Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][NH:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.[CH2:15]=[C:16]1O[C:18](=[O:19])[CH2:17]1.N1C2C(=CC=CC=2)C=CC1=O>C(O)(=O)C.S(=O)(=O)(O)O>[CH3:1][N:2]1[C:3]2[C:8](=[CH:7][CH:6]=[CH:5][C:4]=2[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[C:16]([CH3:15])=[CH:17][C:18]1=[O:19]
Reactant: CNc1ccccc1-c1ccccc1
Reactant: C=C1CC(=O)O1
Agent: O=S(=O)(O)O
Agent: O=c1ccc2ccccc2[nH]1
Solvent: CC(=O)O
Product: Cc1cc(=O)n(C)c2c(-c3ccccc3)cccc12

Procedure:
The starting material is 2-phcnylaniline, which is methylated with potassium carbonate and methyl iodide to obtain N-methyl-2-phenylaniline. The N-methyl-2-phenylaniline is treated with diketene and acid and is cyclized in acetic acid/sulfuric acid as in Example 3 to generate the desired quinolone.
Reaction SMILES: C([O:8][C:9]1[CH:14]=[C:13](/[CH:15]=[CH:16]/[CH:17]2[CH2:26][C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[CH2:19][NH:18]2)[CH:12]=[CH:11][C:10]=1[N:27]1[S:31](=[O:33])(=[O:32])[N:30](CC[Si](C)(C)C)[C:29](=[O:40])[CH2:28]1)C1C=CC=CC=1.[F:41][C:42]([F:54])([F:53])[C:43]1[CH:48]=[CH:47][C:46]([S:49](Cl)(=[O:51])=[O:50])=[CH:45][CH:44]=1>>[OH:8][C:9]1[CH:14]=[C:13]([CH2:15][CH2:16][CH:17]2[CH2:26][C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[CH2:19][N:18]2[S:49]([C:46]2[CH:45]=[CH:44][C:43]([C:42]([F:41])([F:53])[F:54])=[CH:48][CH:47]=2)(=[O:51])=[O:50])[CH:12]=[CH:11][C:10]=1[N:27]1[S:31](=[O:33])(=[O:32])[NH:30][C:29](=[O:40])[CH2:28]1
Reactant: C[Si](C)(C)CCN1C(=O)CN(c2ccc(/C=C/C3Cc4ccccc4CN3)cc2OCc2ccccc2)S1(=O)=O
Reactant: O=S(=O)(Cl)c1ccc(C(F)(F)F)cc1
Product: O=C1CN(c2ccc(CCC3Cc4ccccc4CN3S(=O)(=O)c3ccc(C(F)(F)F)cc3)cc2O)S(=O)(=O)N1

Procedure:
The title compound is prepared from 5-{2-benzyloxy-4-[(E)-2-(1,2,3,4-tetrahydroisoquinolin-3-yl)-vinyl]-phenyl}-1,1-dioxo-2-(2-trimethylsilanylethyl)-1,2,5-thiadiazolidin-3-one and 4-trifluoromethylbenzenesulfonyl chloride analogous to Example 200, steps F, G and H: (M−1)−=546.
Reaction SMILES: [C:1](Cl)(=[O:4])[CH:2]=[CH2:3].C(N(CC)CC)C.[CH3:13][NH:14][CH2:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=1>C(OCC)C>[CH3:13][N:14]([CH2:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=1)[C:1](=[O:4])[CH:2]=[CH2:3]
Reactant: C=CC(=O)Cl
Reactant: CNCCc1ccccn1
Solvent: CCN(CC)CC
Solvent: CCOCC
Product: C=CC(=O)N(C)CCc1ccccn1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Acryloyl chloride (4.52 g, 0.05 mole) was added dropwise to a stirring solution of triethylamine (30 ml) and 2-(β-methylaminoethyl)pyridine (6.81 g, 0.05 mole) in ethyl ether (500 ml). After stirring overnight at room temperature, the white solid was removed by filtration and washed well with ethyl ether. The organic phases were combined, dried over sodium sulfate, filtered then concentrated to dryness to give an orange oil. The structure was confirmed by NMR.
Reaction SMILES: [C:1]([CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][NH:9][C:10](=[S:13])SC)([OH:3])=[O:2].[N-:14]=[N+:15]=[N-:16].[Na+].[OH-].[Na+]>>[C:1]([CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][N:9]1[C:10]([SH:13])=[N:16][N:15]=[N:14]1)([OH:3])=[O:2]
Reactant: [N-]=[N+]=[N-]
Reactant: CSC(=S)NCCCCCC(=O)O
Agent: [Na+]
Agent: [OH-]
Product: O=C(O)CCCCCn1nnnc1S

