Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:16]=[C:15]([F:17])[CH:14]=[CH:13][C:3]=1[CH2:4][NH:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].[CH3:18][O:19][C:20]([C:22]1[CH:39]=[CH:38][CH:37]=[CH:36][C:23]=1[CH2:24][O:25][C:26]1[CH:31]=[CH:30][C:29]([CH2:32][C:33]([OH:35])=O)=[CH:28][CH:27]=1)=[O:21].C(Cl)CCl>C(Cl)Cl.CN(C1C=CN=CC=1)C>[F:1][C:2]1[CH:16]=[C:15]([F:17])[CH:14]=[CH:13][C:3]=1[CH2:4][N:5]([CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12])[C:33](=[O:35])[CH2:32][C:29]1[CH:28]=[CH:27][C:26]([O:25][CH2:24][C:23]2[CH:36]=[CH:37][CH:38]=[CH:39][C:22]=2[C:20]([O:19][CH3:18])=[O:21])=[CH:31][CH:30]=1
Reactant: CCCCCCCNCc1ccc(F)cc1F
Reactant: COC(=O)c1ccccc1COc1ccc(CC(=O)O)cc1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: ClCCCl
Product: CCCCCCCN(Cc1ccc(F)cc1F)C(=O)Cc1ccc(OCc2ccccc2C(=O)OC)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 74 %

Procedure:
N-(2,4-Difluorobenzyl)-N-heptylamine (106 mg, 0.44 mmol) was added into (4-{[2-(methoxycarbonyl)benzyl]oxy}phenyl)acetic acid (120 mg, 0.4 mmol) in DCM (10 ml) and followed by EDC (84.3 mg, 0.44 mmol) and then DMAP (54 mg, 0.44 mmol). The mixture was stirred at room temperature overnight, and then washed with 1% hydrochloric acid, water and brine and dried with magnesium sulphate and evaporated. Chromatography of the residue on a column (ISOLUTE®SI, 5 g/15 ml) using DCM and MeOH/DCM (0.5:99.5) as eluant gave 155 mg desired product, yield 74%.
Reaction SMILES: Cl[C:2]1[C:3]([C:8]2(O)[CH2:13][CH2:12][CH2:11][N:10]([CH3:14])[CH2:9]2)=[N:4][CH:5]=[CH:6][N:7]=1.S(Cl)(Cl)=O.[C:20]([OH:25])(=[O:24])[C:21]([OH:23])=[O:22]>C(OCC)(=O)C>[C:20]([OH:25])(=[O:24])[C:21]([OH:23])=[O:22].[CH3:21][O:22][C:2]1[C:3]([C:8]2[CH2:9][N:10]([CH3:14])[CH2:11][CH2:12][CH:13]=2)=[N:4][CH:5]=[CH:6][N:7]=1
Reactant: CN1CCCC(O)(c2nccnc2Cl)C1
Agent: O=C(O)C(=O)O
Solvent: CCOC(C)=O
Solvent: O=S(Cl)Cl
Product: COc1nccnc1C1=CCCN(C)C1

