Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[NH:9]C(=O)[C:7]2=[O:12].[OH-:13].[Na+].OO.Cl>O>[NH2:9][C:10]1[C:2]([F:1])=[CH:3][CH:4]=[CH:5][C:6]=1[C:7]([OH:12])=[O:13]
Reactant: O=C1Nc2c(F)cccc2C1=O
Reactant: [OH-]
Agent: Cl
Agent: OO
Agent: [Na+]
Solvent: O
Product: Nc1c(F)cccc1C(=O)O
Temperature: 70 °C
Reaction time: 0.17 h

Procedure:
A mixture of 19.27 g of the product of Step B and 197 ml of 10N sodium hydroxide solution was heated to 70° C. with stirring and heating was ceased to add 36.5 ml of 30% hydrogen peroxide over 20 minutes during which the temperature rose to 80° C. and descended to 70° C. At the end of the addition, the mixture was heated to 80° C. and held there for 10 minutes and then was cooled during which a mass formed. The latter was added to 200 ml of water with stirring and the pH was adjusted to 1 by addition of concentrated hydrochloric acid at a temperature less than 20° C. The mixture was stirred for 90 minutes and was vacuum filtered. The product was empasted twice with iced water and dried under reduced pressure at 70° C. The product was crystallized from 100 ml of a 1-1 ethanol-water mixture and 3 ml of acetic acid. The mixture was iced for one hour and was vacuum filtered. The product was empasted with a 1-1 ethanol-water mixture and dried at 70° C. under reduced presssure to obtain 14.8 g of 2-amino-3-fluoro-benzoic acid melting at 188° C.
Reaction SMILES: [C:1]1(=[O:11])[NH:5][C:4](=[O:6])[C@H:3]2[CH2:7][CH:8]=[CH:9][CH2:10][C@@H:2]12.[Na]>CO>[C:1]1(=[O:11])[N:5]([CH2:2][CH2:3][CH2:4][OH:6])[C:4](=[O:6])[C@H:3]2[CH2:7][CH:8]=[CH:9][CH2:10][C@@H:2]12
Reactant: O=C1NC(=O)[C@@H]2CC=CC[C@H]12
Agent: [Na]
Solvent: CO
Product: O=C1[C@H]2CC=CC[C@H]2C(=O)N1CCCO
Temperature: 0 °C

Procedure:
15.1 g. of cis-1,2,3,6-tetrahydrophthalimide are dissolved in 15 ml of methanol in which has previously been dissolved, 2.3 g of sodium metal. The mixture is evaporated to dryness under reduced pressure. 14 g. of 3-bromo-1-propanol are added to the solid, warming occurs. When the heating subsides, 40 ml of dimethylformamide are added with heating under reflux for 6 hours. After cooling, 200 ml of water and 100 ml of methylene chloride are added. The mixture is shaken and the aqueous phase discarded. The organic extract is washed with water (2×50 ml) and the methylene chloride solution is dried over anhydrous sodium sulfate. The solution is concentrated to about 50 ml and hexane added near the cloud point. Cooling to 0° C. precipitates 3-(cis-1,2,3,6-tetrahydrophthalimido)-1-propanol (1b).
Reaction SMILES: [CH2:1]([N:8]1[CH2:14][CH2:13][C:12](=S)[NH:11][CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:16][NH2:17]>CC(O)C.C1COCC1>[CH2:1]([N:8]1[CH2:14][CH2:13]/[C:12](=[N:16]/[NH2:17])/[NH:11][CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: S=C1CCN(Cc2ccccc2)CCN1
Reactant: NN
Solvent: C1CCOC1
Solvent: CC(C)O
Product: N/N=C1/CCN(Cc2ccccc2)CCN1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of the compound from Step A (1.00 g, 4.54 mmol) in 2-propanol (8.0 mL) and THF (20 mL), hydrazine (0.68 g, 21.7 mmol) was added. The mixture was stirred at room temperature overnight. The crude product was concentrated, and the residue purified by preparative TLC (silcia gel, 1:9 10% ammonium hydroxide in methanol:dichloromethane) to yield the desired compound.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7]2[O:8][CH:9]=[CH:10][N:11]=2)[CH:2]=1.Br[C:13]1[N:18]=[C:17]([C:19]2[N:24]=[CH:23][CH:22]=[CH:21][N:20]=2)[CH:16]=[CH:15][CH:14]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7]2[O:8][C:9]([C:13]3[N:18]=[C:17]([C:19]4[N:20]=[CH:21][CH:22]=[CH:23][N:24]=4)[CH:16]=[CH:15][CH:14]=3)=[CH:10][N:11]=2)[CH:2]=1
Reactant: c1cncc(-c2ncco2)c1
Reactant: Brc1cccc(-c2ncccn2)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: c1cnc(-c2cccc(-c3cnc(-c4cccnc4)o3)n2)nc1
Temperature: 120 °C
Reaction time: 16 h

