Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([Li])CCC.[C:6]1([CH2:12][C:13]2[S:14][CH:15]=[CH:16][CH:17]=2)[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.CN(C)[CH:20]=[O:21].[Cl-].[Na+]>CCCCCC.C(OCC)C>[C:6]1([CH2:12][C:13]2[S:14][C:15]([CH:20]=[O:21])=[CH:16][CH:17]=2)[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=1
Reactant: c1ccc(Cc2cccs2)cc1
Reactant: CN(C)C=O
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [Na+]
Solvent: CCOCC
Solvent: CCCCCC
Product: O=Cc1ccc(Cc2ccccc2)s1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 86.8 %

Procedure:
Under a nitrogen atmosphere, 25.7 grams (0.40 mole) of n-butyllithium in 168 ml of hexane was added by syringe to 300 ml of diethyl ether. The stirred solution was cooled in an ice-water bath and 70.0 grams (0.40 mole) of 2-(phenylmethyl)thiophene in 100 ml of diethyl ether was added dropwise during a 0.75 hour period. Upon complete addition, the cooling bath was removed and the reaction mixture stirred for 1.5 hours, then transferred to a Morton flask using a nitrogen pressure differential and tubing connecting the reaction vessel with the Morton flask. A solution of 32.3 grams (0.44 mole) of dimethylformamide in 200 ml of diethyl ether was added dropwise. During the addition the reaction mixture was allowed to warm to reflux temperature, then was stirred for 4.5 hours while cooling to ambient temperature. Stirring was continued for an additional 16 hours. The reaction mixture was poured into 400 grams of ice, and solid sodium chloride was added to saturation. After an additional 0.25 hour stirring, the organic layer was separated and the aqueous layer was extracted with two portions of 400 ml each of diethyl ether. The extracts and the organic layer above were combined and washed, in succession, with one portion of 300 ml of a saturated aqueous solution of sodium chloride, one portion of 300 ml of aqueous 2 N hydrochloric acid, one portion of 300 ml of a saturated aqueous solution of sodium chloride, one portion of 300 ml of a saturated aqueous solution of sodium bicarbonate, and finally, one portion of 300 ml of a saturated aqueous solution of sodium chloride. The organic layer was dried with magnesium sulfate, filtered and the filtrate concentrated under reduced pressure to give a residual oil. The residual oil was distilled under reduced pressure using a Kugelrohr distilling system to give 70.2 grams of 5-(phenylmethyl)thiophene-2-carboxaldehyde; b.p. 105° C./0.25 mm.
Reaction SMILES: N1C2C(=CC=CC=2)C=C1.C([N:17]1[C:29]2[C:28]([O:30][CH2:31][CH2:32][CH2:33]Br)=[C:27]3[N:35](C(OC(C)(C)C)=O)[C:36]4[CH:37]=[CH:38][C:39]([Br:42])=[CH:40][C:41]=4[C:26]3=[CH:25][C:24]=2[C:23]2[C:18]1=[CH:19][CH:20]=[C:21]([Br:50])[CH:22]=2)(OC(C)(C)C)=O.[NH:51]1[CH2:56][CH2:55][O:54][CH2:53][CH2:52]1>>[Br:50][C:21]1[CH:22]=[C:23]2[C:18](=[CH:19][CH:20]=1)[NH:17][C:29]1[C:28]([O:30][CH2:31][CH2:32][CH2:33][N:51]3[CH2:56][CH2:55][O:54][CH2:53][CH2:52]3)=[C:27]3[NH:35][C:36]4[CH:37]=[CH:38][C:39]([Br:42])=[CH:40][C:41]=4[C:26]3=[CH:25][C:24]2=1
Reactant: CC(C)(C)OC(=O)n1c2ccc(Br)cc2c2cc3c4cc(Br)ccc4n(C(=O)OC(C)(C)C)c3c(OCCCBr)c21
Reactant: C1COCCN1
Agent: c1ccc2[nH]ccc2c1
Product: Brc1ccc2[nH]c3c(OCCCN4CCOCC4)c4[nH]c5ccc(Br)cc5c4cc3c2c1

