Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:27]=[CH:26][C:8]([C:9]([N:11]2[CH2:16][CH2:15][N:14]([CH2:17][CH2:18][C:19]3[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][CH:20]=3)[CH2:13][CH2:12]2)=[O:10])=[CH:7][CH:6]=1)(=[O:3])[CH3:2].[H-].[Na+].[CH2:30](I)[CH2:31][CH3:32]>CN(C=O)C>[C:1]([N:4]([C:5]1[CH:27]=[CH:26][C:8]([C:9]([N:11]2[CH2:12][CH2:13][N:14]([CH2:17][CH2:18][C:19]3[CH:20]=[CH:21][C:22]([Cl:25])=[CH:23][CH:24]=3)[CH2:15][CH2:16]2)=[O:10])=[CH:7][CH:6]=1)[CH2:30][CH2:31][CH3:32])(=[O:3])[CH3:2]
Reactant: CC(=O)Nc1ccc(C(=O)N2CCN(CCc3ccc(Cl)cc3)CC2)cc1
Reactant: CCCI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCCN(C(C)=O)c1ccc(C(=O)N2CCN(CCc3ccc(Cl)cc3)CC2)cc1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
1.7 g of 1-[4-(N-acetylamino)benzoyl]-4-[2-(4-chlorophenyl)ethyl]-piperazine, dissolved in 20 ml DMF, is added to a suspension of 0.23 g 50% NaH in 20 ml DMF. After 1.5 h of stirring at RT, 0.97 g n-propyl iodide, dissolved in 5 ml DMF, are added dropwise. The reaction mixture is stirred overnight. DMF is distilled off in vacuo, water is added, and the product is extracted with ethyl acetate. The organic phase is concentrated by evaporation, and the residue is crystallised from ether/petroleum ether; thus 1-[4-(N-acetyl-N-propylamino)benzoyl]-4-[2-(4-chlorophenyl)ethyl]-piperazine is obtained m.p. 112°-113°.
Reaction SMILES: [SH:1][CH2:2][CH2:3][S:4][CH2:5][CH2:6][SH:7].C(=O)([O-])[O-].[K+].[K+].Cl[C:15]1[CH:20]=[CH:19][C:18]([C:21](=[O:31])[C:22]([CH3:30])([N:24]2[CH2:29][CH2:28][O:27][CH2:26][CH2:25]2)[CH3:23])=[CH:17][CH:16]=1>CC(N(C)C)=O.C(OCC)(=O)C>[SH:1][CH2:2][CH2:3][S:4][CH2:5][CH2:6][S:7][C:15]1[CH:16]=[CH:17][C:18]([C:21](=[O:31])[C:22]([CH3:23])([N:24]2[CH2:25][CH2:26][O:27][CH2:28][CH2:29]2)[CH3:30])=[CH:19][CH:20]=1
Reactant: SCCSCCS
Reactant: CC(C)(C(=O)c1ccc(Cl)cc1)N1CCOCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CC(=O)N(C)C
Product: CC(C)(C(=O)c1ccc(SCCSCCS)cc1)N1CCOCC1
Reaction time: 5 h

Procedure:
25.7 g (0.15 mol) of 2-mercaptoethylsulfide (purity 90%) are added to a suspension of 8.3 g (0.06 mol) of potassium carbonate in 50 ml of dimethylacetamide. A solution of 8.0 g (0.03 mol) 1-(4-chlorophenyl)-2-methyl-2-morpholin-4-yl-propan-1-one in 25 ml of dimethylacetamide is added dropwise at 85° C. over 60 min. After stirring for 5 h, the reaction mixture is cooled, diluted with ethyl acetate (100 ml), extracted with water (3×100 ml) to remove the carbonate and dimethylacetamide, dried over MgSO4, and concentrated under vacuum. The resulting yellow liquid (stench) is purified by flash chromatography on silica gel (hexane/ethyl acetate 85:15) to yield a pale yellow oil. The structure is confirmed by the 1H-NMR spectrum (CDCl3): δ [ppm] 1.31 (s, 6H), 1.750 (t, SH), 2.57 (t, 4H), 2.71-2.85 (m, 6H), 3.20 (t, 2H), 3.70 (t, 4), 7.31 (d, 2H), 8.51 (d, 2H).
Reaction SMILES: S[C:2]1[S:3][C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=2[N:6]=1.CO.Cl.S>[OH-].[Na+].O.[Fe].[Ni](Cl)Cl>[S:3]1[C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=2[N:6]=[CH:2]1
Reactant: Sc1nc2ccccc2s1
Agent: Cl[Ni]Cl
Agent: [Fe]
Agent: Cl
Solvent: CO
Solvent: O
Product: c1ccc2scnc2c1
Yield: 92 %