Procedure:
Reaction of methyl 5-carboxypentyldithiocarbamate with sodium azide and sodium hydroxide as described in Example 7 gave 1-(5-carboxypentyl)tetrazole-5-thiol, m.p. 100°-100.5°.
Reaction SMILES: CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.[CH:23]1([C:28]([OH:30])=O)[CH2:27][CH2:26][CH2:25][CH2:24]1.[NH:31]1[C:39]2[C:34](=[CH:35][CH:36]=[CH:37][CH:38]=2)[C:33]([C:40]2[N:41]=[N:42][N:43]([C:45]3[CH:50]=[CH:49][C:48]([CH2:51][NH2:52])=[CH:47][CH:46]=3)[CH:44]=2)=[N:32]1.CCN(C(C)C)C(C)C>CN(C=O)C.C(Cl)Cl>[NH:31]1[C:39]2[C:34](=[CH:35][CH:36]=[CH:37][CH:38]=2)[C:33]([C:40]2[N:41]=[N:42][N:43]([C:45]3[CH:50]=[CH:49][C:48]([CH2:51][NH:52][C:28]([CH:23]4[CH2:24][CH2:25][CH2:26][CH2:27]4)=[O:30])=[CH:47][CH:46]=3)[CH:44]=2)=[N:32]1
Reactant: O=C(O)C1CCCC1
Reactant: NCc1ccc(-n2cc(-c3n[nH]c4ccccc34)nn2)cc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: O=C(NCc1ccc(-n2cc(-c3n[nH]c4ccccc34)nn2)cc1)C1CCCC1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
TBTU (185 mg; 0.58 mmol; 1.3 eq.) was added to a cooled (0° C.) solution of cyclopentane carboxylic acid (53 μl; 0.49 mmol; 1.1 eq.) in DMF (2.9 mL). After 10 min, a solution of 1-{4-[4-(1H-indazol-3-yl)-1H-1,2,3-triazol-1-yl]phenyl}methanamine (145 mg; 0.44 mmol; 1.0 eq.) and DIEA (174 μl; 1.02 mmol; 2.3 eq.) in DMF (2.9 mL) was added and the reaction mixture was stirred overnight at RT. DCM was added and the reaction mixture was washed with an aqueous saturated solution of NH4Cl and brine. The organic layer was dried over magnesium sulfate, filtered and concentrated. The crude was purified by preparative HPLC to afford the title compound as a white solid. 1H NMR (300 Mz, DMSO-d 6) δ: 13.36 (brs, 1H), 9.28 (s, 1H), 8.41 (t, J=6.0 Hz, 1H), 8.36 (dt, J=8.2 Hz, 1.0 Hz, 1H), 8.00 (d, J=8.6 Hz, 2H), 7.60 (dt, J=8.2 Hz, 1.0 Hz, 1H), 7.49-7.41 (m, 3H); 7.28-7.23 (m, 1H), 4.35 (d, J=6.0 Hz, 2H), 2.70-2.59 (m, 1H), 1.84-1.49 (m, 8H). HPLC (Condition A): Rt 3.59 min (purity 97.6%). MS (ESI+): 387.3, MS (ESI−): 385.4.
Reaction SMILES: [C:1]([C:5]1[CH:31]=[CH:30][C:8]2[NH:9][C:10]([NH:12][C:13]3[C:14]([O:19][C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=4[C:26]([CH3:29])([CH3:28])[CH3:27])=[N:15][CH:16]=[CH:17][CH:18]=3)=[N:11][C:7]=2[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].I[CH3:35]>C1COCC1>[C:1]([C:5]1[CH:31]=[CH:30][C:8]2[N:9]=[C:10]([NH:12][C:13]3[C:14]([O:19][C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=4[C:26]([CH3:29])([CH3:28])[CH3:27])=[N:15][CH:16]=[CH:17][CH:18]=3)[N:11]([CH3:35])[C:7]=2[CH:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CI
Reactant: CC(C)(C)c1ccc2[nH]c(Nc3cccnc3Oc3ccccc3C(C)(C)C)nc2c1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Cn1c(Nc2cccnc2Oc2ccccc2C(C)(C)C)nc2ccc(C(C)(C)C)cc21
Reaction time: 0.17 h