Procedure:
The title compound was prepared in a manner analogous to Example 70 except the starting indole is 5,7-diBOC-2,10-dibromo-6-(3-bromopropoxy)indolo[2,3-b]carbazole and the reagent is morpholine. 1H-NMR (400 MHz, DMSO-d6) δ ppm 11.28 (s, 2 H), 8.67 (s, 1 H), 8.28 (d, J=2.0 Hz, 2H), 7.51-7.40 (m, 4 H), 4.30 (t, J=6.6 Hz, 2 H), 3.56 (t, J=4.6 Hz, 4 H), 2.52 (t, J=7.2 Hz, 2 H), 2.44-2.32 (m, 4 H), 2.11-2.00 (m, 2 H); MS (ESI) m/z 556.0 (M−H)−
Reaction SMILES: [CH3:1][NH:2][C:3](=[O:23])[C:4]1[CH:9]=[C:8]([O:10][C:11]2[CH:22]=[CH:21][C:14]3[N:15]=[C:16](S(C)=O)[S:17][C:13]=3[CH:12]=2)[CH:7]=[CH:6][N:5]=1.[CH3:24][N:25]1[CH2:30][CH2:29][N:28]([CH2:31][C:32]2[CH:37]=[CH:36][C:35]([CH2:38][NH2:39])=[CH:34][CH:33]=2)[CH2:27][CH2:26]1.CCN(C(C)C)C(C)C>CN1C(=O)CCC1>[CH3:1][NH:2][C:3](=[O:23])[C:4]1[CH:9]=[C:8]([O:10][C:11]2[CH:22]=[CH:21][C:14]3[N:15]=[C:16]([NH:39][CH2:38][C:35]4[CH:34]=[CH:33][C:32]([CH2:31][N:28]5[CH2:27][CH2:26][N:25]([CH3:24])[CH2:30][CH2:29]5)=[CH:37][CH:36]=4)[S:17][C:13]=3[CH:12]=2)[CH:7]=[CH:6][N:5]=1
Reactant: CN1CCN(Cc2ccc(CN)cc2)CC1
Reactant: CNC(=O)c1cc(Oc2ccc3nc(S(C)=O)sc3c2)ccn1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN1CCCC1=O
Product: CNC(=O)c1cc(Oc2ccc3nc(NCc4ccc(CN5CCN(C)CC5)cc4)sc3c2)ccn1
Temperature: 80 °C

Procedure:
To the solution of N-methyl-4-(2-(methylsulfinyl)benzo[d]thiazol-6-yloxy)picolinamide (25 mg, 0.072 mmol, 1.0 eq) in 2 mL of NMP was added (4-((4-methylpiperazin-1-yl)methyl)phenyl)methanamine (23 mg, 0.108 mmol, 1.5 eq) and DIPEA (37 μL, 0.216 mmol, 3.0 eq) and reaction mixture heated at 80° C. in oil bath for 12 hours. Thereafter, the product was purified via reverse phase HPLC. LC/MS (m/z) [503.1] (MH+).
Reaction SMILES: Br[C:2]1[C:7]([Br:8])=[CH:6][CH:5]=[CH:4][N:3]=1.[NH2:9][NH2:10].C(N(CC)CC)C.[C:18](Cl)(=[O:20])[CH3:19]>O1CCOCC1>[Br:8][C:7]1[C:2]([NH:9][NH:10][C:18](=[O:20])[CH3:19])=[N:3][CH:4]=[CH:5][CH:6]=1
Reactant: Brc1cccnc1Br
Reactant: NN
Reactant: CC(=O)Cl
Solvent: CCN(CC)CC
Solvent: C1COCCO1
Product: CC(=O)NNc1ncccc1Br
Temperature: 85 °C
Yield: 28.8 %