Procedure:
87.9 g of 95% pure 2-mercaptobenzothiazole, 111.7 g of iron filings, 11.8 g of nickel chloride (NiCl2 ×6H2O) and 250 ml of methanol were first introduced into a stirred flask, and the mixture was heated to the reflux temperature with stirring. 165 ml of conc. aqueous hydrochloric acid were added dropwise at 70° C. over a period of 2 hours, and the evolving hydrogen sulphide was trapped in aqueous sodium hydroxide solution. The mixture was additionally stirred at 70° C. for 1 hour and then diluted with 200 ml of water. 200 ml of methanol were distilled off. The remaining mixture was brought to a pH of 5.6 with aqueous sodium hydroxide solution and steam distilled. The steam distillate was extracted with toluene. Removal of the solvent by distillation gave 66.3 g of crude, colourless benzothiazole, 93.7% pure (GC), which corresponds to a yield of 92% of theory, having a residual toluene content of 5.3%.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([S:9]([C:12]([F:15])([F:14])[F:13])(=[O:11])=[O:10])=[CH:5][C:4]=1[S:16]([NH:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[NH:26][S:27]([C:30]1[CH:35]=[CH:34][C:33]([N+:36]([O-])=O)=[CH:32][CH:31]=1)(=[O:29])=[O:28])(=[O:18])=[O:17]>CC(O)=O.CCOC(C)=O.[Fe]>[NH2:36][C:33]1[CH:32]=[CH:31][C:30]([S:27]([NH:26][C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=2[NH:19][S:16]([C:4]2[CH:5]=[C:6]([S:9]([C:12]([F:15])([F:14])[F:13])(=[O:10])=[O:11])[CH:7]=[CH:8][C:3]=2[O:2][CH3:1])(=[O:17])=[O:18])(=[O:29])=[O:28])=[CH:35][CH:34]=1
Reactant: COc1ccc(S(=O)(=O)C(F)(F)F)cc1S(=O)(=O)Nc1ccccc1NS(=O)(=O)c1ccc([N+](=O)[O-])cc1
Agent: [Fe]
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: COc1ccc(S(=O)(=O)C(F)(F)F)cc1S(=O)(=O)Nc1ccccc1NS(=O)(=O)c1ccc(N)cc1
Temperature: 100 °C
Yield: 85.9 %

Procedure:
To a solution of the 2-methoxy-N-[2-(4-nitrobenzenesulfonylamino)phenyl]-5-trifluoromethanesulfonylbenzenesulfonamide (1 mmol) in AcOH (5 mL), iron powder (300 mg) was added and the resulting reaction mixture was heated at 100° C. for 30 min. The reaction mixture was filtered through a short pad of Celite and the pad was washed with methanol (50 mL) and dichloromethane (25 mL). The filtrate was concentrated under vacuum. The residue obtained was dissolved in EtOAc (50 mL) and washed with 1% aqueous KOH solution (25 mL). The organic layer was dried over anhydrous sodium sulfate and the solvent was removed to dryness in vacuo to give 486 mg of crude N-[2-(4-aminobenzenesulfonylamino) -phenyl]-2-methoxy-5-trifluoro methanesulfonyl-benzenesulfonamide. LC: Tr 1.09 min; MS: 566.7 (M+1)+.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[C:9](C(C)(C)C)[CH:8]=[C:7]([C:15]([CH3:18])([CH3:17])[CH3:16])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[Br:19]Br>C(Cl)(Cl)(Cl)Cl.[Fe].C(C1C=CC=C(O)C=1O)(C)(C)C>[Br:19][C:9]1[CH:10]=[C:5]([C:1]([CH3:4])([CH3:3])[CH3:2])[CH:6]=[C:7]([C:15]([CH3:18])([CH3:17])[CH3:16])[CH:8]=1
Reactant: CC(C)(C)c1cc(C(C)(C)C)cc(C(C)(C)C)c1
Reactant: BrBr
Agent: [Fe]
Agent: CC(C)(C)c1cccc(O)c1O
Solvent: ClC(Cl)(Cl)Cl
Product: CC(C)(C)c1cc(Br)cc(C(C)(C)C)c1
Temperature: 5 °C
Reaction time: 4 h
Yield: 46.4 %