Procedure:
5-tert-Butyl-N-(2-(2-tert-butylphenoxy)pyridine-3-yl)-1H-benzo[d]imidazol-2-amine (Example 6, 50 mg, 0.121 mmol) was dissolved in THF (2 mL). At 0° C., NaH (2.6 mg, 0.109 mmol) was added and the mixture stirred for 10 min. ICH3 (15 mg, 0.109 mmol) was then slowly introduced. The solution turned purple. After 15 min additional stirring, the solvent was removed under vacuum and the crude product was purified by column chromatography on silica gel (eluting with a continuous gradient of MeOH from 0% to 5% in CH2Cl2). tR=6.265 min (Shimadzu Phenomenex S5 ODS 4.6×50 mm Luna 4.6×50 mm; flow rate 2.5 mL/mn; detection at 220 nM; Gradient elution 0% to 100% B over 8 min; (A=10% MeOH, 90% H2O, 0.2% H3PO4 & B=90% MeOH, 10% H2O, 0.2% H3PO4). HRMS (ESI) m/z calcd for C27H32N4O [M+H]+429.2654, found 429.2636.
Reaction SMILES: [OH:1][CH:2]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[C:3]1[NH:4][C:5](=[O:23])[C:6]2[N:11]=[N:10][N:9]([CH:12]([CH3:22])[CH2:13][CH2:14][CH2:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[C:7]=2[N:8]=1.C(N(CC)CC)C>CS(C)=O.ClCCl>[C:2]([C:3]1[NH:4][C:5](=[O:23])[C:6]2[N:11]=[N:10][N:9]([CH:12]([CH3:22])[CH2:13][CH2:14][CH2:15][C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=3)[C:7]=2[N:8]=1)(=[O:1])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: CC(CCCc1ccccc1)n1nnc2c(=O)[nH]c(C(O)c3ccccc3)nc21
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Product: CC(CCCc1ccccc1)n1nnc2c(=O)[nH]c(C(=O)c3ccccc3)nc21
Temperature: 0 °C
Reaction time: 15 h
Yield: 48.3 %

Procedure:
384 mg (0.988 mmol) of 5-(hydroxy-phenyl-methyl)-3-(1-methyl-4-phenyl-butyl)-3,6-dihydro-[1,2,3]triazolo[4,5-d]pyrimidin-7-one are dissolved in a mixture of 3 ml of DMSO and 10 ml of dichloromethane, and the solution is cooled to 0° C. 1.37 ml (9.88 mmol) of triethylamine and 692 mg (4.35 mmol) of pyridine-SO3 complex are added, and the reaction mixture is then stirred at room temperature for 15 hours. For work-up, the mixture is diluted with 100 ml of dichloromethane and the organic phase is washed with 1N HCl and saturated sodium bicarbonate solution and then dried over sodium sulphate. The solvent is removed, and chromatographic purification gives 185 mg (48%) of a solid, m.p.: 105° C.
Reaction SMILES: [OH:1][NH2:2].C([O:5][C:6](=O)[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][N:13]([C:20]1[CH:25]=[C:24]([O:26][CH:27]([CH3:29])[CH3:28])[CH:23]=[CH:22][N:21]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=1)C>CN(C=O)C.CO>[OH:1][NH:2][C:6](=[O:5])[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][N:13]([C:20]1[CH:25]=[C:24]([O:26][CH:27]([CH3:29])[CH3:28])[CH:23]=[CH:22][N:21]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=1
Reactant: NO
Reactant: CCOC(=O)CCCCCCN(c1ccccn1)c1cc(OC(C)C)ccn1
Solvent: CN(C)C=O
Solvent: CO
Product: CC(C)Oc1ccnc(N(CCCCCCC(=O)NO)c2ccccn2)c1
Reaction time: 26 h
Yield: 65 %