Procedure:
A mixture of 0.32 g of (1) (0.0014 mol) and 10 ml of thionyl chloride was heated to reflux for 1.5 h. The excess thionyl chloride was evaporated, the residue treated with ice-water and made basic with saturated aqueous K2CO3. The mixture was extracted 3× with 25 ml of CH2Cl2, the extracts washed with brine, dried, and the solvent evaporated. The residue was dissolved in 5 ml of methanol and added to 25 ml of methanol that had reacted with 0.35 g of Na (0.015 mol). The reaction was heated to reflux for 1.5 h. The solvent was evaporated, the residue was treated with ice-water and the mixture extracted 3× with 25 ml of CH2Cl2. The extracts were washed with brine, dried, and the solvent evaporated to give a dark liquid, 0.15 g. The liquid was dissolved in ethyl acetate and treated with oxalic acid to give 0.05 g of (2) after recrystallization from ethyl acetate, mp 150°-151° C. NMR ppm (D2O) 2.6-2.9 (2H, m), 3.1 (3H, s), 3.3 (1H, m), 3.65 (1H, m), 4.0 (3H, s), 4.05 (1H, dd), 4.35 (1H, d), 6.95 (1H, bs), 8.07 (1H, d), 8.1 (1H, d). Anal. C11H15N3O-C2H2O4 requires C: 52.88; H: 5.80; N: 14.23%. Found C: 52.66; H: 5.94; N: 14.04%.
Reaction SMILES: [NH2:1][C@@H:2]1[CH2:8][CH2:7][CH2:6][C@H:5]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[N:4]([CH2:15][C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[C:3]1=[O:23].[O:24]=[C:25]1[N:34]([CH:35]2[CH2:40][CH2:39][N:38]([C:41](Cl)=[O:42])[CH2:37][CH2:36]2)[CH2:33][C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[NH:26]1>>[O:23]=[C:3]1[C@H:2]([NH:1][C:41]([N:38]2[CH2:39][CH2:40][CH:35]([N:34]3[CH2:33][C:32]4[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=4)[NH:26][C:25]3=[O:24])[CH2:36][CH2:37]2)=[O:42])[CH2:8][CH2:7][CH2:6][C@H:5]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[N:4]1[CH2:15][C:16]([O:18][C:19]([CH3:20])([CH3:22])[CH3:21])=[O:17]
Reactant: O=C(Cl)N1CCC(N2Cc3ccccc3NC2=O)CC1
Reactant: CC(C)(C)OC(=O)CN1C(=O)[C@H](N)CCC[C@@H]1c1ccccc1
Product: CC(C)(C)OC(=O)CN1C(=O)[C@H](NC(=O)N2CCC(N3Cc4ccccc4NC3=O)CC2)CCC[C@@H]1c1ccccc1

Procedure:
The title compound was prepared with tert-butyl [(3R,7R)-3-amino-2-oxo-7-phenylazepan-1-yl]acetate and 4-(2-oxo-1,4-dihydroquinazolin-3(2H)-yl)piperidine-1-carbonyl chloride using a similar procedure to Example 1. MS 576 (M+1).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[N:5][N:6]2[C:11]([C:12]([F:15])([F:14])[F:13])=[CH:10][C:9]([C:16]3[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][CH:17]=3)=[N:8][C:7]=12)#[CH:2].Br[C:27]1[CH:28]=[CH:29][C:30]([CH3:40])=[C:31]([S:33]([NH:36][CH2:37][CH2:38][OH:39])(=[O:35])=[O:34])[CH:32]=1>>[OH:39][CH2:38][CH2:37][NH:36][S:33]([C:31]1[CH:32]=[C:27]([C:2]#[C:1][C:3]2[CH:4]=[N:5][N:6]3[C:11]([C:12]([F:14])([F:13])[F:15])=[CH:10][C:9]([C:16]4[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][CH:17]=4)=[N:8][C:7]=23)[CH:28]=[CH:29][C:30]=1[CH3:40])(=[O:35])=[O:34]
Reactant: C#Cc1cnn2c(C(F)(F)F)cc(-c3ccc(C(F)(F)F)cc3)nc12
Reactant: Cc1ccc(Br)cc1S(=O)(=O)NCCO
Product: Cc1ccc(C#Cc2cnn3c(C(F)(F)F)cc(-c4ccc(C(F)(F)F)cc4)nc23)cc1S(=O)(=O)NCCO