Procedure:
1,3,5-Tri-t-butylbenzene (150 g, 0.6 mol) was dissolved in carbon tetrachloride (300 mL) in a three-necked flask which had been painted black to avoid light and equipped with an overhead stirrer, thermometer and addition funnel under argon. Iron pellets (36 g. 0.64 mol) were added and the slurry was cooled to 5° C. t-Butylcatechol (1.0 g) was added and a solution of bromine (201.6 g, 1.26 mol) in carbon tetrachloride (75 mL) was added over a one hour period. The slurry was stirred for an additional 4 hours at 5° C. and quenched by pouring into ice water. The layers were separated and the organics washed with 10% sodium hydroxide solution. The solution then was washed with salt brine and dried over magnesium sulfate. The solvent was evaporated and the product was distilled under vacuum twice to give 75 g of product which was then recrystallized from heptane to give 47 g of pure product (29% yield).
Reaction SMILES: [NH2:1][C:2]([C:4]1[O:5][C:6]2[CH:12]=[C:11]([C:13]([O:15]C)=[O:14])[CH:10]=[CH:9][C:7]=2[CH:8]=1)=[O:3].[OH-].[Na+]>CO.O>[NH2:1][C:2]([C:4]1[O:5][C:6]2[CH:12]=[C:11]([C:13]([OH:15])=[O:14])[CH:10]=[CH:9][C:7]=2[CH:8]=1)=[O:3]
Reactant: COC(=O)c1ccc2cc(C(N)=O)oc2c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: NC(=O)c1cc2ccc(C(=O)O)cc2o1
Temperature: 50 °C
Yield: 92.3 %

Procedure:
Methyl 2-(aminocarbonyl)-1-benzofuran-6-carboxylate(164 mg, 0.75 mmol) is dissolved in MeOH (5 mL) and water (1 mL), treated drop-wise with 2N NaOH (450 μL, 0.9 mmol) and monitored by TLC. The volatiles are removed in vacuo, and the resulting tan solid is dissolved in water (5 mL) and acidified to pH 3 with concentrated HCl. The resulting solid is collected via filtration and dried in a vacuum oven with heat 50° C. to afford 142 mg (93%) of 2-(aminocarbonyl)-1-benzofuran-6-carboxylic acid as an orange solid. HRMS (EI) calcd for C10H7NO4: 205.0375, found 205.0378 (M)+.
Reaction SMILES: [OH:1][C:2]1[CH:12]=[CH:11][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:4][C:3]=1I.[C:14]([Cu])#[N:15]>CS(C)=O>[C:14]([C:3]1[CH:4]=[C:5]([CH:11]=[CH:12][C:2]=1[OH:1])[C:6]([O:8][CH2:9][CH3:10])=[O:7])#[N:15]
Reactant: CCOC(=O)c1ccc(O)c(I)c1
Reactant: N#C[Cu]
Solvent: CS(C)=O
Product: CCOC(=O)c1ccc(O)c(C#N)c1
Temperature: 100 °C
Reaction time: 8 h
Yield: 75.9 %

Procedure:
Dissolve ethyl 4-hydroxy-3-iodo-benzoate (45 g, 154.1 mmoles) in DMSO (125 mL). Add CuCN (15.17 g, 169.5 mmoles). Stir the mixture at 100° C. overnight. After cooling, pour the mixture into ice/water. Filter the solid obtained, wash with water and dry under reduced pressure. Dissolve the solid in EtOAc. Filter through Celite®. Dry over MgSO4 and remove the solvent to obtain 22.36 g of ethyl 3-cyano-4-hydroxy-benzoate (76% yield). MS(ES): m/z=190.0 [M-H].
Reaction SMILES: [C:1]1([CH2:7][CH2:8]/[CH:9]=[CH:10]/[C:11]([OH:13])=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.ClC(OCC)=O.[CH2:20]([N:22](CC)CC)[CH3:21].C(N)C.[Cl-].[Na+]>C1COCC1>[CH2:20]([NH:22][C:11](=[O:13])/[CH:10]=[CH:9]/[CH2:8][CH2:7][C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)[CH3:21]
Reactant: CCN(CC)CC
Reactant: O=C(O)/C=C/CCc1ccccc1
Agent: CCN
Agent: CCOC(=O)Cl
Agent: [Cl-]
Solvent: C1CCOC1
Product: CCNC(=O)/C=C/CCc1ccccc1
Yield: 39 %