Procedure:
Under argon, 130 mg (0.88 mmol) of 2-(3-pyridinyl)oxazole (Hel. Chim. Acta 1962, 42, 375-381), 175 mg (0.74 mmol) of 2-(6-bromo-2-pyridyl)pyrimidine, 11 mg (0.02 mmol) of [(t-Bu)2P(OH)]2PdCl2 (POPd) and 205 mg (1.48 mmol) of potassium carbonate were initially charged in 5 ml of N,N-dimethylformamide, and the mixture was stirred at 120° C. for 16 hours. For work-up, the reaction mixture was concentrated under reduced pressure and the crude product that remained was purified by chromatography on silica gel (mobile phase: dichloromethane/methanol). This gave 126 mg (54% of theory) of 2-{6-[2-(pyridin-3-yl)-1,3-oxazol-5-yl]pyridin-2-yl}pyrimidine.
Reaction SMILES: [O:1]([C:8]1[CH:13]=[CH:12][C:11]([C:14]2([C:17]([OH:19])=O)[CH2:16][CH2:15]2)=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.Cl.[NH:22]1[CH2:26][CH2:25][C:24]2([C:34]3[CH:33]=[CH:32][N:31]=[CH:30][C:29]=3[C:28](=[O:35])[O:27]2)[CH2:23]1.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C>CN(C)C=O>[O:1]([C:8]1[CH:9]=[CH:10][C:11]([C:14]2([C:17]([N:22]3[CH2:26][CH2:25][C:24]4([C:34]5[CH:33]=[CH:32][N:31]=[CH:30][C:29]=5[C:28](=[O:35])[O:27]4)[CH2:23]3)=[O:19])[CH2:15][CH2:16]2)=[CH:12][CH:13]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)C1(c2ccc(Oc3ccccc3)cc2)CC1
Reactant: O=C1OC2(CCNC2)c2ccncc21
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C1OC2(CCN(C(=O)C3(c4ccc(Oc5ccccc5)cc4)CC3)C2)c2ccncc21
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A mixture of 1-(4-phenoxyphenyl)cyclopropanecarboxylic acid (15 mg, 0.059 mmol), 3H-spiro[furo[3,4-c]pyridine-1,3′-pyrrolidin]-3-one dihydrochloride (16 mg, 0.059 mmol), benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate (27.4 mg, 0.062 mmol), and N,N-diisopropylethylamine (36 ul, 0.21 mmol) in N,N-dimethylformamide (1 ml) was stirred at room temperature for 4 hours. The desired product then was obtained from the mixture by prep-HPLC (6.2 mg, 25%). LCMS: m/z 427.1 (M+H)+; 449.1 (M+Na)+.
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[CH:4][C:3]=1[CH:9](O)[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17].O=P12OP3(OP(OP(O3)(O1)=O)(=O)O2)=O>[Pd]>[F:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17]
Reactant: CCCCCCCCC(O)c1cccc(F)c1F
Agent: [Pd]
Agent: O=P12OP3(=O)OP(=O)(O1)OP(=O)(O2)O3
Product: CCCCCCCCCc1cccc(F)c1F

Procedure:
Quantities: compound from Example 20 (84.6 g, 0.33 mol), phosphorus pentoxide (142 g, 1mol) and 5% palladium-on-charcoal (7 g). The experimental procedure was as described in Example 22.
Reaction SMILES: [NH2:1][NH2:2].C(N(CC)CC)C.[Cl:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]2([C:21](F)=[O:22])[CH2:20][CH2:19][CH2:18]2)=[CH:13][CH:12]=1>C(#N)C>[Cl:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]2([C:21]([NH:1][NH2:2])=[O:22])[CH2:20][CH2:19][CH2:18]2)=[CH:13][CH:12]=1
Reactant: O=C(F)C1(c2ccc(Cl)cc2)CCC1
Reactant: NN
Solvent: CC#N
Solvent: CCN(CC)CC
Product: NNC(=O)C1(c2ccc(Cl)cc2)CCC1
Temperature: 0 °C