Procedure:
HONH2 (50% aqueous, 2 mL) was added to III (23 mg, 0.06 mmol) in DMF (0.5 mL) and MeOH (2 mL) at rt. The reaction mixture was stirred for 26 h, after which the solvents were evaporated under reduced pressure. The resulting residue was dissolved and co-evaporated with toluene (2×2 mL) then was purified by silica gel column chromatography eluting with CH2Cl2/MeOH (100:5 to 100:8) to furnish IV as a colourless oil (14 mg, 65%).
Reaction SMILES: [C:1]([C:5]1[C:6]([O:23]S(C2C=CC(C)=CC=2)(=O)=O)=[N:7][N:8]2[C:13]=1[C:12]([CH3:14])=[N:11][N:10]=[C:9]2[C:15]1[CH:20]=[C:19]([F:21])[CH:18]=[CH:17][C:16]=1[F:22])([CH3:4])([CH3:3])[CH3:2].[CH2:34]([N:36]1[C:40]([CH2:41]O)=[N:39][CH:38]=[N:37]1)[CH3:35].[H-].[Na+].O>CN(C=O)C>[C:1]([C:5]1[C:6]([O:23][CH2:41][C:40]2[N:36]([CH2:34][CH3:35])[N:37]=[CH:38][N:39]=2)=[N:7][N:8]2[C:13]=1[C:12]([CH3:14])=[N:11][N:10]=[C:9]2[C:15]1[CH:20]=[C:19]([F:21])[CH:18]=[CH:17][C:16]=1[F:22])([CH3:4])([CH3:2])[CH3:3]
Reactant: CCn1ncnc1CO
Reactant: Cc1ccc(S(=O)(=O)Oc2nn3c(-c4cc(F)ccc4F)nnc(C)c3c2C(C)(C)C)cc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCn1ncnc1COc1nn2c(-c3cc(F)ccc3F)nnc(C)c2c1C(C)(C)C
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To toluene-4-sulfonic acid 3-tert-butyl-7-(2,5-difluorophenyl)-4-methylpyrazolo[1,5-d][1,2,4]triazin-2-yl ester (0.3 g, 0.636 mmol) and (2-ethyl-2H-[1,2,4]triazol-3-yl)methanol (97.3 mg, 1.2 molar eq; prepared as described in EP-A-170073) in DMF (10 ml) was added sodium hydride (30 mg of a 60% dispersion in mineral oil; 1.2 molar eq) and the mixture was stirred at room temperature for 1 h. Water (150 ml) was added then the solution was extracted with diethyl ether (4×50 ml). The combined ether layers were washed with brine (1×100 ml), dried (Na2SO4), the solvent was removed in vacuo and the residue was purified by flash chromatography on silica gel eluting with 0 to 50% ethyl acetate in dichloromethane. 3-tert-Butyl-7-(2,5-difluorophenyl)-2-(2-ethyl-2H-[1,2,4]triazol-3-ylmethoxy)-4-methylpyrazolo[1,5-d][1,2,4]triazine was isolated as a gum, which solidified upon trituration under diethyl ether/isohexane (10 mg, mp=109° C.). 1H NMR (360 MHz, CDCl3) δ 1.40 (3H, t, J=7.3 Hz), 1.55 (9H, s), 3.08 (3H, s), 4.14 (2H, q, J=7.3 Hz), 5.48 (2H, s), 7.18-7.41 (3H, m), 7.88 (1H, s); MS (ES+) m/e 428 [MH]+.
Reaction SMILES: FC(F)(F)C(O)=O.[Cl:8][C:9]1[CH:14]=[C:13]2[NH:15][C:16](=[O:38])[C:17]3([CH:21]([C:22]4[CH:27]=[CH:26][CH:25]=[C:24]([Cl:28])[C:23]=4[F:29])[CH:20]([C:30]([OH:32])=O)[NH:19][CH:18]3[CH2:33][C:34]([CH3:37])([CH3:36])[CH3:35])[C:12]2=[CH:11][CH:10]=1.C(N(C(C)C)CC)(C)C.C1(P(Cl)(C2C=CC=CC=2)=O)C=CC=CC=1.[NH2:63][C:64]1[CH:65]=[N:66][C:67]([C:70]#[N:71])=[N:68][CH:69]=1>>[C:70]([C:67]1[N:68]=[CH:69][C:64]([NH:63][C:30]([CH:20]2[NH:19][CH:18]([CH2:33][C:34]([CH3:37])([CH3:35])[CH3:36])[C:17]3([C:12]4[C:13](=[CH:14][C:9]([Cl:8])=[CH:10][CH:11]=4)[NH:15][C:16]3=[O:38])[CH:21]2[C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([Cl:28])[C:23]=2[F:29])=[O:32])=[CH:65][N:66]=1)#[N:71]
Reactant: CC(C)(C)CC1NC(C(=O)O)C(c2cccc(Cl)c2F)C12C(=O)Nc1cc(Cl)ccc12
Reactant: N#Cc1ncc(N)cn1
Agent: O=P(Cl)(c1ccccc1)c1ccccc1
Solvent: O=C(O)C(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)CC1NC(C(=O)Nc2cnc(C#N)nc2)C(c2cccc(Cl)c2F)C12C(=O)Nc1cc(Cl)ccc12
Yield: 9.3 %