Procedure:
5-Phenyl-2E-pentenoic acid 1 eq, ethyl chloroformate 1.5 eq, triethylamine 1.5 eq, ethylamine 1.5 eq as a 2.0M solution in THF, quench with 10% sodium chloride solution, yield=39%.
Reaction SMILES: C(N1CCN(C2C=CC(C)=C(N)C=2)CC1)C.C(N1CCNCC1)C.CC1C=CC(N2CCOCC2)=CC=1N.COC1C=CC(CN(CC2C=CC(OC)=CC=2)C2N=CC(C3C4CCNC=4N=C(N4CCOCC4)N=3)=CN=2)=CC=1.[CH2:79]([N:81]1[CH2:86][CH2:85][N:84]([C:87]2[CH:88]=[CH:89][C:90]([CH3:136])=[C:91]([NH:93][C:94]([N:96]3[C:100]4[N:101]=[C:102]([N:130]5[CH2:135][CH2:134][O:133][CH2:132][CH2:131]5)[N:103]=[C:104]([C:105]5[CH:106]=[N:107][C:108]([N:111](CC6C=CC(OC)=CC=6)CC6C=CC(OC)=CC=6)=[N:109][CH:110]=5)[C:99]=4[CH2:98][CH2:97]3)=[O:95])[CH:92]=2)[CH2:83][CH2:82]1)[CH3:80]>>[CH2:79]([N:81]1[CH2:86][CH2:85][N:84]([C:87]2[CH:88]=[CH:89][C:90]([CH3:136])=[C:91]([NH:93][C:94]([N:96]3[C:100]4[N:101]=[C:102]([N:130]5[CH2:131][CH2:132][O:133][CH2:134][CH2:135]5)[N:103]=[C:104]([C:105]5[CH:110]=[N:109][C:108]([NH2:111])=[N:107][CH:106]=5)[C:99]=4[CH2:98][CH2:97]3)=[O:95])[CH:92]=2)[CH2:83][CH2:82]1)[CH3:80]
Reactant: CCN1CCN(c2ccc(C)c(NC(=O)N3CCc4c(-c5cnc(N(Cc6ccc(OC)cc6)Cc6ccc(OC)cc6)nc5)nc(N5CCOCC5)nc43)c2)CC1
Agent: CCN1CCN(c2ccc(C)c(N)c2)CC1
Agent: CCN1CCNCC1
Agent: COc1ccc(CN(Cc2ccc(OC)cc2)c2ncc(-c3nc(N4CCOCC4)nc4c3CCN4)cn2)cc1
Product: CCN1CCN(c2ccc(C)c(NC(=O)N3CCc4c(-c5cnc(N)nc5)nc(N5CCOCC5)nc43)c2)CC1

Procedure:
Using 5-(4-ethyl-piperazin-1-yl)-2-methyl-phenylamine (73 mg) obtained using 1-ethyl-piperazine instead of morpholine in the same manner as Step A and Step B in Example 1-D-237, instead of 2-methyl-5-morpholin-4-yl-phenylamine, from bis-(4-methoxy-benzyl)-[5-(2-morpholin-4-yl-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-4-yl)-pyrimidin-2-yl]-amine (200 mg), in the same manner as Step C in Example 1-D-237, 4-{2-[bis-(4-methoxy-benzyl)-amino]-pyrimidin-5-yl}-2-morpholin-4-yl-5,6-dihydro-pyrrolo[2,3-d]pyrimidine-7-carboxylic acid [5-(4-ethyl-piperazin-1-yl)-2-methyl-phenyl]-amide was obtained as a crude product. The PMB groups were removed according to Deprotection method 2, to obtain the desired compound (D-239) as an ivory solid (62 mg, 41%).
Reaction SMILES: [F:1][C:2]([F:31])([F:30])[C:3]1[CH:4]=[C:5]([NH:13][C:14](SC)=[C:15]([S:18]([C:21]2[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][CH:22]=2)(=[O:20])=[O:19])[C:16]#[N:17])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.[CH3:32][C:33]([NH2:37])([CH3:36])[CH2:34][CH3:35]>>[F:31][C:2]([F:30])([F:1])[C:3]1[CH:4]=[C:5]([NH:13][C:14]([NH:37][C:33]([CH3:36])([CH3:32])[CH2:34][CH3:35])=[C:15]([S:18]([C:21]2[CH:22]=[CH:23][C:24]([Cl:27])=[CH:25][CH:26]=2)(=[O:19])=[O:20])[C:16]#[N:17])[CH:6]=[C:7]([C:9]([F:11])([F:10])[F:12])[CH:8]=1
Reactant: CCC(C)(C)N
Reactant: CSC(Nc1cc(C(F)(F)F)cc(C(F)(F)F)c1)=C(C#N)S(=O)(=O)c1ccc(Cl)cc1
Product: CCC(C)(C)NC(Nc1cc(C(F)(F)F)cc(C(F)(F)F)c1)=C(C#N)S(=O)(=O)c1ccc(Cl)cc1
Yield: 8 %