Procedure:
Anhydrous hydrazine (2.02 mL, 1.4 eq) was dissolved in acetonitrile (100 μL) and cooled to 0° C. Triethylamine (12.8 mL, 2.0 eq.) was added followed by 1-(4-chlorophenyl)cyclobutanecarbonyl fluoride (10 g, 1.0 eq) in acetonitrile (25 mL). After stirring at room temperature for one hour the acetonitrile was removed by evaporation. Product was obtained after silica gel chromatography.
Reaction SMILES: CS([O:5][CH2:6][C:7]1[C:8]([C:16]2[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][C:17]=2[F:24])=[N:9][S:10][C:11]=1[C:12]([F:15])([F:14])[F:13])(=O)=O.O[C:26]1[C:31]([F:32])=[CH:30][C:29]([CH2:33][CH2:34][C:35]([O:37]CC)=[O:36])=[CH:28][C:27]=1[F:40]>>[F:32][C:31]1[CH:30]=[C:29]([CH2:33][CH2:34][C:35]([OH:37])=[O:36])[CH:28]=[C:27]([F:40])[C:26]=1[O:5][CH2:6][C:7]1[C:8]([C:16]2[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][C:17]=2[F:24])=[N:9][S:10][C:11]=1[C:12]([F:15])([F:14])[F:13]
Reactant: COc1ccc(-c2nsc(C(F)(F)F)c2COS(C)(=O)=O)c(F)c1
Reactant: CCOC(=O)CCc1cc(F)c(O)c(F)c1
Product: COc1ccc(-c2nsc(C(F)(F)F)c2COc2c(F)cc(CCC(=O)O)cc2F)c(F)c1

Procedure:
The title compound was prepared according to the procedure described in Example 1 starting following Step 5 and 6 coupling (3-(2-fluoro-4-methoxyphenyl)-5-(trifluoromethyl)isothiazol-4-yl)methyl methanesulfonate and ethyl 3-(4-hydroxy-3,5-difluorophenyl)propanoate followed by hydrolysis to afford the desired product as an off-white solid. 1H NMR (300 MHz, CD3OD) δ 7.25-7.30 (m, 1H), 6.70-6.83 (m, 4H), 5.15 (s, 2H), 3.87 (s, 3H), 2.82 (t, J=7.8 Hz, 2H), 2.57 (t, J=7.8 Hz, 2H). Mass spectrum (ESI, m/z): Calcd. for C21H17F6NO4S, 490.1 (M−H). found 489.9.
Reaction SMILES: [CH:1]([O:4][C:5]1[CH:14]=[C:13]([C:15]([F:18])([F:17])[F:16])[C:12]2[C:7](=[CH:8][CH:9]=[C:10]3[NH:22][C@H:21]([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=4)[CH2:20][O:19][C:11]3=2)[N:6]=1)([CH3:3])[CH3:2].[BH4-].[Na+]>C(O)(C(F)(F)F)=O>[CH:1]([O:4][C:5]1[CH:14]=[C:13]([C:15]([F:17])([F:16])[F:18])[C:12]2[C:7](=[CH:8][CH:9]=[C:10]3[N:22]([CH2:13][C:15]([F:18])([F:17])[F:16])[C@H:21]([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=4)[CH2:20][O:19][C:11]3=2)[N:6]=1)([CH3:3])[CH3:2]
Reactant: CC(C)Oc1cc(C(F)(F)F)c2c3c(ccc2n1)N[C@H](c1ccccc1)CO3
Agent: [BH4-]
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Product: CC(C)Oc1cc(C(F)(F)F)c2c3c(ccc2n1)N(CC(F)(F)F)[C@H](c1ccccc1)CO3
Yield: 169.7 %