Procedure:
To a solution of 0.800 g (3.38 mmol) of 2,3-dibromopyridine in 10 mL of anhydrous 1,4-dioxane was added 0.325 g (10.1 mmol) of anhydrous hydrazine and the resulting mixture was heated to 85° C. for 8 h. The reaction mixture was cooled to ambient temperature then evaporated to dryness in vacuo. The crude residue was dissolved in anhydrous dichloromethane and cooled to −78° C. in a dry ice acetone bath under an atmosphere of nitrogen. Next, 1.0 mL (6.8 mmol) of triethylamine was added followed by 0.210 g (2.72 mmol) of acetyl chloride. The resulting mixture was allowed to warm to ambient temperature over 20 min then all volatiles were removed in vacuo. The residue was suspended in 20 mL of water and extracted with ethyl acetate (3×10 mL). The combined extracts were washed with brine, dried over magnesium sulfate, filtered and evaporated to afford the title compound (0.18 g, 23%). LC-MS: m/z (ES) 230, 232 (MH)+ and 188, 190 (MH—COCH3)+.
Reaction SMILES: C[O:2][C:3](=[O:14])[C:4]1[CH:9]=[C:8]([F:10])[C:7]([O:11][CH3:12])=[C:6]([Br:13])[CH:5]=1.[OH-].[Li+]>C1COCC1.O>[Br:13][C:6]1[CH:5]=[C:4]([CH:9]=[C:8]([F:10])[C:7]=1[O:11][CH3:12])[C:3]([OH:14])=[O:2]
Reactant: COC(=O)c1cc(F)c(OC)c(Br)c1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: COc1c(F)cc(C(=O)O)cc1Br
Reaction time: 72 h
Yield: 52.8 %

Procedure:
5.8 g of the product obtained in step 2 were dissolved in 100 ml of a mixture of THF and water (9:1), 1.06 g (44.1 mmol) of lithium hydroxide were added and the mixture was stirred for 3 days. The solvent was evaporated and the residue was purified by preparative RP HPLC (water/ACN gradient). 2.9 g of the title compound were obtained.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH:13]([CH2:17][CH:18]2[CH2:22][CH2:21][CH2:20][CH2:19]2)[C:14]([OH:16])=O)[CH:6]=[CH:7][C:8]=1[S:9]([CH3:12])(=[O:11])=[O:10])#[N:2].C(Cl)(=O)C(Cl)=O.[NH2:29][C:30]1[CH:35]=[CH:34][N:33]=[C:32]([CH3:36])[N:31]=1.C(N(CC)CC)C>C(Cl)Cl.CN(C)C=O>[C:1]([C:3]1[CH:4]=[C:5]([CH:13]([CH2:17][CH:18]2[CH2:22][CH2:21][CH2:20][CH2:19]2)[C:14]([NH:29][C:30]2[CH:35]=[CH:34][N:33]=[C:32]([CH3:36])[N:31]=2)=[O:16])[CH:6]=[CH:7][C:8]=1[S:9]([CH3:12])(=[O:11])=[O:10])#[N:2]
Reactant: Cc1nccc(N)n1
Reactant: CS(=O)(=O)c1ccc(C(CC2CCCC2)C(=O)O)cc1C#N
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: CN(C)C=O
Product: Cc1nccc(NC(=O)C(CC2CCCC2)c2ccc(S(C)(=O)=O)c(C#N)c2)n1
Temperature: 0 °C
Reaction time: 1 h
Yield: 5.8 %

Procedure:
A solution of 2-(3-cyano-4-methanesulfonyl-phenyl)-3-cyclopentyl-propionic acid (prepared as in Example 75, 200 mg, 0.622 mmol) in methylene chloride (5 mL) was treated with N,N-dimethylformamide (2 drops) and then cooled to 0° C. The reaction mixture was then treated with oxalyl chloride (0.081 mL, 0.933 mmol). The resulting reaction mixture was allowed to warm to 25° C. where it was stirred for 1 h. The reaction mixture was then concentrated in vacuo. The resulting yellow gel was diluted with methylene chloride (2 mL) and then slowly added to a mixture of 4-amino-2-methylpyrimidine (102 mg, 0.933 mmol) and triethylamine (0.173 mL, 1.24 mmol) in N,N-dimethylformamide (3 mL). The resulting reaction mixture was stirred at 25° C. for 24 h. The crude reaction mixture was directly purified by Biotage chromatography (FLASH 40S, Silica, 19/1 methylene chloride/methanol) to afford 2-(3-cyano-4-methanesulfonyl-phenyl)-3-cyclopentyl-N-(2-methyl-pyrimidin-4-yl)-propionamide (15 mg, 6%) as a white foam: mp 89-94° C. (foam to gel); EI-HRMS m/e calcd for C21H24N4O3S (M+) 412.1569, found 412.1568.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[C:10]([C:17]([OH:19])=O)=[CH:11][N:12]([CH3:16])[C:13](=[O:15])[CH:14]=2)=[C:4]([F:20])[CH:3]=1.CCN=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1.[CH:43]1([CH2:46][O:47][NH2:48])[CH2:45][CH2:44]1.CCN(CC)CC>CN(C=O)C.CCOC(C)=O>[CH:43]1([CH2:46][O:47][NH:48][C:17]([C:10]2[C:9]([NH:8][C:5]3[CH:6]=[CH:7][C:2]([Br:1])=[CH:3][C:4]=3[F:20])=[CH:14][C:13](=[O:15])[N:12]([CH3:16])[CH:11]=2)=[O:19])[CH2:45][CH2:44]1
Reactant: Cn1cc(C(=O)O)c(Nc2ccc(Br)cc2F)cc1=O
Reactant: NOCC1CC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: Cn1cc(C(=O)NOCC2CC2)c(Nc2ccc(Br)cc2F)cc1=O
Reaction time: 0.5 h
Yield: 88.4 %