Procedure:
3-(3,5-Bis(trifluoromethyl)phenylamino)-2-(4-chloro-phenylsulfonyl)-3-methylsulfanyl-2-propenenitrile (0.300 g, 0.6 mmol) was stirred in 1,1-dimethylpropylamine (1 ml) for 40 h at 60° C. and for 43 h at 110° C. under nitrogen. The reaction mixture was concentrated and the residue dissolved in DCM, washed twice with 1N aqueous HCl and once with water. The organic phase was dried (sodium sulfate) and concentrated. The residue was purified by flash chromatography using from ethyl acetate/heptane 1:2 as eluent followed recrystallisation from ethyl acetate/heptane 1:2 to give 25 mg (8%) of the title compound. Mp 205-207° C. 1H NMR (200 MHz, CDCl3): δ=0.98 (t, 3H), 1.54 (s, 6H), 1.68 (q, 2H), 7.10 (s, 2H), 7.53 (d, 2H), 7.60 (s, 1H), 7.81 (d, 2H); EI SP/MS: 539 (M+).
Reaction SMILES: C(O[CH2:5][C:6]1[N:10]2[C:11]3[CH:30]=[CH:29][CH:28]=[CH:27][C:12]=3[O:13][C:14]3([CH2:19][CH2:18][N:17](CC4C=CC=CC=4)[CH2:16][CH2:15]3)[C:9]2=[CH:8][CH:7]=1)(=O)C.C(O)(=O)C>C(OCC)(=O)C.[Pd]>[CH3:5][C:6]1[N:10]2[C:11]3[CH:30]=[CH:29][CH:28]=[CH:27][C:12]=3[O:13][C:14]3([CH2:15][CH2:16][NH:17][CH2:18][CH2:19]3)[C:9]2=[CH:8][CH:7]=1
Reactant: CC(=O)OCc1ccc2n1-c1ccccc1OC21CCN(Cc2ccccc2)CC1
Agent: [Pd]
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: Cc1ccc2n1-c1ccccc1OC21CCNCC1
Temperature: 25 °C
Reaction time: 20 h
Yield: 34.1 %

Procedure:
To a solution of (1′-benzylspiro[benzo[b]pyrrolo[1,2-d][1,4]oxazine-4,4′-piperidine]-1-yl)methyl acetate (300 mg, 0.75 mmol) in ethyl acetate (30 mL) was added acetic acid (17 μL, 0.30 mmol). The reaction was flushed with nitrogen then 10% Pd/C (40 mg, 0.37 mmol) was added. The reaction was placed under hydrogen gas and was stirred for 20 h at room temperature. The suspension was filtered through celite, concentrated, then purified by column chromatography (silica gel: 0.1-15% methanol in dichloromethane) to give 1-methylspiro[benzo[b]pyrrolo[1,2-d][1,4]oxazine-4,4′-piperidine] (65 mg, 34%). ESI-MS m/z calc. 254.3, found 255.3 (M+1)+; Retention time: 1.93 minutes (3 min run). 1H NMR (400 MHz, CDCl3) δ 7.56 (d, J=7.9 Hz, 1H), 7.16-6.99 (m, 3H), 6.03 (d, J=3.2 Hz, 1H), 5.94 (d, J=3.4 Hz, 1H), 3.14 (t, J=12.2 Hz, 2H), 2.94 (d, J=12.3 Hz, 2H), 2.56 (s, 3H), 2.19 (m, 1H), 2.04 (d, J=12.7 Hz, 2H), 1.97-1.84 (m, 2H).
Reaction SMILES: [Na].[CH2:2]([O:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[OH:13])[CH2:3][CH2:4][CH3:5].Cl.[N:15]1([CH2:21][CH2:22]Cl)[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1>C(O)C>[CH2:2]([O:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[O:13][CH2:22][CH2:21][N:15]1[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1)[CH2:3][CH2:4][CH3:5]
Reactant: ClCCN1CCCCC1
Reactant: CCCCOc1ccccc1O
Agent: Cl
Agent: [Na]
Solvent: CCO
Product: CCCCOc1ccccc1OCCN1CCCCC1