Procedure:
In a manner similar to the method described in Example 5, rac-(2′S,3′R,4′S,5′R)-6-chloro-4′-(3-chloro-2-fluoro-phenyl)-2′-(2,2-dimethyl-propyl)-2-oxo-1,2-dihydro-spiro[indole-3,3′-pyrrolidine]-5′-carboxylic acid trifluoroacetic acid prepared in Example 4 (0.33 g, 0.57 mmol), was reacted with diisopropylethylamine (0.37 g, 2.9 mmol), diphenylphosphinic chloride (0.27 g, 1.1 mmol), then reacted with 5-aminopyrimidine-2-carbonitrile (Accelachem) (0.1 g, 0.9 mmol) to give rac-(2′S,3′R,4′S,5′R)-6-chloro-4′-(3-chloro-2-fluoro-phenyl)-2′-(2,2-dimethyl-propyl)-2-oxo-1,2-dihydro-spiro[indole-3,3′-pyrrolidine]-5′-carboxylic acid (2-cyano-pyrimidin-5-yl)-amide as a yellow solid (Yield 30 mg, 9%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([C:7]([NH:18][C:19]3[CH:23]=[C:22]([CH3:24])[NH:21][N:20]=3)=[N:8][C:9]([C:13]([O:15]CC)=O)=[N:10]2)=[CH:5][CH:4]=1.[F:25][C:26]1[CH:31]=[CH:30][C:29]([Mg]Br)=[CH:28][CH:27]=1.C1COCC1>CC(N(C)C)=O>[F:25][C:26]1[CH:31]=[CH:30][C:29]([C:13]([C:9]2[N:8]=[C:7]([NH:18][C:19]3[CH:23]=[C:22]([CH3:24])[NH:21][N:20]=3)[C:6]3[C:11](=[CH:12][C:3]([O:2][CH3:1])=[CH:4][CH:5]=3)[N:10]=2)=[O:15])=[CH:28][CH:27]=1
Reactant: CCOC(=O)c1nc(Nc2cc(C)[nH]n2)c2ccc(OC)cc2n1
Reactant: Fc1ccc([Mg]Br)cc1
Solvent: CC(=O)N(C)C
Solvent: C1CCOC1
Product: COc1ccc2c(Nc3cc(C)[nH]n3)nc(C(=O)c3ccc(F)cc3)nc2c1
Yield: 95 %

Procedure:
To ethyl 7-methoxy-4-(5-methyl-1H-pyrazol-3-ylamino)quinazoline-2-carboxylate (379 mg, 1.16 mmol) in dry DMA (16 mL) cooled in a −30° C. bath was added dropwise 1N 4-fluorophenylmagnesium bromide in THF (4.05 mL, 4.05 mmol). After 4 h the reaction mixture was quenched by addition of a saturated ammonium chloride solution. The solution was concentrated and H2O was added. The precipitate was washed with water and diethyl ether to give a yellow solid (415 mg, 95%). 1H NMR (300 MHz, DMSO-d6) δ ppm 2.18 (br. s., 3 H) 3.92 (br. s., 3 H) 6.48 (br. s., 1 H) 7.27 (br. s., 2 H) 7.39 (br. s., 2 H) 8.07 (br. s., 2 H) 8.62 (br. s., 1 H) 10.50 (br. s., 1 H) 12.15 (br. s., 1 H) LC-MS (ESI) m/z 378 (M+H)+.
Reaction SMILES: [Al+3].[Cl-].[Cl-].[Cl-].[CH3:5][C:6]([CH3:18])=[CH:7][C:8]([NH:10][C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([Br:17])[CH:12]=1)=[O:9]>C(Cl)Cl>[CH3:5][C:6]1([CH3:18])[C:16]2[C:11](=[CH:12][C:13]([Br:17])=[CH:14][CH:15]=2)[NH:10][C:8](=[O:9])[CH2:7]1
Reactant: CC(C)=CC(=O)Nc1cccc(Br)c1
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: CC1(C)CC(=O)Nc2cc(Br)ccc21
Temperature: 0 °C
Reaction time: 72 h