Procedure:
This compound was prepared according to General Method 6 (EXAMPLE 3) from (3R)-3,4-dihydro-8-isopropoxy-3-phenyl-10-(trifluoromethyl)-2H-[1,4]oxazino[2,3-f]quinoline (49.5 mg, 0.127 mmol) and NaBH4 (300 mg, 7.9 mmol) in 5 mL TFA, to afford 50.7 mg (85%) of (3R)-3,4-dihydro-8-isopropoxy-3-phenyl-4-(2,2,2-trifluoroethyl)-10-(trifluoromethyl)-2H-[1,4]oxazino[2,3-f]quinoline, a yellow solid, after column chromatography (1:3 CH2Cl2:hexanes). 1H NMR (400 MHz, CDCl3) δ 7.55–7.10 (m, 8H), 5.50 (septet, 1H, J=6.2), 4,77 (dd, 1H, J=4.4, 3.4), 4.39 (dd, 1H, J=11.0, 3.4), 4.29 (dd, 1H, J=11.0, 4.4), 4.10 (m, 1H), 3.66 (m, 1H), 1.40 (d, 6H, J=6.2).
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([CH:15]=1)=[C:13]([Cl:16])[CH:12]=[C:11]([Cl:17])[C:10]=2[O:18][CH3:19])=O)C.O.[NH2:21][NH2:22]>C(O)C>[Cl:16][C:13]1[CH:12]=[C:11]([Cl:17])[C:10]([O:18][CH3:19])=[C:9]2[C:14]=1[CH:15]=[C:6]([C:4]([NH:21][NH2:22])=[O:3])[CH:7]=[N:8]2
Reactant: CCOC(=O)c1cnc2c(OC)c(Cl)cc(Cl)c2c1
Reactant: NN
Solvent: CCO
Solvent: O
Product: COc1c(Cl)cc(Cl)c2cc(C(=O)NN)cnc12
Yield: 79.5 %

Procedure:
A solution of 5,7-dichloro-8-methoxy-quinoline-3-carboxylic acid ethyl ester 27 (404 mg, 1.35 mmol) and hydrazine monohydrate (1.0 g) in ethanol (10 ml) was heated under reflux for 5 hours. Upon cooling, a white crystalline solid was deposited. This was isolated via filtration, washed with ethanol, and dried, yielding the hydrazide 28 (307 mg, 80%) as a white solid. 1H-NMR (DMSO-d6, 400 MHz): δ 10.32 (br, 1 H), 9.33 (d, J=2.4, 1 H), 8.89 (d, J=2.4, 1 H), 8.02 (s, 1 H), 4.66 (br, 2H), 4.06 (s, 3 H).
Reaction SMILES: C([O:3][C:4](=[O:24])[C:5]([O:15][C:16]1[CH:21]=[CH:20][C:19]([CH3:22])=[C:18]([CH3:23])[CH:17]=1)([CH3:14])[CH2:6][C:7]1[CH:12]=[CH:11][C:10](O)=[CH:9][CH:8]=1)C.[CH3:25][C:26]1[O:30][C:29]([C:31]2[CH:36]=[CH:35][C:34]([C:37]3[S:38][CH:39]=[CH:40][CH:41]=3)=[CH:33][CH:32]=2)=[N:28][C:27]=1[CH2:42][CH2:43][O:44]S(C1C=CC(C)=CC=1)(=O)=O.C([O-])([O-])=O.[K+].[K+].[OH-].[Na+]>C(O)C>[CH3:23][C:18]1[CH:17]=[C:16]([CH:21]=[CH:20][C:19]=1[CH3:22])[O:15][C:5]([CH3:14])([CH2:6][C:7]1[CH:8]=[CH:9][C:10]([O:44][CH2:43][CH2:42][C:27]2[N:28]=[C:29]([C:31]3[CH:32]=[CH:33][C:34]([C:37]4[S:38][CH:39]=[CH:40][CH:41]=4)=[CH:35][CH:36]=3)[O:30][C:26]=2[CH3:25])=[CH:11][CH:12]=1)[C:4]([OH:24])=[O:3]
Reactant: Cc1ccc(S(=O)(=O)OCCc2nc(-c3ccc(-c4cccs4)cc3)oc2C)cc1
Reactant: CCOC(=O)C(C)(Cc1ccc(O)cc1)Oc1ccc(C)c(C)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Agent: [Na+]
Solvent: CCO
Product: Cc1ccc(OC(C)(Cc2ccc(OCCc3nc(-c4ccc(-c5cccs5)cc4)oc3C)cc2)C(=O)O)cc1C