Procedure:
The compound was prepared as described in Example 1, using sodium (2.3 g, 100 mmole), o-butoxyphenol (8.30 g, 50 mmole) and piperidinoethylchloride hydrochloride (9.2 g, 50 mmole) in 150 ml of ethanol. Yield 4.4 g (32%) of product boiling at 121° C under a pressure of 0.02 mm Hg; nD25 1.5135.
Reaction SMILES: [OH-].[Na+].[C:3]([O:7][C:8]([NH:10][C@H:11]1[C@@H:15]([CH3:16])[CH2:14][N:13]([C:17]2[CH:26]=[C:25]3[C:20]([C:21](=[O:35])[C:22]([C:30]([O:32]CC)=[O:31])=[CH:23][N:24]3[CH:27]3[CH2:29][CH2:28]3)=[CH:19][C:18]=2[F:36])[CH2:12]1)=[O:9])([CH3:6])([CH3:5])[CH3:4].Cl>C(O)C>[C:3]([O:7][C:8]([NH:10][C@H:11]1[C@@H:15]([CH3:16])[CH2:14][N:13]([C:17]2[CH:26]=[C:25]3[C:20]([C:21](=[O:35])[C:22]([C:30]([OH:32])=[O:31])=[CH:23][N:24]3[CH:27]3[CH2:29][CH2:28]3)=[CH:19][C:18]=2[F:36])[CH2:12]1)=[O:9])([CH3:4])([CH3:5])[CH3:6]
Reactant: CCOC(=O)c1cn(C2CC2)c2cc(N3C[C@H](C)[C@H](NC(=O)OC(C)(C)C)C3)c(F)cc2c1=O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: C[C@H]1CN(c2cc3c(cc2F)c(=O)c(C(=O)O)cn3C2CC2)C[C@H]1NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 3 h
Yield: 48.1 %

Procedure:
A 1 mol/L aqueous sodium hydroxide solution (5 mL, 5 mmol) was added under cooling with ice to ethyl 7-[(3S,4S)-3-(tert-butoxycarbonyl)amino-4-methylpyrrolidin-1-yl]-1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxoquinoline-3-carboxylate (957 mg, 1.96 mmol) in ethanol (10 mL), and the mixture was stirred at room temperature for 3 hours. The resultant mixture was neutralized with 1 mol/L hydrochloric acid under cooling with ice, and ethanol was removed under reduced pressure. Subsequently, 1 mol/L hydrochloric acid was added thereto, followed by extraction with ethyl acetate (100 mL×3). The ethyl acetate layer was washed by saturated brine (100 mL), and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The obtained residue was dissolved in concentrated hydrochloric acid (5 mL), and the solution was washed by chloroform (50 mL). The pH of the resultant mixture was adjusted to 7.8 with an aqueous sodium hydroxide solution, followed by extraction with chloroform (100 mL×3) and drying over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure, and the obtained residue was recrystallized from ethanol, to thereby yield the title compound as pale yellow crystals (420 mg, 58.2%).
Reaction SMILES: [F:1][C:2]([F:11])([F:10])[C:3]1[CH:8]=[CH:7][C:6]([OH:9])=[CH:5][CH:4]=1.Br[CH2:13][C:14]#[N:15].C(=O)([O-])[O-].[Na+].[Na+].[I-].[Na+]>CN(C=O)C>[F:1][C:2]([F:10])([F:11])[C:3]1[CH:4]=[CH:5][C:6]([O:9][CH2:13][C:14]#[N:15])=[CH:7][CH:8]=1
Reactant: N#CCBr
Reactant: Oc1ccc(C(F)(F)F)cc1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: N#CCOc1ccc(C(F)(F)F)cc1
Temperature: 100 °C
Yield: 96.2 %