Procedure:
A mixture of 4-(4-bromo-2-fluorophenylamino)-1-methyl-6-oxo-1,6-dihydropyridine-3-carboxylic acid (0.078 g, 0.229 mmol), EDCl (0.13 g, 0.69 mmol), and HOBt (0.093 g, 0.69 mmol) in DMF (5 mL) was stirred for 30 minutes. O-Cyclopropylmethyl-hydroxylamine (0.060 g, 0.69 mmol) was added followed by Et3N (0.096 mL, 0.69 mmol). After 1 hour, the reaction mixture was diluted with EtOAc and washed with saturated NH4Cl solution, saturated NaHCO3 solution and brine. The organic layer was dried (MgSO4) and concentrated to yield 83 mg (89%) clean desired product. MS APCI (+) m/z 410, 412 (M+, Br pattern) detected; 1H NMR (400 mHz, DMSO-d6) δ 11.57 (s, 1H), 9.42 (s, 1H), 8.10 (s, 1H), 7.67 (d, 1H), 7.43 (m, 2H), 3.70 (d, 2H), 3.35 (s, 3H), 1.11 (m, 1H), 0.54 (m, 2H), 0.27 (m, 2H).
Reaction SMILES: [CH3:1][N:2]([CH:10]1[CH2:15][CH2:14][N:13]([CH3:16])[CH2:12][CH2:11]1)[C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([NH2:9])[N:4]=1.[O:17]1[CH:21]=[CH:20][CH:19]=[C:18]1[C:22]([Cl:24])=[O:23]>N1C=CC=CC=1>[ClH:24].[CH3:1][N:2]([CH:10]1[CH2:15][CH2:14][N:13]([CH3:16])[CH2:12][CH2:11]1)[C:3]1[N:4]=[C:5]([NH:9][C:22]([C:18]2[O:17][CH:21]=[CH:20][CH:19]=2)=[O:23])[CH:6]=[CH:7][CH:8]=1
Reactant: O=C(Cl)c1ccco1
Reactant: CN1CCC(N(C)c2cccc(N)n2)CC1
Solvent: c1ccncc1
Product: CN1CCC(N(C)c2cccc(NC(=O)c3ccco3)n2)CC1
Product: Cl
Yield: 87.2 %