Procedure:
A mixture of 2-(3,4-dimethylphenoxy)-3-(4-hydroxyphenyl)-2-methyl-propionic acid ethyl ester (0.030 mmol), toluene-4-sulfonic acid 2-(5-methyl-2-(4-thiophen-2-yl-phenyl)-oxazol-4-yl)ethyl ester (0.030 mmol) (see Ex. 3, Part B) and 325 mesh K2CO3 (0.084 g, 0.60 mmol) in ethanol (2 mL) was heated to reflux for 24 h under N2. Aqueous 5N NaOH (0.5 mL) and additional ethanol (1 mL) was added to the reaction mixture and it was heated at reflux for an additional 2 h. The reaction was cooled and the solvent removed in vacuo. The residue was acidified with aqueous 1 N HCl (5 mL), extracted with water and CH2Cl2 and the organic layer dried by passing it through a Varian Chem Elut 1003 cartridge. The solvent was removed in vacuo to give 2-(3,4-dimethyl-phenoxy)-2-methyl-3-(4-{2-[5-methyl-2-(4-thiophen-2-yl-phenyl)-oxazol-4-yl]-ethoxy}-phenyl)-propionic acid. 1H NMR (400 MHz, CDCl3) δ 8.16–8.07 (m, 2H), 7.74–7.71 (m, 2H), 7.44–7.35 (m, 2H), 7.18 (d, 2H, J=8.8 Hz), 7.14–7.11 (m, 1H), 7.00 (d, 1H, J=8.4 Hz), 6.83 (d, 2H, J=8.8 Hz), 6.70 (d, 1H, J=2.6 Hz), 6.64 (dd, 1H, J=8.4, 2.6 Hz), 4.31–4.26 (m, 2H), 3.21 and 3.11 (d of Abq, 2H, J=14.0 Hz), 3.12–3.08 (m, 2H), 2.44 (s, 3H), 2.20 (s, 3H), 2.18 (s, 3H), 1.39 (s, 3H). IR (KBr) 3480, 3000, 1716, 1610, 1512, 1250, 1119 cm−1. HRMS (ES+) m/z exact mass calcd for C34H34NO5S 568.2158, found 568.2168.
Reaction SMILES: C[O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[CH:10]=[N:11][NH:12][CH:13]=1.B(Br)(Br)Br>ClCCl>[NH:11]1[CH:10]=[C:9]([C:4]2[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=2[OH:2])[CH:13]=[N:12]1
Reactant: COc1ccccc1-c1cn[nH]c1
Agent: BrB(Br)Br
Solvent: ClCCl
Product: Oc1ccccc1-c1cn[nH]c1
Temperature: 25 °C
Yield: 98 %

Procedure:
To a solution of 4-(2-methoxyphenyl)pyrazole (300 mg, 1.72 mmol) in dichloromethane (13 ml) is added a 1M solution of boron tribromide (3.8 ml) in dichloromethane. The mixture is stirred at room temperature over night then concentrated under reduced pressure. The residue is chromatographed (silica gel, dichloromethane/ethanol 9:1) to give 270 mg of 2-(pyrazol-4-yl)phenol (98%).
Reaction SMILES: [N:1]1([C@H:6]2[CH2:10][CH2:9][CH2:8][C@H:7]2[NH2:11])[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH:12]([C:15]1[CH:23]=[C:22]([C:24]([F:27])([F:26])[F:25])[CH:21]=[CH:20][C:16]=1[C:17](O)=[O:18])([CH3:14])[CH3:13]>>[CH:12]([C:15]1[CH:23]=[C:22]([C:24]([F:25])([F:26])[F:27])[CH:21]=[CH:20][C:16]=1[C:17]([NH:11][CH:7]1[CH2:8][CH2:9][CH2:10][CH:6]1[N:1]1[CH2:2][CH2:3][CH2:4][CH2:5]1)=[O:18])([CH3:14])[CH3:13]
Reactant: N[C@@H]1CCC[C@@H]1N1CCCC1
Reactant: CC(C)c1cc(C(F)(F)F)ccc1C(=O)O
Product: CC(C)c1cc(C(F)(F)F)ccc1C(=O)NC1CCCC1N1CCCC1

Procedure:
The title compound, orange solid, MS: m/e=369.2 [(M+H)+], was prepared in accordance with the general method of example 5 from cis-2-pyrrolidin-1-yl-cyclopentylamine (intermediate Q) and 2-isopropyl-4-trifluoromethyl-benzoic acid (intermediate AH).
Reaction SMILES: Cl.[CH2:2]([O:4][C:5](=[O:9])[CH2:6][NH:7][CH3:8])[CH3:3].C(N(CC)CC)C.[S:17](Cl)([C:20]1[CH:26]=[CH:25][C:23]([CH3:24])=[CH:22][CH:21]=1)(=[O:19])=[O:18]>C(Cl)Cl>[CH3:8][N:7]([S:17]([C:20]1[CH:26]=[CH:25][C:23]([CH3:24])=[CH:22][CH:21]=1)(=[O:19])=[O:18])[CH2:6][C:5]([O:4][CH2:2][CH3:3])=[O:9]
Reactant: CCOC(=O)CNC
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOC(=O)CN(C)S(=O)(=O)c1ccc(C)cc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 105 %