Procedure:
Into a 500 ml round-buttom flask was placed 13.52 g (101 mmol) of AlCl3 under nitrogen purge and kept at 0° C. Thereafter, 22.41 g of N-3,3-dimethylacryloyl-3-bromoaniline (Compound 17) in 350 ml CH2Cl2 was slowly added by syringe. The reaction mixture was stirred at 0° C. for 72 h, and thereafter slowly quenched with small chunks of ice-cubes and finally with water. The aqueous layer was washed with CH2Cl2 and the organic layer was dried over Na2SO4. The solvent was evaporated and the residue purified by recrystallization from EtOAc-hexane to give the title compound as off-white solids.
Reaction SMILES: C([O:3][C:4]([C:6]1[N:11]=[C:10]([C:12](OCC)=[O:13])[N:9]=[C:8]([C:17](OCC)=[O:18])[N:7]=1)=O)C.C(O)C.[BH4-].[Na+].[Cl-].[Ca+2].[Cl-]>ClCCl>[OH:18][CH2:17][C:8]1[N:7]=[C:6]([CH2:4][OH:3])[N:11]=[C:10]([CH2:12][OH:13])[N:9]=1
Reactant: CCOC(=O)c1nc(C(=O)OCC)nc(C(=O)OCC)n1
Agent: [BH4-]
Agent: [Ca+2]
Agent: [Cl-]
Solvent: ClCCl
Solvent: CCO
Product: OCc1nc(CO)nc(CO)n1
Temperature: 25 °C

Procedure:
2,4,6-Triethoxycarbonyl-s-triazine (1 g, 3.36 mmol) is dissolved in dichloromethane (15 mL) and absolute ethanol (25 mL) then cooled to 0° C. before sodium borohydride (127 mg, 3.36 mmol) is added. After 15 minutes calcium chloride (373 mg, 2.97 mmol) is added and the reaction mixture is warmed to room temperature. The reaction mixture is dried to a yellow solid and subjected to soxhlet extraction with ethanol. The ethanol is evaporated to a white solid. The product is crystallized from Methanol and water or purified by silica gel flash column chromatography to give the title compound.
Reaction SMILES: [N:1]1([C:6]2[O:7][C:8]3[CH:18]=[C:17]([N:19]([CH3:24])[S:20]([CH3:23])(=[O:22])=[O:21])[C:16](B4OC(C)(C)C(C)(C)O4)=[CH:15][C:9]=3[C:10]=2[C:11]([NH:13][CH3:14])=[O:12])[CH:5]=[CH:4][N:3]=[CH:2]1.Cl[C:35]1[CH:36]=[CH:37][C:38]2[O:51][CH2:50][N:41]3[C:42]4[CH:43]=[CH:44][CH:45]=[C:46]([F:49])[C:47]=4[CH:48]=[C:40]3[C:39]=2[N:52]=1.C([O-])([O-])=O.[K+].[K+].CC(C1C=C(C(C)C)C(C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)=C(C(C)C)C=1)C>O1CCOCC1.O.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[F:49][C:46]1[C:47]2[CH:48]=[C:40]3[C:39]4[N:52]=[C:35]([C:16]5[C:17]([N:19]([CH3:24])[S:20]([CH3:23])(=[O:22])=[O:21])=[CH:18][C:8]6[O:7][C:6]([N:1]7[CH:5]=[CH:4][N:3]=[CH:2]7)=[C:10]([C:11]([NH:13][CH3:14])=[O:12])[C:9]=6[CH:15]=5)[CH:36]=[CH:37][C:38]=4[O:51][CH2:50][N:41]3[C:42]=2[CH:43]=[CH:44][CH:45]=1
Reactant: Fc1cccc2c1cc1n2COc2ccc(Cl)nc2-1
Reactant: CNC(=O)c1c(-n2ccnc2)oc2cc(N(C)S(C)(=O)=O)c(B3OC(C)(C)C(C)(C)O3)cc12
Agent: [Pd]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: O
Solvent: C1COCCO1
Product: CNC(=O)c1c(-n2ccnc2)oc2cc(N(C)S(C)(=O)=O)c(-c3ccc4c(n3)-c3cc5c(F)cccc5n3CO4)cc12
Temperature: 110 °C
Yield: 39.3 %