Procedure:
The title compound was prepared from 3-ethynyl-7-trifluoromethyl-5-(4-trifluoromethyl-phenyl)-pyrazolo[1,5-a]pyrimidine (example C.1) (150 mg, 0.9 mmol) and 5-Bromo-N-(2-hydroxy-ethyl)-2-methyl-benzenesulfonamide (example B.17) (129 mg, 1.0 mmol) according to general procedure II. Obtained as an orange solid (59 mg, 25%). MS (ISP) 569.2 [(M+H)+]; mp 174-175° C.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:25])[CH2:5][CH:6]1[O:10][B:9]([OH:11])[C:8]2[CH:12]=[C:13]([O:17][C:18]3[CH:23]=[CH:22][CH:21]=[C:20]([OH:24])[CH:19]=3)[CH:14]=[C:15]([CH3:16])[C:7]1=2)[CH3:2].[C:26]([O:30][C:31](=[O:37])[NH:32][CH2:33][CH2:34][CH2:35]Br)([CH3:29])([CH3:28])[CH3:27].[H-].[Na+].[NH4+].[Cl-].Cl>CN(C=O)C.O>[CH2:1]([O:3][C:4](=[O:25])[CH2:5][CH:6]1[O:10][B:9]([OH:11])[C:8]2[CH:12]=[C:13]([O:17][C:18]3[CH:23]=[CH:22][CH:21]=[C:20]([O:24][CH2:35][CH2:34][CH2:33][NH:32][C:31]([O:30][C:26]([CH3:27])([CH3:29])[CH3:28])=[O:37])[CH:19]=3)[CH:14]=[C:15]([CH3:16])[C:7]1=2)[CH3:2]
Reactant: CC(C)(C)OC(=O)NCCCBr
Reactant: CCOC(=O)CC1OB(O)c2cc(Oc3cccc(O)c3)cc(C)c21
Agent: Cl
Agent: [Cl-]
Agent: [H-]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)CC1OB(O)c2cc(Oc3cccc(OCCCNC(=O)OC(C)(C)C)c3)cc(C)c21
Temperature: 25 °C
Reaction time: 20 h
Yield: 67.6 %

Procedure:
To a solution of [1-hydroxy-6-(3-hydroxy-phenoxy)-4-methyl-1,3-dihydro-benzo[c][1,2]oxaborol-3-yl]-acetic acid ethyl ester (0.53 g, 1.54 mmol) and (3-bromo-propyl)-carbamic acid tert-butyl ester (0.74 g, 3.09 mmol) in DMF (20 mL) at 0° C. was added NaH (0.22 g, 4.64 mmol). The reaction mixture was allowed to warm to room temperature and stirred for 20 hours. Saturated NH4Cl (10 mL) and water (10 mL) were added and the solution acidified to pH˜5 with dilute HCl. The mixture was extracted with EtOAc (2×20 mL) and the organic extracts washed with water (10 mL), dried and concentrated in vacuo. The residue was purified by silica gel flash column chromatography (DCM:MeOH 95:5) to give {6-[3-(3-tert-butoxycarbonylamino-propoxy)-phenoxy]-1-hydroxy-4-methyl-1,3-dihydro-benzo[c][1,2]oxaborol-3-yl}-acetic acid ethyl ester (0.52 g, 67%). 1H NMR (400 MHz, DMSO): δ 9.18 (s, 1H), 7.24 (t, J=8.0 Hz, 1H), 7.06 (s, 1H), 6.95 (d, J=6.0 Hz, 1H), 6.85 (s, 1H), 6.67 (d, J=8.4 Hz, 1H), 6.51 (d, J=6.0 Hz, 2H), 5.47 (t, J=11.6 Hz, 1H), 4.02 (q, J=7.2 Hz, 2H), 3.93 (t, J=6.0 Hz, 2H), 3.07-3.02 (m, 3H), 2.28-2.27 (m, 1H), 2.26 (s, 3H), 1.77 (t, J=6.4 Hz, 2H), 1.33 (s, 12H), 1.11 (t, J=6.8 Hz, 3H).
Reaction SMILES: Br[C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[C:4]1([CH2:22][O:21][C:20]3[CH:23]=[C:24]4[C:28](=[CH:29][C:19]1=3)[CH2:27][CH2:26][O:25]4)[C:5](=[O:18])[N:6]2[CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=1.BrC1C=CC=C2C=1[C:33]1([C:49]3=CC4OCOC=4C=[C:48]3[O:47][CH2:46]1)C(=O)N2CCCCC.O1C=CC(B(O)O)=C1.CN(C)C1N=CC(B(O)O)=CC=1>>[O:47]1[CH:48]=[CH:49][C:33]([C:2]2[CH:10]=[CH:9][CH:8]=[C:7]3[C:3]=2[C:4]2([CH2:22][O:21][C:20]4[CH:23]=[C:24]5[C:28](=[CH:29][C:19]2=4)[CH2:27][CH2:26][O:25]5)[C:5](=[O:18])[N:6]3[CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=2)=[CH:46]1
Reactant: O=C1N(Cc2ccccn2)c2cccc(Br)c2C12COc1cc3c(cc12)CCO3
Reactant: CCCCCN1C(=O)C2(COc3cc4c(cc32)OCO4)c2c(Br)cccc21
Agent: CN(C)c1ccc(B(O)O)cn1
Agent: OB(O)c1ccoc1
Product: O=C1N(Cc2ccccn2)c2cccc(-c3ccoc3)c2C12COc1cc3c(cc12)CCO3