Procedure:
An ice cold suspension of sarcosine ethyl ester hydrochloride salt (3.1 g, 20 mmol) in CH2Cl2 (150 mL) was sequentially treated with triethyl amine (4.45 g, 44 mmol) and tosyl chloride (4.19 g, 22 mmol) and stirred for 1 h, after which time the ice bath was removed, and the reaction was allowed to stir for an additional 1 h. The reaction mixture was then partitioned between water and CH2Cl2 and the organic extract was washed with brine, dried, filtered, and concentrated to give 5.7 g of the title compound as a white solid.
Reaction SMILES: F[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[N+:12]([O-:14])=[O:13])[NH:8][C:7](=[O:15])[N:6]([NH:16][S:17]([CH3:20])(=[O:19])=[O:18])[C:5]2=[O:21].[NH2:22][C@H:23]([C:26]1[CH:31]=[CH:30][C:29]([O:32][CH3:33])=[C:28]([O:34][CH3:35])[CH:27]=1)[CH2:24][OH:25]>>[CH3:35][O:34][C:28]1[CH:27]=[C:26]([C@@H:23]([NH:22][C:2]2[CH:3]=[C:4]3[C:9](=[CH:10][C:11]=2[N+:12]([O-:14])=[O:13])[NH:8][C:7](=[O:15])[N:6]([NH:16][S:17]([CH3:20])(=[O:19])=[O:18])[C:5]3=[O:21])[CH2:24][OH:25])[CH:31]=[CH:30][C:29]=1[O:32][CH3:33]
Reactant: CS(=O)(=O)Nn1c(=O)[nH]c2cc([N+](=O)[O-])c(F)cc2c1=O
Reactant: COc1ccc([C@@H](N)CO)cc1OC
Product: COc1ccc([C@H](CO)Nc2cc3c(=O)n(NS(C)(=O)=O)c(=O)[nH]c3cc2[N+](=O)[O-])cc1OC
Yield: 53 %

Procedure:
N-(6-Fluoro-7-nitro-2,4-dioxo-1,4-dihydro-2H-quinazolin-3-yl)-methanesulfonamide (30 mg, 0.0943 mmol) is reacted with (R)-2-amino-2-(3,4-dimethoxy-phenyl)-ethanol according to the GPA affording 24.8 mg (53%) of a red powder. Rt=3.80 min.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[OH:11][CH:12]([CH:14]([CH2:38][CH2:39][CH2:40][C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1)[C:15]([NH:17][CH:18]([C:20]1[C:21](=[O:37])[NH:22][C:23]([CH2:26][C:27]2[C:36]3[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=3)[CH:30]=[CH:29][CH:28]=2)=[N:24][N:25]=1)[CH3:19])=[O:16])[CH3:13].C(N(C(C)C)C(C)C)C>>[C:12]([CH:14]([CH2:38][CH2:39][CH2:40][C:41]1[CH:42]=[CH:43][CH:44]=[CH:45][CH:46]=1)[C:15]([NH:17][CH:18]([C:20]1[C:21](=[O:37])[NH:22][C:23]([CH2:26][C:27]2[C:36]3[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=3)[CH:30]=[CH:29][CH:28]=2)=[N:24][N:25]=1)[CH3:19])=[O:16])(=[O:11])[CH3:13]
Reactant: CC(NC(=O)C(CCCc1ccccc1)C(C)O)c1nnc(Cc2cccc3ccccc23)[nH]c1=O
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CS(C)=O
Product: CC(=O)C(CCCc1ccccc1)C(=O)NC(C)c1nnc(Cc2cccc3ccccc23)[nH]c1=O

Procedure:
Analogously to Example 40, 310 mg (2.44 mmol) of oxalyl chloride, 239 mg (3.05 mmol) of dimethyl sulphoxide, 740 mg (1.53 mmol) of 2-(1-hydroxyethyl)-N-{1-[3-(1-naphthylmethyl)-5-oxo-4,5-dihydro-1,2,4-triazin-6-yl]ethyl}-5-phenyl-pentanamide and 790 mg (6.11 mmol) of N-ethyldiisopropylamine are reacted to give 2-acetyl-N-{1-[3-(1-naphthylmethyl)-5-oxo-4,5-dihydro-1,2,4-triazin-6-yl]ethyl}-5-phenylpentanamide.
Reaction SMILES: [CH2:1]([O:3][C:4]1[C:5](O)=[N:6][CH:7]=[CH:8][CH:9]=1)[CH3:2].C(N(CC)C1C=CC=CC=1)C.P(Cl)(Cl)([Cl:24])=O>O>[Cl:24][C:5]1[C:4]([O:3][CH2:1][CH3:2])=[CH:9][CH:8]=[CH:7][N:6]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: CCOc1cccnc1O
Solvent: O
Solvent: CCN(CC)c1ccccc1
Product: CCOc1cccnc1Cl
Temperature: 150 °C
Yield: 70.5 %