Procedure:
A mixture of 4-trifluoromethyl-phenol (25.0 g, 0.154 mol), bromoacetonitrile (12.9 mL, 0.185 mol), sodium carbonate (32.7 g, 0.308 mol), and sodium iodide (23.1 g, 0.154 mol) in 214 mL of DMF was heated at 100° C. for 2 hours. The reaction was cooled, and partitioned between water and EtOAc. The organic layers were washed with water and brine, dried with Na2SO4, filtered and the filtrate was concentrated. The residue was purified by chromatography (silica, hexanes:EtOAc, 4:1) to afford the title compound as a colorless oil (29.8 g, 96%). 1H NMR (400 MHz, CD3Cl) δ (ppm): 7.63 (d, 2H), 7.07 (d, 2H), 4.83 (s, 2H).
Reaction SMILES: [NH2:1][C:2]1[C:11]([N+:12]([O-])=O)=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[C:4]([F:15])[CH:3]=1>CO.[Pd]>[NH2:1][C:2]1[C:11]([NH2:12])=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[C:4]([F:15])[CH:3]=1
Reactant: COC(=O)c1cc([N+](=O)[O-])c(N)cc1F
Agent: [Pd]
Solvent: CO
Product: COC(=O)c1cc(N)c(N)cc1F
Reaction time: 20 h
Yield: 40.2 %

Procedure:
A suspension of methyl 4-amino-2-fluoro-5-nitrobenzoate (6.84 g, 31.9 mmol) and 10% Pd/C (1.2 g) in methanol (200 mL) was hydrogenated under an atmosphere of hydrogen (balloon) for 20 h, filtered through Celite and the filtrate concentrated in vacuo to a residue. The residue was purified by flash chromatography (20% EtOAc/DCM) to afford the desired methyl 4,5-diamino-2-fluorobenzoate as a pink solid (2.36 g, 40%). 1H NMR (CDCl3) δ 7.90 (s, 1H), 7.93 (s, 1H), 7.13 (d, J=8.7 Hz, 1H), 6.88 (s, 1H), 6.37 (d, J=13.5 Hz, 1H), 3.60 (t, J=6.9 Hz, 2H), 2.86 (t, J=6.9 Hz, 12H).
Reaction SMILES: [N:1]1[C:2]([CH2:19][C:20]([O:22][CH3:23])=[O:21])=[CH:3][N:4]2[C:10]=1[C:9]1[CH:11]=[CH:12][CH:13]=[CH:14][C:8]=1[NH:7][C:6]1[N:15]=[CH:16][CH:17]=[CH:18][C:5]2=1.[Br:24]N1C(=O)CCC1=O>C1COCC1>[Br:24][C:3]1[N:4]2[C:5]3[CH:18]=[CH:17][CH:16]=[N:15][C:6]=3[NH:7][C:8]3[CH:14]=[CH:13][CH:12]=[CH:11][C:9]=3[C:10]2=[N:1][C:2]=1[CH2:19][C:20]([O:22][CH3:23])=[O:21]
Reactant: O=C1CCC(=O)N1Br
Reactant: COC(=O)Cc1cn2c(n1)-c1ccccc1Nc1ncccc1-2
Solvent: C1CCOC1
Product: COC(=O)Cc1nc2n(c1Br)-c1cccnc1Nc1ccccc1-2
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 97.2 %