Procedure:
Following the procedure as described in EXAMPLE 4, and making non-critical variations using 4′-bromo-1′-(pyridin-2-ylmethyl)-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2′(1′H)-one to replace 4′-bromo-1′-pentylspiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one, and 3-furanboronic acid to replace [6-(dimethylamino)pyridin-3-yl]boronic acid, the title compound was obtained (75%) as a colorless solid: mp 195-197° C.; 1H NMR (300 MHz, CDCl3) δ 8.58 (d, 1H), 7.68 (t, 1H), 7.32-7.21 (m, 4H), 6.97 (d, 1H), 6.92 (d, 1H), 6.77 (s, 1H), 6.60 (s, 1H), 6.35 (s, 1H), 5.99 (s, 1H), 5.12 (ABq, 2H), 4.71 (ABq, 2H), 4.57 (t, 2H), 3.03 (t, 2H); MS (ES+) m/z 437.4 (M+1).
Reaction SMILES: Br[C:2]1[CH:16]=[CH:15][CH:14]=[CH:13][C:3]=1[CH2:4][O:5][Si:6]([C:9]([CH3:12])([CH3:11])[CH3:10])([CH3:8])[CH3:7].[Cl:17][C:18]1[N:19]=[C:20]2[CH:25]=[CH:24][C:23](B3OC(C)(C)C(C)(C)O3)=[CH:22][N:21]2[CH:35]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCCC1.O>[Si:6]([O:5][CH2:4][C:3]1[CH:13]=[CH:14][CH:15]=[CH:16][C:2]=1[C:35]1[N:21]2[CH:22]=[CH:23][CH:24]=[CH:25][C:20]2=[N:19][C:18]=1[Cl:17])([C:9]([CH3:12])([CH3:11])[CH3:10])([CH3:8])[CH3:7]
Reactant: CC1(C)OB(c2ccc3nc(Cl)cn3c2)OC1(C)C
Reactant: CC(C)(C)[Si](C)(C)OCc1ccccc1Br
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)[Si](C)(C)OCc1ccccc1-c1c(Cl)nc2ccccn12
Yield: 46.7 %

Procedure:
450 mg of (2-bromobenzyloxy)-tert-butyldimethylsilane, 500 mg of 2-chloro-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)imidazo[1,2-a]pyridine and 1.46 g of caesium carbonate are dissolved in 8 ml of tetrahydrofuran and 1 ml of water. The mixture is degassed with argon for 10 min, 110 mg of [1,1′-bis(diphenylphosphino)-ferrocene]dichloropalladium are added and the mixture is heated at the reflux of the solvent for 16 hours. After cooling, the reaction mixture is hydrolysed with water, and the organic phase, which has been extracted with dichloromethane, is separated, dried and concentrated under reduced pressure. The oil obtained is purified by silica gel chromatography, elution being carried out with a heptane/ethyl acetate mixture. 260 mg of compound are obtained.
Reaction SMILES: [Br:1][C:2]1[C:7]([CH3:8])=[CH:6][C:5]([OH:9])=[CH:4][C:3]=1[CH3:10].[CH3:11]I>CC(C)=O>[Br:1][C:2]1[C:7]([CH3:8])=[CH:6][C:5]([O:9][CH3:11])=[CH:4][C:3]=1[CH3:10]
Reactant: CI
Reactant: Cc1cc(O)cc(C)c1Br
Solvent: CC(C)=O
Product: COc1cc(C)c(Br)c(C)c1
Temperature: 40 °C
Yield: 94.5 %