Procedure:
Prepare according to procedure in Example 69 starting with N-methyl-N-(1-methyl-piperidin-4-yl)-pyridine-2,6-diamine (Preparation 34, 175 mg, 0.794 mmol), 2-furoyl chloride (117 μL, 1.19 mmol), and pyridine (15 mL) to yield 243 mg (87%) of the title compound: mass spectrum (ion spray): m/z=315.1 (M+1); Analysis calc'd for C17H23N4O2Cl.0.2H2O: C, 57.60; H, 6.65; N, 15.81. Found: C, 57.31; H, 6.72; N, 15.81. mp 116–9° C.
Reaction SMILES: [C:1]1([C:7]2[N:8]=[C:9]([C:12]([OH:14])=O)[S:10][CH:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl.CN(C)CCCN=C=NCC.[CH3:27][O:28][C:29](=[O:39])[C@H:30]([CH2:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)[NH2:31]>CN(C=O)C>[CH3:27][O:28][C:29](=[O:39])[CH:30]([NH:31][C:12]([C:9]1[S:10][CH:11]=[C:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[N:8]=1)=[O:14])[CH2:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1
Reactant: COC(=O)[C@@H](N)Cc1ccccc1
Reactant: O=C(O)c1nc(-c2ccccc2)cs1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CN(C)C=O
Product: COC(=O)C(Cc1ccccc1)NC(=O)c1nc(-c2ccccc2)cs1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a suspension of 4-Phenyl-thiazole-2-carboxylic acid (100 mg, 0.4 mmol) and 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (0.44 mmol) in DMF (4 mL) at 25° C. was added phenylalanine methyl ester (72 mg, 0.4 mmol), the resulting mixture was stirring at 25° C. for overnight and concentrated in vacuo, and the residue was dissolved in CH2Cl2 (20 mL) was washed with 5% NaHCO3, dried with MgSO4 and concentrated in vacuo. The residue was purified by HPLC. The product was obtained 92 mg (61%) as white solid.
Reaction SMILES: Br[CH:2]([C:16](=O)[CH3:17])[CH2:3][CH2:4][N:5]1[C:13](=[O:14])[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6]1=[O:15].[C:19]([NH2:27])(=[NH:26])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[CH3:17][C:16]1[NH:27][C:19]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[N:26][C:2]=1[CH2:3][CH2:4][N:5]1[C:13](=[O:14])[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6]1=[O:15]
Reactant: CC(=O)C(Br)CCN1C(=O)c2ccccc2C1=O
Reactant: N=C(N)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1[nH]c(-c2ccccc2)nc1CCN1C(=O)c2ccccc2C1=O
Temperature: 80 °C
Reaction time: 4 h
Yield: 41.5 %

Procedure:
To a solution of 2-(3-bromo-4-oxo-pentyl)-isoindole-1,3-dione (12.4 g) [CAS 112357-34-3] in abs. DMF (50 ml) was added benzamidine 85% (5.65 g) and potassium carbonate (11.03 g). The reaction mixture was stirred at 80° C. for 4 h, concentrated under vacuum. To the residue was added ice/water, and the mixture was extracted with ethyl acetate. The organic phase was washed with water and brine, dried over magnesium sulphate and concentrated. The crude product was purified by chromatography on silica gel using methylene chloride/methanol 5% and 10% as eluent to obtain 2-[2-(5-methyl-2-phenyl-1H-imidazol-4-yl)-ethyl]-isoindole-1,3-dione (5.5 g) as a yellow foam.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:14](=[O:15])[N:13]2[CH2:16][CH2:17][N:18]([CH:19]([CH3:21])[CH3:20])[C:12]2=[N:11][C:10]=1[C:22](O)=[O:23])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[F:26][C:27]1[CH:34]=[CH:33][C:30]([CH2:31][NH2:32])=[C:29]([S:35](=[O:40])(=[O:39])[N:36]([CH3:38])[CH3:37])[CH:28]=1>>[F:26][C:27]1[CH:34]=[CH:33][C:30]([CH2:31][NH:32][C:22]([C:10]2[N:11]=[C:12]3[N:18]([CH:19]([CH3:21])[CH3:20])[CH2:17][CH2:16][N:13]3[C:14](=[O:15])[C:9]=2[O:8][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[O:23])=[C:29]([S:35](=[O:39])(=[O:40])[N:36]([CH3:38])[CH3:37])[CH:28]=1
Reactant: CC(C)N1CCn2c1nc(C(=O)O)c(OCc1ccccc1)c2=O
Reactant: CN(C)S(=O)(=O)c1cc(F)ccc1CN
Agent: Cl
Product: CC(C)N1CCn2c1nc(C(=O)NCc1ccc(F)cc1S(=O)(=O)N(C)C)c(OCc1ccccc1)c2=O
Yield: 77.7 %