Procedure:
To a solution of methyl 2-(9H-benzo[f]imidazo[1,2-d]pyrido[2,3-b][1,4]diazepin-2-yl)acetate (0.14 g, 1 eq.) in THF (10 mL) was added N-bromosuccinimide (0.077 g, 1 eq.). The reaction was stirred at room temperature for 30 minutes, poured onto water (30 mL) and extracted with ethyl acetate (2×30 mL). The organic extracts were combined, washed with water (1×50 mL), brine (1×50 mL) and dried over sodium sulfate. After filtration and concentration under reduced pressure, the crude product was purified by column chromatography (2-5% methanol in dichloromethane). The methyl 2-(3-bromo-9H-benzo[f]imidazo[1,2-d]pyrido[2,3-b][1,4]diazepin-2-yl)acetate (0.162 g, 98%) was obtained. 1H NMR (DMSO-d6) 400 MHz δ 8.23 (dd, JA=4.4 Hz, JB=1.6 Hz, 1H), 7.96 (dd, JA=7.6 Hz, JB=1.6 Hz, 1H), 7.77 (dd, JA=8.0 Hz, JB=1.6 Hz, 1H), 7.38-7.33 (m, 1H), 7.19 (dd, JA=8.0 Hz, JB=4.8 Hz, 1H), 7.14-7.05 (m, 2H), 3.75 (s, 2H), 3.74 (s, 3H); LCMS: 385, 387 [M+H].
Reaction SMILES: [Br:1][C:2]1[C:3]([N:17]2[CH2:22][CH2:21][C:20]([CH3:24])([CH3:23])[CH2:19][CH2:18]2)=[C:4]([C:10](=[O:16])[C:11]([O:13][CH2:14][CH3:15])=[O:12])[C:5]([CH3:9])=[N:6][C:7]=1[CH3:8].CB1N2CCC[C@@H]2C(C2C=CC=CC=2)(C2C=CC=CC=2)O1.[B]1OC2C(=CC=CC=2)O1>C1(C)C=CC=CC=1.CCOC(C)=O>[Br:1][C:2]1[C:3]([N:17]2[CH2:18][CH2:19][C:20]([CH3:23])([CH3:24])[CH2:21][CH2:22]2)=[C:4]([C@H:10]([OH:16])[C:11]([O:13][CH2:14][CH3:15])=[O:12])[C:5]([CH3:9])=[N:6][C:7]=1[CH3:8]
Reactant: CCOC(=O)C(=O)c1c(C)nc(C)c(Br)c1N1CCC(C)(C)CC1
Agent: CB1OC(c2ccccc2)(c2ccccc2)[C@H]2CCCN12
Agent: [B]1Oc2ccccc2O1
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: CCOC(=O)[C@@H](O)c1c(C)nc(C)c(Br)c1N1CCC(C)(C)CC1
Temperature: -15 °C
Reaction time: 2 h
Yield: 100 %

Procedure:
To stirred yellow solution of ethyl 2-(5-bromo-4-(4,4-dimethylpiperidin-1-yl)-2,6-dimethylpyridin-3-yl)-2-oxoacetate (2.25 g, 5.66 mmol) and (R)-1-methyl-3,3-diphenylhexahydropyrrolo[1,2-c][1,3,2]oxazaborole (0.314 g, 1.133 mmol) in toluene (30 mL) at −35° C. was added drop wise 50% catecholborane (1.819 ml, 8.49 mmol) over 10 min. The reaction mixture was slowly warmed to −15° C. over 1 h and then left for 2 h at −15° C. Then, diluted with EtOAc (100 mL), washed with sat Na2CO3 (4×25 mL) by vigorously stirring and separating aqueous layers. The organic layer dried (MgSO4), filtered, concentrated and purified by flash chromatography using 10, 20 and 25% EtOAc/Hex to afford desired (S)-ethyl 2-(5-bromo-4-(4,4-dimethylpiperidin-1-yl)-2,6-dimethylpyridin-3-yl)-2-hydroxyacetate (2.2596 g, 5.66 mmol, 100% yield) contaminated with about 10% of (S)-ethyl 2-(5-bromo-4-chloro-2,6-dimethylpyridin-3-yl)-2-hydroxyacetate. Used in the next step without further purification. 1H NMR (500 MHz, CDCl3) δ 5.71 (d, J=7.3 Hz, 1H), 5.54 (d, J=7.4 Hz, 1H), 4.29 (dq, J=10.8, 7.1 Hz, 1H), 4.16 (dq, J=10.8, 7.1 Hz, 1H), 3.94-3.83 (m, 2H), 2.71 (d, J=11.9 Hz, 1H), 2.67 (s, 3H), 2.59 (s, 3H), 2.54 (d, J=12.0 Hz, 1H), 1.71 (td, J=12.7, 4.7 Hz, 1H), 1.62 (td, J=13.0, 4.7 Hz, 1H), 1.42 (dd, J=13.1, 2.2 Hz, 1H), 1.37 (dd, J=12.9, 2.4 Hz, 1H), 1.25 (t, J=7.1 Hz, 3H), 1.09 (s, 3H), 1.04 (s, 3H). LCMS (M+H)=401.3.