Procedure:
A solution of 4-bromo-3,5-dimethylphenol (1.00 g, 4.97 mmol) in acetone (40 mL) was treated with solid CsCO3 (1.17 g, 4.97 mmol) and methyl iodide (0.310 mL, 4.97 mmol) and heated to 40° C. for 3 h. Additional methyl iodide (0.310 mL, 4.97 mmol) was added over the course of the reaction to replace that lost to evaporation. The acetone was removed in vacuo. The resulting white solid residue was partitioned between water and CH2Cl2. The layers were separated and the aqueous layer was further extracted with CH2Cl2 (2×25 mL). The combined organic layers were washed with water (1×25 mL) and dried over MgSO4. The solvent was removed in vacuo to afford the product 2-bromo-5-methoxy-1,3-dimethyl-benzene (1.01 g, 94%) as a colorless oil, which slowly solidified upon standing. 1H NMR (CDCl3): δ 6.644 (s, 2H), 3.762 (s, 3H), 2.382 (s, 6H).
Reaction SMILES: [F:1][C:2]([F:31])([F:30])[C:3]1[CH:4]=[C:5]([C@H:13]2[O:17][C:16](=[O:18])[N:15]([CH2:19][C:20]3[C:25](Br)=[CH:24][N:23]=[C:22]([S:27][CH3:28])[N:21]=3)[C@H:14]2[CH3:29])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.[CH3:32][O:33][C:34]1[CH:39]=[CH:38][C:37]([CH2:40][CH2:41][C:42]([O:44][CH3:45])=[O:43])=[CH:36][C:35]=1B1OC(C)(C)C(C)(C)O1.C(=O)([O-])[O-].[K+].[K+]>C1COCC1>[F:1][C:2]([F:31])([F:30])[C:3]1[CH:4]=[C:5]([C@H:13]2[O:17][C:16](=[O:18])[N:15]([CH2:19][C:20]3[C:25]([C:39]4[CH:38]=[C:37]([CH2:40][CH2:41][C:42]([O:44][CH3:45])=[O:43])[CH:36]=[CH:35][C:34]=4[O:33][CH3:32])=[CH:24][N:23]=[C:22]([S:27][CH3:28])[N:21]=3)[C@H:14]2[CH3:29])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1
Reactant: COC(=O)CCc1ccc(OC)c(B2OC(C)(C)C(C)(C)O2)c1
Reactant: CSc1ncc(Br)c(CN2C(=O)O[C@H](c3cc(C(F)(F)F)cc(C(F)(F)F)c3)[C@@H]2C)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: COC(=O)CCc1ccc(OC)c(-c2cnc(SC)nc2CN2C(=O)O[C@H](c3cc(C(F)(F)F)cc(C(F)(F)F)c3)[C@@H]2C)c1