Procedure:
Coupling of 6-(benzyloxy)-1-isopropyl-5-oxo-1,2,3,5-tetrahydroimidazo[1,2-a]pyrimidine-7-carboxylic acid (0.150 g, 0.45 mmol) and 4-fluoro-2-(N,N-dimethylsulfamoyl)benzylamine hydrochloride (0.147 g, 0.55 mmol) as described for the synthesis of intermediate 3 gave 0.190 g (75% yield) of the title amide as white crystals; mp 161-163° C. (ethyl acetate-hexane). 1HNMR 400 MHz (CDCl3) δ (ppm): 1.23 (6H, d, J=6.9 Hz, 2×CH3), 2.85 (6H, s, 2×NCH3), 3.65 (2H, t, J=9 Hz, CH2),4.12 (2H, t, J=9 Hz, CH2),4.40 (1H, m, CH), 4.81 (2H, d, J=6.6 Hz, NCH2), 5.13 (2H, s, OCH2), 7.22 (1H, m, aromatic), 7.28-7.34 (3H, m, aromatics), 7.49-7.52 (2H, m, aromatics), 7.55 (1H, dd, J=2.6 Hz and J=8.6 Hz, aromatic), 7.71 (1H, dd, J=5.6 Hz and J=8.6 Hz, aromatic), 8.26 (1H, broad t, NH). Anal. Calcd for C26H30FN5O5S: C, 57.44; H, 5.56; N, 12.88. Found: C, 57.40; H, 5.46; N, 12.85.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:8]([I:11])=[CH:7][C:3]=1[C:4](O)=[O:5].[CH:12]([NH2:14])=O>O>[I:11][C:8]1[CH:7]=[C:3]2[C:2](=[CH:10][CH:9]=1)[N:1]=[CH:12][NH:14][C:4]2=[O:5]
Reactant: Nc1ccc(I)cc1C(=O)O
Reactant: NC=O
Solvent: O
Product: O=c1[nH]cnc2ccc(I)cc12
Temperature: 25 °C
Yield: 81 %

Procedure:
A solution of 2-amino-5-iodobenzoic acid (14.2 g, 50 mmol) and formamide (100 mL) was refluxed for 10 hours. After cooling to room temperature, water (100 mL) was added. The solid product was collected by filtration, washed with water. Further drying in a vacuum provided 6-Iodo-4-quinazolinone (11 g, 81%) as a gray solid.
Reaction SMILES: [F:1][C:2]1[C:3](F)=[C:4]2[O:9][CH2:8][CH:7](C)[N:6]3[CH:11]=[C:12]([C:17]([OH:19])=[O:18])[C:13](=[O:16])[C:14]([CH:15]=1)=[C:5]23.[NH:21]1[CH2:25][CH2:24][CH:23]([CH2:26][NH2:27])[CH2:22]1.[C:28](#N)C>>[NH2:27][CH2:26][CH:23]1[CH2:24][CH2:25][N:21]([C:3]2[C:2]([F:1])=[CH:15][C:14]3[C:13](=[O:16])[C:12]([C:17]([OH:19])=[O:18])=[CH:11][N:6]4[CH2:7][CH:8]([CH3:28])[O:9][C:4]=2[C:5]=34)[CH2:22]1
Reactant: CC1COc2c(F)c(F)cc3c(=O)c(C(=O)O)cn1c23
Reactant: CC#N
Reactant: NCC1CCNC1
Product: CC1Cn2cc(C(=O)O)c(=O)c3cc(F)c(N4CCC(CN)C4)c(c32)O1

