in ethanol (850 ml), was treated with 2 molar hydrochloric acid (50 ml) and the mixture stirred at room temperature for 24 hr. The solvent was then removed under reduced pressure, the residue dissolved in ethanol and the solvent removed under reduced pressure (repeated). The residue was triturated with diethyl ether, the mixture filtered and the collected material washed with diethyl ether and pentane, then dried to afford the title compound as a solid (14.3 g). MS: 341 (MH+)
Reaction SMILES: [NH2:1][C@H:2]([C:10]([OH:12])=[O:11])[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[OH-].[Na+].[C:15](Cl)(=[O:22])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.Cl>CCOCC>[C:15]([NH:1][C@H:2]([C:10]([OH:12])=[O:11])[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)(=[O:22])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: N[C@@H](Cc1ccccc1)C(=O)O
Reactant: O=C(Cl)c1ccccc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCOCC
Product: O=C(N[C@@H](Cc1ccccc1)C(=O)O)c1ccccc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 99.9 %

Procedure:
To a mixture of phenylalanine (500 g, 3.03 mol), 2N aqueous sodium hydroxide solution (4 L) and ether (500 mL) was added dropwise benzoyl chloride (455 mL, 3.93 mol) under ice-cooling over about 55 min. The resulting mixture was stirred at room temperature for 16 h, cooled with ice and acidified with conc. hydrochloric acid to pH 2. The precipitated crystals were extracted with ethyl acetate. The obtained extracts were combined and washed with water, dried over anhydrous sodium sulfate and concentrated to ca. 2 L. Then hexane was added to the resulting suspension. The resulting precipitate was collected by filtration to give 815 g (100%) of N-benzoylphenylalanine.
Reaction SMILES: [CH3:1][C:2]1[S:10][C:9]2[CH:8]([OH:11])[CH2:7][NH:6][CH2:5][C:4]=2[CH:3]=1.[Cl:12][C:13]1[CH:14]=[C:15](F)[CH:16]=[CH:17][C:18]=1[Cl:19]>>[Cl:12][C:13]1[CH:14]=[C:15]([O:11][CH:8]2[CH2:7][NH:6][CH2:5][C:4]3[CH:3]=[C:2]([CH3:1])[S:10][C:9]2=3)[CH:16]=[CH:17][C:18]=1[Cl:19]
Reactant: Fc1ccc(Cl)c(Cl)c1
Reactant: Cc1cc2c(s1)C(O)CNC2
Product: Cc1cc2c(s1)C(Oc1ccc(Cl)c(Cl)c1)CNC2

Procedure:
The same method as in Example 1 was conducted using 2-methyl-4,5,6,7-tetrahydrothieno[3,2-c]pyridin-7-ol (Reference Example 30) instead of 6-methyl-4,5,6,7-tetrahydrothieno[2,3-c]pyridin-4-ol (Reference Example 6) and was conducted using 3,4-dichloro-1-fluorobenzene instead of 1-fluoronaphthalene to give the objective compound.
Reaction SMILES: [F:1][C:2]([F:18])([F:17])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:14]=[CH:13][C:12]([CH2:15][OH:16])=[CH:11][CH:10]=2)=[CH:5][CH:4]=1.N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O.C(P(CCCC)CCCC)CCC.[CH3:50][O:51][C:52](=[O:65])[CH2:53][CH2:54][NH:55][C:56](=[O:64])[C:57]1[CH:62]=[CH:61][C:60](O)=[CH:59][CH:58]=1>C1COCC1.C1(C)C=CC=CC=1>[CH3:50][O:51][C:52](=[O:65])[CH2:53][CH2:54][NH:55][C:56](=[O:64])[C:57]1[CH:62]=[CH:61][C:60]([O:16][CH2:15][C:12]2[CH:13]=[N:14][C:9]([C:6]3[CH:5]=[CH:4][C:3]([C:2]([F:17])([F:1])[F:18])=[CH:8][CH:7]=3)=[CH:10][CH:11]=2)=[CH:59][CH:58]=1
Reactant: COC(=O)CCNC(=O)c1ccc(O)cc1
Reactant: OCc1ccc(-c2ccc(C(F)(F)F)cc2)nc1
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: COC(=O)CCNC(=O)c1ccc(OCc2ccc(-c3ccc(C(F)(F)F)cc3)nc2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of [6-(4-trifluoromethyl-phenyl)-pyridin-3-yl]-methanol (120 mg, 0.47 mmol) in THF (2 mL) and toluene (4 mL) is added 1,1′-(azodicarbonyl)dipiperidine (ADDP, 179.5 mg, 0.71 mmol) at 0° C., followed by the addition of tributylphosphine (0.18 mL, 0.71 mmol) and 3-(4-hydroxy-benzoylamino)-propionic acid methyl ester (127 mg, 0.57 mmol). The reaction mixture is warmed up to room temperature and stirred overnight. The mixture is loaded on silica gel, eluted with hexanes with a gradient from 0% of ethyl acetate to 50% of ethyl acetate giving 3-{4-[6-(4-trifluoromethyl-phenyl)-pyridin-3-ylmethoxy]-benzoylamino}-propionic acid methyl ester. The ester product is taken into ethanol (2 mL), treated with sodium hydroxide (5N aqueous, 1 mL) for 3 h at room temperature. The mixture is concentrated, diluted with ethyl acetate, acidified with 5 N HCl (1.1 mL), extracted with ethyl acetate. The organic layers are dried and concentrated giving 3-{4-[6-(4-Trifluoromethyl-phenyl)-pyridin-3-ylmethoxy]-benzoylamino}-propionic acid (33 mg). MS (ES): 443.2 [M+H]−.
Reaction SMILES: [CH3:1][C:2]([N:5]1[C:9]2[NH:10][C:11](=O)[CH:12]=[C:13]([C:14]([OH:16])=[O:15])[C:8]=2[C:7]([CH3:18])=[N:6]1)([CH3:4])[CH3:3].P(Cl)(Cl)([Cl:21])=O>>[Cl:21][C:11]1[CH:12]=[C:13]([C:14]([OH:16])=[O:15])[C:8]2[C:7]([CH3:18])=[N:6][N:5]([C:2]([CH3:4])([CH3:3])[CH3:1])[C:9]=2[N:10]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: Cc1nn(C(C)(C)C)c2[nH]c(=O)cc(C(=O)O)c12
Product: Cc1nn(C(C)(C)C)c2nc(Cl)cc(C(=O)O)c12
Reaction time: 0.25 h