Procedure:
(4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-3-{[5-bromo-2-(methylsulfanyl)pyrimidin-4-yl]methyl}-4-methyl-1,3-oxazolidin-2-one (INTERMEDIATE 45) (307 mg, 0.579 mmol), methyl 3-[4-methoxy-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]propanoate (INTERMEDIATE 2) (185 mg, 0.579 mmol), 1,1bis(di-tert-butylphosphino)ferrocene palladium dichloride (39.4 mg, 0.058 mmol), potassium carbonate (0.724 ml, 1.447 mmol) and THF (5 mL) were sealed in a uw vessel and subject to microwave irradiation at 140° C. for 20 min. The reaction crude was dried over Na2SO4, filtered and purified by preparative TLC (silica gel) developed with EtOAc/hexanes (40% ethyl acetate v/v) to give a brown solid as the titled compound. LCMS calc.=643.16. found=644.17 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[CH:10][C:6]([C:7]([OH:9])=O)=[CH:5][C:4]=1[S:12][CH2:13][CH2:14][C:15]1[CH:16]=[C:17]([CH3:21])[CH:18]=[CH:19][CH:20]=1.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.Cl.C[O:48][C:49]([C:51]1([NH2:60])[CH2:59][C:58]2[C:53](=[CH:54][CH:55]=[CH:56][CH:57]=2)[CH2:52]1)=[O:50].[Cl-].[Li+].[OH-].[Li+]>CN(C=O)C.C1COCC1.O.CC(=O)OCC>[CH3:1][O:2][C:3]1[CH:11]=[CH:10][C:6]([C:7]([NH:60][C:51]2([C:49]([OH:50])=[O:48])[CH2:52][C:53]3[C:58](=[CH:57][CH:56]=[CH:55][CH:54]=3)[CH2:59]2)=[O:9])=[CH:5][C:4]=1[S:12][CH2:13][CH2:14][C:15]1[CH:16]=[C:17]([CH3:21])[CH:18]=[CH:19][CH:20]=1
Reactant: COC(=O)C1(N)Cc2ccccc2C1
Reactant: COc1ccc(C(=O)O)cc1SCCc1cccc(C)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCOC(C)=O
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccc(C(=O)NC2(C(=O)O)Cc3ccccc3C2)cc1SCCc1cccc(C)c1
Reaction time: 8 h
Yield: 20.8 %

Procedure:
700 mg of the crude compound of step 2 were dissolved in 5 ml of DMF and 598 mg (4.63 mmol) of EDIA and 968 mg (2.55 mmol) of O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate were added. Then a solution of 527 mg (2.32 mmol) of 2-amino-indane-2-carboxylic acid methyl ester hydrochloride in 5 ml of DMF was added. After stirring overnight, EA and an aqueous solution of lithium chloride (4%) were added, the organic phase was separated, washed once with a solution of lithium chloride and twice with a solution of sodium hydrogencarbonate, dried and evaporated. The solid residue was dissolved in 10 ml of a 9:1 mixture of THF and water, and 131 mg (5.47 mmol) of lithium hydroxide were added. After stirring overnight, the mixture was evaporated to dryness. The residue was purified by preparative RP HPLC (water/ACN gradient) to give 222 mg of the title compound.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][C:5]2[C:13](=[O:14])[N:8]3[CH2:9][CH2:10][NH:11][CH2:12][CH:7]3[C:6]=2[N:15]=1.[Br:16][C:17]1[CH:22]=[C:21]([C:23]([F:26])([F:25])[F:24])[CH:20]=[CH:19][C:18]=1[S:27](Cl)(=[O:29])=[O:28]>ClCCl.CCN(C(C)C)C(C)C>[Br:16][C:17]1[CH:22]=[C:21]([C:23]([F:25])([F:24])[F:26])[CH:20]=[CH:19][C:18]=1[S:27]([N:11]1[CH2:10][CH2:9][N:8]2[C:13](=[O:14])[C:5]3[CH:4]=[CH:3][C:2]([CH3:1])=[N:15][C:6]=3[CH:7]2[CH2:12]1)(=[O:29])=[O:28]
Reactant: O=S(=O)(Cl)c1ccc(C(F)(F)F)cc1Br
Reactant: Cc1ccc2c(n1)C1CNCCN1C2=O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: Cc1ccc2c(n1)C1CN(S(=O)(=O)c3ccc(C(F)(F)F)cc3Br)CCN1C2=O
Temperature: 25 °C
Reaction time: 3 h
Yield: 70.5 %