Procedure:
A mixture of 3-ethoxy-pyridin-2-ol (4.0 g, 28.8 mmol, 1.0 equiv), N,N-diethylaniline (4.61 mL, 4.29 g, 28.8 mmol, 1.0 equiv) and phosphorus oxychloride (2.62 mL, 4.41 g, 28.8 mmol, 1.0 equiv) was heated to 150° C. under microwave irradiation for 20 min. The crude reaction mixture was poured into water (100 mL), the solution adjusted to pH 7 and extracted with dichloromethane (3×100 mL). The combined organic phases were dried over MgSO4, the solvent removed by evaporation under reduced pressure and the crude material purified with column chromatography on silica eluting with hexane/ethyl acetate (4:1) providing 3.2 g (71%) of the title compound. 1H NMR (300 MHz, CDCl3): δ 1.50 (t, J=7.0 Hz, 3H), 4.12 (q, J=7.0 Hz, 2H), 7.18 (d, J=3.2 Hz, 2H), 7.98 (t, J=3.2 Hz, 1H). MS (ISP): 157.7 [M+H]+.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][C:5]([C:21]#[N:22])([C:11]1[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[C:13]([O:19][CH3:20])[CH:12]=1)[C:6]([O:8][CH2:9][CH3:10])=[O:7].[CH3:23][NH:24][CH2:25][CH2:26][C:27]1[CH:37]=[CH:36][C:30]([C:31]([O:33][CH2:34][CH3:35])=[O:32])=[CH:29][CH:28]=1>>[C:21]([C:5]([C:11]1[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[C:13]([O:19][CH3:20])[CH:12]=1)([C:6]([O:8][CH2:9][CH3:10])=[O:7])[CH2:4][CH2:3][CH2:2][N:24]([CH3:23])[CH2:25][CH2:26][C:27]1[CH:37]=[CH:36][C:30]([C:31]([O:33][CH2:34][CH3:35])=[O:32])=[CH:29][CH:28]=1)#[N:22]
Reactant: CCOC(=O)c1ccc(CCNC)cc1
Reactant: CCOC(=O)C(C#N)(CCCBr)c1ccc(OC)c(OC)c1
Product: CCOC(=O)c1ccc(CCN(C)CCCC(C#N)(C(=O)OCC)c2ccc(OC)c(OC)c2)cc1

Procedure:
Reaction of 1c with 2c produced 3q. MS found M+H=497. The oxalate salt of 3q was recrystallized from ethyl acetate; mp 83-84° C.
Reaction SMILES: [CH3:1][C:2]1[C:3](=[O:36])[N:4]2[C:16](=[CH:17][C:18]=1[CH:19]([O:22][C:23](=[O:35])[C:24]([NH:27]C(OC(C)(C)C)=O)([CH3:26])[CH3:25])[CH2:20][CH3:21])[C:7]1=[N:8][C:9]3[C:14]([CH:15]=[C:6]1[CH2:5]2)=[CH:13][CH:12]=[CH:11][CH:10]=3.C(C(O)=O)(F)(F)F>O>[NH2:27][C:24]([CH3:25])([CH3:26])[C:23]([O:22][CH:19]([C:18]1[CH:17]=[C:16]2[N:4]([CH2:5][C:6]3[C:7]2=[N:8][C:9]2[C:14]([CH:15]=3)=[CH:13][CH:12]=[CH:11][CH:10]=2)[C:3](=[O:36])[C:2]=1[CH3:1])[CH2:20][CH3:21])=[O:35]
Reactant: CCC(OC(=O)C(C)(C)NC(=O)OC(C)(C)C)c1cc2n(c(=O)c1C)Cc1cc3ccccc3nc1-2
Solvent: O
Solvent: O=C(O)C(F)(F)F
Product: CCC(OC(=O)C(C)(C)N)c1cc2n(c(=O)c1C)Cc1cc3ccccc3nc1-2