Procedure:
1-(1,1-Dimethylethyl)-3-methyl-6-oxo-6,7-dihydro-1H-pyrazolo[3,4-b]pyridine-4-carboxylic acid (5.07 g, 20.34 mmol) and phosphorus oxychloride (28.4 ml, 305 mmol) were heated at 100° C. for 16 hours. The contents were concentrated in vacuo. The residue was added to ice water followed by 1N NaOH until basic (pH>10). After stirring for 15 minutes, the mixture was adjusted to pH 3-4 by addition of 1N HCl. The contents were extracted with EtOAc, then washed with water, brine and concentrated in vacuo. The crude product was purified by reverse phase HPLC (40-70% ACN/H2O, 0.1% TFA). The product was collected as a solid, 0.50 g (9%). LCMS E-S (M+H)=268.3 1H NMR (400 MHz, DMSO-d6) δ ppm 1.73 (s, 9H), 2.56 (s, 3H), 7.48 (s, 1H), 14.17 (br. s., 1H).
Reaction SMILES: Cl([O-])=O.[Na+].P([O-])(O)(O)=O.[K+].[F:11][C:12]1[CH:19]=[CH:18][C:17]([CH:20]=[O:21])=[CH:16][C:13]=1[C:14]#[N:15].CC(=CC)C.S(OS([O-])=O)([O-])=[O:28].[Na+].[Na+]>O.C(O)(C)(C)C.C(Cl)Cl>[C:14]([C:13]1[CH:16]=[C:17]([CH:18]=[CH:19][C:12]=1[F:11])[C:20]([OH:28])=[O:21])#[N:15]
Reactant: N#Cc1cc(C=O)ccc1F
Reactant: O=S([O-])OS(=O)[O-]
Agent: CC=C(C)C
Agent: O=P([O-])(O)O
Agent: [K+]
Solvent: CC(C)(C)O
Solvent: ClCCl
Solvent: O
Product: N#Cc1cc(C(=O)O)ccc1F
Temperature: 25 °C
Reaction time: 2 h
Yield: 98.4 %

Procedure:
Sodium chlorite (1.819 g, 20.12 mmol) and potassium dihydrogen phosphate (0.228 g, 1.676 mmol) in water (20.00 ml) was added to 2-fluoro-5-formylbenzonitrile (Aldrich; 1 g, 6.71 mmol) in t-butanol (20 ml), followed by 2-methyl-2-butene (10.06 ml, 20.12 mmol). The resulting mixture was stirred at room temperature for 2 hrs. A solution of 4.5 g of sodium disulfite in water (100 ml) was then added carefully. DCM (150 ml) was added and phases were separated. The aqueous layer was then extracted once more with DCM (150 ml). The combined organic extracts were passed through a phase separation cartridge, concentrated under vacuum and dried in a vacuum oven to give the title compound as a white solid (1.09 g).