Procedure:
To a solution of 2-(1H-imidazol-1-yl)-N-methyl-6-(N-methylmethylsulfonamido)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzofuran-3-carboxamide (60 mg, 0.13 mmol), 2-chloro-11-fluoro-6H-pyrido[2′,3′:5,6][1,3]oxazino[3,4-a]indole (42 mg, 0.15 mmol) and K2CO3 (26 mg, 0.19 mmol) in 1,4-dioxane (1 mL) and water (0.01 mL) were added X-Phos (10 mg) and Pd2(dba)3 (10 mg) under nitrogen. The mixture was heated at 110° C. for 3 hours and filtered through the celite pad. The filtrate was extracted with EtOAc and the combined organic phase was washed with brine, dried over Na2SO4 and concentrated in vacuo. The crude product was purified by prep-HPLC to give 5-(11-fluoro-6H-pyrido[2′,3′:5,6][1,3]oxazino[3,4-a]indol-2-yl)-2-(1H-imidazol-1-yl)-N-methyl-6-(N-methylmethylsulfonamido)benzofuran-3-carboxamide (30 mg, yield: 40%). 1H-NMR (400 MHz, CDCl3) δ 8.36 (s, 1H), 8.03 (s, 1H), 7.73 (s, 1H), 7.68 (s, 1H), 7.52 (s, 2H), 7.20˜7.25 (m, 3H), 7.12 (d, J=8.4 Hz, 1H), 6.84˜6.88 (m, 1H), 6.02 (s, 2H), 5.93 (d, J=4.8 Hz, 1H), 3.35 (s, 3H), 3.02 (d, J=4.8 Hz, 3H), 2.78 (s, 3H). MS (M+H)+: 587.
Reaction SMILES: [CH2:1]([N:4]([CH:10]([CH3:13])[CH:11]=O)[C:5](=[O:9])[O:6][CH2:7][CH3:8])[CH:2]=[CH2:3].O.[NH:15]([CH2:17]C(O)=O)[CH3:16]>C1(C)C=CC=CC=1>[CH3:16][N:15]1[CH2:17][CH2:3][CH:2]2[CH:11]1[CH:10]([CH3:13])[N:4]([C:5]([O:6][CH2:7][CH3:8])=[O:9])[CH2:1]2
Reactant: C=CCN(C(=O)OCC)C(C)C=O
Reactant: CNCC(=O)O
Solvent: O
Solvent: Cc1ccccc1
Product: CCOC(=O)N1CC2CCN(C)C2C1C

Procedure:
18.5 g (0.1 mol) of ethyl N-allyl-N-(1-oxoprop -2-yl)-carbamate are heated under reflux overnight in a water separator with 9 g (0.1 mol) of sarcosine in 300 ml of toluene. The mixture is concentrated and the residue is distilled.
Reaction SMILES: [C:1]([O:5][C:6](=[O:23])[CH2:7][C@H:8]([NH:12][C:13]([O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[O:14])[C:9](O)=[O:10])([CH3:4])([CH3:3])[CH3:2].C[N:25]1CCOCC1.[OH-].[NH4+]>C(Cl)Cl>[C:1]([O:5][C:6](=[O:23])[CH2:7][CH:8]([NH:12][C:13]([O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[O:14])[C:9]([NH2:25])=[O:10])([CH3:4])([CH3:3])[CH3:2]
Reactant: CN1CCOCC1
Reactant: CC(C)(C)OC(=O)C[C@H](NC(=O)OCc1ccccc1)C(=O)O
Agent: [NH4+]
Agent: [OH-]
Solvent: ClCCl
Product: CC(C)(C)OC(=O)CC(NC(=O)OCc1ccccc1)C(N)=O
Temperature: -10 °C
Reaction time: 0.5 h
Yield: 95 %

Procedure:
To a solution of (S)-2-benzyloxycarbonylamino-succinic acid-4-tert-butyl ester (20.0 g, 61.9 mmol) in CH2Cl2 (100 mL) at −10° C. in a salt/ice/water bath was added N-methylmorpholine (8.20 mL, 74.20 mmol). This was followed by dropwise addition of isobutyl chlorofomate (9.63 mL, 74.20 mmol), over 20 min. After 30 min of stirring at −10° C., ammonium hydroxide solution (28% w/w ammonia, 100 mL) was added portionwise over 5 min. The reaction mixture was stirred for another 8 h then followed by removal of the CH2Cl2 in vacuo. The remaining solution was extracted with EtOAc. The combined extracts were washed with 100 mL of each of the following: 5% citric acid, saturated NaHCO3, and brine. Drying and removal of solvents under vacuum gave crude oil which crystallized from Et2O/hexanes mixture. 3-benzyloxycarbonylamino-succinamic acid tert-butyl ester was obtained in 95% yield (19.0 g). MS (APCI) m/z 323.2 (M+1).
Reaction SMILES: [CH:1](=O)[CH:2]=[CH:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[CH:11](=[O:16])[CH2:12][CH2:13][CH2:14][CH3:15].[OH-].[Na+]>CO>[CH2:13]([C:12](=[CH:1][CH:2]=[CH:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)[CH:11]=[O:16])[CH2:14][CH3:15]
Reactant: O=CC=Cc1ccccc1
Reactant: CCCCC=O
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CCCC(C=O)=CC=Cc1ccccc1
Reaction time: 2 h
Yield: 68 %