Procedure:
The title compound was prepared according to the procedure in Example 3B except using (±)-8-methyl-7-[1-[[2-[[(1,1-dimethylethoxy)carbonyl]amino]-2-methyl-1-oxopropyl]oxy]propyl]indolizino[1,2-b]quinolin-9(11H)-one. 1H NMR (DMSO-d6) d 8.67 (s, 1H), 8.11 (m, 2H), 7.84 (m, 1H), 7.70 (m, 1H), 7.21 (s, 1H), 5.85 (dd, J=7.9, 5.8 Hz, 1H), 5.25 (s, 2H), 2.24 (s, 3H), 2.1-1.83 (m, 2H), 1.52 (s, 3H), 1.49 (s, 3H), 0.97 (t, J=7.3 Hz, 3H). Anal. Calcd for C23H25N3O3.CF3CO2H.2 H2O: C, 55.45; H, 5.58; N, 7.76. Found: C, 55.85; H, 5.19; N, 7.83.
Reaction SMILES: [O:1]=[C:2]1[C:6]([CH2:7][C@H:8]([NH:16]C(OC(C)(C)C)=O)[C:9]([O:11]C(C)(C)C)=[O:10])=[CH:5][C:4](=[O:24])[NH:3]1>C(C(O)=O)(F)(F)F>[O:1]=[C:2]1[C:6]([CH2:7][C@H:8]([NH2:16])[C:9]([OH:11])=[O:10])=[CH:5][C:4](=[O:24])[NH:3]1
Reactant: CC(C)(C)OC(=O)N[C@@H](CC1=CC(=O)NC1=O)C(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Product: N[C@@H](CC1=CC(=O)NC1=O)C(=O)O
Temperature: 25 °C
Reaction time: 8 h
Yield: 83.5 %

Procedure:
Compound 11 (0.4 g, 1.17 mmol) was dissolved in CF3CO2H and the mixture was stirred at room temperature overnight. The excess CF3CO2H was evaporated under vacuum and the resulting residue was chromatographed on a cationexchange column (AG 50W-X8) with water as the eluting solvent. The fractions containing the product were lyophilized to give 0.18 g (83%) of 2 as a white solid: mp 142° C. dec; [α]D +5° (c 0.5, H2O); 1H NMR (300 MHz, D2O) δ 3.1-3.2 (m, 2 H, CH2), 4.42-4.48 (m, 1 H, α-CH), 6.76 (s, 1 H, HC=C); 13C NMR (75 MHz, D2O) δ 26.02 (CH2), 52.31 (α-C), 130.87 (C=CH), 144.01 (C=CH), 171.89 (C--O), 173.07 (C=O), 173.53 (C=O). Anal. (C7H8N2O4) C, H, N.
Reaction SMILES: [Cl:1][C:2]1[CH:27]=[CH:26][C:5]([CH2:6][NH:7][C:8]([C:10]2[C:11](=[O:25])[C:12]3[CH:20]=[C:19]([C:21]#[C:22][CH2:23][OH:24])[S:18][C:13]=3[N:14]([CH2:16][CH3:17])[CH:15]=2)=[O:9])=[CH:4][CH:3]=1.[C:28]1(=[O:34])[O:33][C:31](=[O:32])[CH2:30][CH2:29]1>N1C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][NH:7][C:8]([C:10]2[C:11](=[O:25])[C:12]3[CH:20]=[C:19]([C:21]#[C:22][CH2:23][O:24][C:28](=[O:34])[CH2:29][CH2:30][C:31]([OH:33])=[O:32])[S:18][C:13]=3[N:14]([CH2:16][CH3:17])[CH:15]=2)=[O:9])=[CH:26][CH:27]=1
Reactant: CCn1cc(C(=O)NCc2ccc(Cl)cc2)c(=O)c2cc(C#CCO)sc21
Reactant: O=C1CCC(=O)O1
Solvent: c1ccncc1
Product: CCn1cc(C(=O)NCc2ccc(Cl)cc2)c(=O)c2cc(C#CCOC(=O)CCC(=O)O)sc21
Temperature: 25 °C
Reaction time: 18 h
Yield: 84 %

Procedure:
To a solution of N-(4-chlorobenzyl)-7-ethyl-2-(3-hydroxy-1-propynyl)-4-oxo-4,7-dihydrothieno[2,3-b]pyridine-5-carboxamide (Example No. 14) (0.200 g) in pyridine (10 mL) is added succinic anhydride (0.639 g). The reaction is stirred at rt for 18 h then at 40° C. for 1 h. The reaction mixture is concentrated in vacuo. The residue is suspended in H2O (25 mL) and stirred for 1 h. An off-white solid is filtered off and recrystallized from ethanol to yield 0.210 g (84%) of the title compound as a pale yellow, crystalline solid.