Procedure:
0.75 g (0.27 mmole) of 9,10-difluoro-2,3-dihydro3-methyl-7-oxo-7H-pyrido[1,2,3-de]-1,4-benzoxazine-6-carboxylic acid, 40 ml acetonitrile, and 0.80 g (8.0 mmole) of 3-pyrrolidinemethanamine were refluxed overnight. The solvent was removed at reduced pressure and the residue titurated with 40 ml of ethanol/ether (1:1), to give 0.90 g of 10-[3-(aminomethyl)-1-pyrrolidinyl]-9-fluoro-2,3-dihydro- methyl-7-oxo-7H-pyrido[1,2,3-de]-1,4-benzoxazine-6-carboxylic acid, mp 213°-216° C.
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][CH2:15][CH2:16][C:17](O)=O)[CH2:10][CH2:9]1)(OC(C)(C)C)=O.C[CH2:21][O:22][CH2:23]C.S(Cl)(Cl)=[O:26].[N+](=C)=[N-]>N1C=CC=CC=1.CO.C([O-])(=O)C1C=CC=CC=1.[Ag+].CCN(CC)CC>[NH:8]1[CH2:9][CH2:10][CH:11]([CH2:14][CH2:15][CH2:16][CH2:17][C:21]([O:22][CH3:23])=[O:26])[CH2:12][CH2:13]1
Reactant: CCOCC
Reactant: O=S(Cl)Cl
Reactant: CC(C)(C)OC(=O)N1CCC(CCCC(=O)O)CC1
Agent: [Ag+]
Agent: C=[N+]=[N-]
Agent: O=C([O-])c1ccccc1
Solvent: CCN(CC)CC
Solvent: CO
Solvent: c1ccncc1
Product: COC(=O)CCCCC1CCNCC1
Temperature: 0 °C

Procedure:
To a stirred solution of carboxylic acid 14 (600 mg, 2.2 mmol), ether (4.0 mL), and pyridine (2 drops) at ambient temperature was added thionyl chloride in one portion to effect an exotherm. After 25 minutes the ether, pyridine, and thionyl chloride were evaporated. The intermediate acid chloride was dissolved in ether (5 mL), cooled to 0° C., then treated with an ethereal solution of diazomethane (15 mL, ~10 mmol). After 2.0 hours the excess diazomethane was removed by purging with argon. Evaporation in situ gave a solid that was dissolved in CH3OH (10 mL) then treated sequentially with NEt3 (0.5 mL) and silver benzoate (20 mg). After 15 minutes the black reaction mixture was concentrated and the residue subjected to flash chromatography (silica, 10% ethyl acetate/hexanes) to give 15 (300 mg) as an oil.
Reaction SMILES: [F:1][C:2]([C:5]1[N:6]=[C:7]([CH2:10][N:11]2[N:15]=[C:14]([NH2:16])[CH:13]=[N:12]2)[S:8][CH:9]=1)([F:4])[CH3:3].[CH:17]1([C:20]2[O:21][C:22]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)=[C:23]([C:25](O)=[O:26])[N:24]=2)[CH2:19][CH2:18]1>>[F:1][C:2]([C:5]1[N:6]=[C:7]([CH2:10][N:11]2[N:15]=[C:14]([NH:16][C:25]([C:23]3[N:24]=[C:20]([CH:17]4[CH2:18][CH2:19]4)[O:21][C:22]=3[C:28]3[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=3)=[O:26])[CH:13]=[N:12]2)[S:8][CH:9]=1)([F:4])[CH3:3]
Reactant: CC(F)(F)c1csc(Cn2ncc(N)n2)n1
Reactant: O=C(O)c1nc(C2CC2)oc1-c1ccccc1
Product: CC(F)(F)c1csc(Cn2ncc(NC(=O)c3nc(C4CC4)oc3-c3ccccc3)n2)n1

Procedure:
Following general procedure Z2, starting from 2-[4-(1,1-difluoro-ethyl)-thiazol-2-ylmethyl]-2H-[1,2,3]triazol-4-ylamine and 2-cyclopropyl-5-phenyl-oxazole-4-carboxylic acid.
Reaction SMILES: [CH3:1][S:2][CH2:3][CH2:4][C@@H:5]([OH:8])[CH2:6][OH:7].[CH3:9][S:10](Cl)(=[O:12])=[O:11].C(OCC)(=O)C>N1C=CC=CC=1>[CH3:9][S:10]([O:7][CH2:6][C@H:5]([O:8][S:10]([CH3:9])(=[O:12])=[O:11])[CH2:4][CH2:3][S:2][CH3:1])(=[O:12])=[O:11]
Reactant: CS(=O)(=O)Cl
Reactant: CSCC[C@@H](O)CO
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Product: CSCC[C@H](COS(C)(=O)=O)OS(C)(=O)=O
Temperature: 0 °C
Reaction time: 2 h