Procedure:
A mixture of cinnamaldehyde (400 g) and valeraldehyde (300 g) was added to a solution of 52 g of NaOH in 1950 g methanol over a period of 2 hours. After the addition is completed, stirring was continued for another 2 hours. The reaction mixture was washed with water, the solvent removed and the resulting product distilled. 412 g 2-n-Propyl-5-phenylpenta-2,4-dienal were obtained as a yellowish oil (content 90%; 60% theoretical yield).
Reaction SMILES: [Br:1][C:2]1[CH2:6][CH:5]([C:7]([O:9]CC)=O)[O:4][N:3]=1.[NH3:12]>CO>[Br:1][C:2]1[CH2:6][CH:5]([C:7]([NH2:12])=[O:9])[O:4][N:3]=1
Reactant: N
Reactant: CCOC(=O)C1CC(Br)=NO1
Solvent: CO
Product: NC(=O)C1CC(Br)=NO1

Procedure:
A mixture of ethyl 3-bromo-4,5-dihydroisoxazole-5-carboxylate (6.2 g, 28 mmol) and a solution of 2 M ammonia in MeOH (56 mL) was stirred at room temperature for 1 to 2 hours. Volatile materials were removed in vacuo to give the crude title compound as a white solid.
Reaction SMILES: [NH2:1][CH:2]1[C:8](=[O:9])[N:7]([CH3:10])[C:6]2[CH:11]=[CH:12][CH:13]=[CH:14][C:5]=2[C:4]2[CH:15]=[CH:16][CH:17]=[CH:18][C:3]1=2.[F:19][C:20]1[CH:21]=[C:22]([CH:34]=[C:35]([F:37])[CH:36]=1)[CH2:23][NH:24][C:25](=[O:33])[CH:26]([CH2:30][CH2:31][CH3:32])[C:27](O)=[O:28]>>[F:19][C:20]1[CH:21]=[C:22]([CH:34]=[C:35]([F:37])[CH:36]=1)[CH2:23][NH:24][C:25](=[O:33])[CH:26]([CH2:30][CH2:31][CH3:32])[C:27]([NH:1][CH:2]1[C:8](=[O:9])[N:7]([CH3:10])[C:6]2[CH:11]=[CH:12][CH:13]=[CH:14][C:5]=2[C:4]2[CH:15]=[CH:16][CH:17]=[CH:18][C:3]1=2)=[O:28]
Reactant: CCCC(C(=O)O)C(=O)NCc1cc(F)cc(F)c1
Reactant: CN1C(=O)C(N)c2ccccc2-c2ccccc21
Product: CCCC(C(=O)NCc1cc(F)cc(F)c1)C(=O)NC1C(=O)N(C)c2ccccc2-c2ccccc21

Procedure:
The title compound, MS: m/e=492.3 (M+H+), was prepared in analogy to example 16 from 7-amino-5-methyl-5H,7H-dibenzo[b,d]azepin-6-one and N-(3,5-difluoro-benzyl)-2-propyl-malonamic acid.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([C:10]([OH:12])=[O:11])=[CH:2]1.[H-].[Na+].[CH2:15](Br)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>CN(C=O)C>[CH2:15]([N:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([C:10]([OH:12])=[O:11])=[CH:2]1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: O=C(O)c1c[nH]c2ccccc12
Reactant: BrCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=C(O)c1cn(Cc2ccccc2)c2ccccc12
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 78.3 %

Procedure:
To a stirred solution of 0.50 g (3.10 mmol) 1H-indole-3-carboxylic acid in 5 ml DMF was added 0.27 g (6.75 mmol) of NaH (60% in oil). The mixture was stirred at RT for 30 min. and then 0.39 ml (3.28 mmol) of benzyl bromid was added. The mixture was stirred an additional hour and then poured onto water and extracted with ethyl acetate. The combined organic phases were dried over Na2SO4 and concentrated in vacuo. Crystallization in Et2O afforded 0.61 g (78%) of 1-benzyl-1H-indole-3-carboxylic acid as a white solid. ES-MS m/e (%): 250 (M−H+).