Procedure:
(R)-4-(Methylthio)-1,2-butanediol (0.47 g, 3.4 mmol) was dissolved in 5 ml of pyridine and cooled to 0° C. Methanesulfonyl chloride (0.66 ml, 8.5 mmol) was added and the mixture stirred for 2 hours while warming to room temperature, by which time tlc (ethyl acetate) indicated complete conversion of starting material (Rf 0.4) to title product (Rf 0.85). The reaction mixture was diluted with 10 ml H2O and extracted 2×15 ml of ethyl acetate. The organic layers were combined, dried (MgSO4) and stripped to in vacuo to yield title product an an oil, all of which was used in the next step; tlc Rf 0.85 (ethyl acetate).
Reaction SMILES: Br[C:2]1[S:6][C:5]([CH2:7][CH2:8][N:9]2[C@H:13]([CH3:14])[CH2:12][O:11][C:10]2=[O:15])=[CH:4][CH:3]=1.[CH:16]1([CH2:22][CH2:23][CH2:24][C:25]#[CH:26])[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1.C(N(CC)CC)C.O>CN(C)C=O.[Cu]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>[CH:16]1([CH2:22][CH2:23][CH2:24][C:25]#[C:26][C:2]2[S:6][C:5]([CH2:7][CH2:8][N:9]3[C@H:13]([CH3:14])[CH2:12][O:11][C:10]3=[O:15])=[CH:4][CH:3]=2)[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1
Reactant: C[C@@H]1COC(=O)N1CCc1ccc(Br)s1
Reactant: C#CCCCC1CCCCC1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: C[C@@H]1COC(=O)N1CCc1ccc(C#CCCCC2CCCCC2)s1
Temperature: 80 °C
Reaction time: 2 h
Yield: 10 %

Procedure:
(4R)-[2-(5-Bromothiophen-2-yl)]ethyl-4-methyloxazolidin-2-one (450 mg, 1.55 mmol) obtained in Example 1 (g) was dissolved in dimethylformamide (4.5 ml), and 5-cyclohexylpent-1-yne (50% xylene solution) (1.4 g, 4.65 mmol), triethylamine (2.16 ml, 15.5 mmol), copper (I) iodide (30 mg, 0.16 mmol) and dichlorobis(triphenylphosphine)palladium (109 mg, 0.16 mmol) were added thereto, and then the reaction mixture was stirred for 2 hours at 80° C. under a nitrogen atmosphere. The reaction solution was poured into water, extracted with ethyl acetate, and the ethyl acetate layer was washed with a saturated aqueous sodium chloride solution. After the ethyl acetate layer was dried over anhydrous sodium sulfate, the solvent was concentrated in vacuo, and the residue was purified by chromatography on a silica gel column (elution solvent; hexane:ethyl acetate=4:1-3:2) to afford the title compound (56 mg, 82% yield).
Reaction SMILES: [NH2:1][CH2:2][C:3]1[C:12](=[O:13])[C:11]2[C:6](=[CH:7][C:8]([Cl:14])=[CH:9][CH:10]=2)[N:5]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH:4]=1.[CH3:21][N:22]1[CH:27]=[CH:26][C:25]([C:28](O)=[O:29])=[CH:24][C:23]1=[O:31]>>[Cl:14][C:8]1[CH:7]=[C:6]2[C:11]([C:12](=[O:13])[C:3]([CH2:2][NH:1][C:28]([C:25]3[CH:26]=[CH:27][N:22]([CH3:21])[C:23](=[O:31])[CH:24]=3)=[O:29])=[CH:4][N:5]2[C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)=[CH:10][CH:9]=1
Reactant: NCc1cn(-c2ccccc2)c2cc(Cl)ccc2c1=O
Reactant: Cn1ccc(C(=O)O)cc1=O
Product: Cn1ccc(C(=O)NCc2cn(-c3ccccc3)c3cc(Cl)ccc3c2=O)cc1=O

Procedure:
Methyl-2-oxo-1,2-dihydro-pyridine-4-carboxylic acid (7-chloro-4-oxo-1-phenyl-1,4-dihydro-quinolin-3-ylmethyl)-amide was prepared starting from intermediate D and 1-methyl-2-oxo-1,2-dihydro-pyridine-4-carboxylic acid. MS calcd. for C23H19ClN3O3 [(M+H)+] 420.1, obsd. 420.0.