Procedure:
To the solution of 2-methyl-8,9,10,10a-tetrahydropyrido[2′,3′:3,4]pyrrolo[1,2-a]pyrazin-5(7H)-one (may be prepared as described in Intermediate 8; 100 mg) in dichloromethane (3.5 ml), DIPEA (0.129 ml) was added under argon atmosphere at room temperature then 2-bromo-4-(trifluoromethyl)benzenesulfonyl chloride (159 mg) was added at 0° C., and then the ice water bath was removed and the reaction mixture allowed to stir at room temperature for 3 h. The reaction mixture was partitioned between DCM (40 ml) and (20 ml) sodium bicarbonate. The organic phase was washed with sodium bicarbonate (20 ml), HCl (2×20 ml) and water (2×20 ml) and then it was dried using phase separator before the DCM was removed under vacuum to give the title compound (170 mg), which was used in next step without purification.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:22])[CH:5]([CH2:11][C:12]([O:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[O:13])[C:6]([O:8][CH2:9][CH3:10])=[O:7])[CH3:2].[CH3:23][C:24]([C:27]1[CH:34]=[CH:33][C:30]([CH2:31]Br)=[CH:29][CH:28]=1)([CH3:26])[CH3:25].[H-].[Na+]>>[C:16]1([CH2:15][O:14][C:12](=[O:13])[CH2:11][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])([C:4]([O:3][CH2:1][CH3:2])=[O:22])[CH2:31][C:30]2[CH:33]=[CH:34][C:27]([C:24]([CH3:26])([CH3:25])[CH3:23])=[CH:28][CH:29]=2)[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: CC(C)(C)c1ccc(CBr)cc1
Reactant: CCOC(=O)C(CC(=O)OCc1ccccc1)C(=O)OCC
Agent: [H-]
Agent: [Na+]
Product: CCOC(=O)C(CC(=O)OCc1ccccc1)(Cc1ccc(C(C)(C)C)cc1)C(=O)OCC
Yield: 53 %

Procedure:
Prepared analogously to Example A62 from diethyl[(phenylmethoxycarbonyl)methyl]-malonoate and 4-(1,1-dimethylethyl)-benzylbromide in the presence of sodium hydride in a yield of 53% of theory.
Reaction SMILES: ClC1C(Cl)=C(C)NC=1C(O)=O.[Cl:12][C:13]1[C:17]([Cl:18])=[C:16]([C:19]#[N:20])[NH:15][C:14]=1[C:21]([O:23]C)=[O:22]>>[Cl:12][C:13]1[C:17]([Cl:18])=[C:16]([C:19]#[N:20])[NH:15][C:14]=1[C:21]([OH:23])=[O:22]
Reactant: COC(=O)c1[nH]c(C#N)c(Cl)c1Cl
Agent: Cc1[nH]c(C(=O)O)c(Cl)c1Cl
Product: N#Cc1[nH]c(C(=O)O)c(Cl)c1Cl

Procedure:
The title compound was prepared by a procedure analogous to Intermediate 3 starting from methyl 3,4-dichloro-5-cyano-1H-pyrrole-2-carboxy late (Intermediate 130).
Reaction SMILES: Cl[C:2](=[CH2:6])[C:3](O)=[O:4].Cl.Cl.[CH3:9][O:10][C:11](=[O:20])[C@H:12]([CH2:14][C:15]1[N:19]=[CH:18][NH:17][CH:16]=1)[NH2:13].C(N(CC)CC)C>C(Cl)Cl>[CH3:9][O:10][C:11](=[O:20])[C@H:12]([CH2:14][C:15]1[N:19]=[CH:18][NH:17][CH:16]=1)[NH:13][C:3](=[O:4])[CH:2]=[CH2:6]
Reactant: C=C(Cl)C(=O)O
Reactant: COC(=O)[C@@H](N)Cc1c[nH]cn1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C=CC(=O)N[C@@H](Cc1c[nH]cn1)C(=O)OC
Yield: 44.8 %

Procedure:
After chloroacrylic acid (1.6 ml, 20 mmol) was dropped, with ice cooling, into a solution of histidine methyl ester dihydrochloride (6.05 g, 25 mmol) and triethylamine (14 mL, 100 mmol) in methylene chloride (200 mL), the same operation as in the synthesis of N(α)-acryloyl-N(π)-methyl-L-histidine methyl ester was conducted to give N(α)-acryloyl-L-histidine methyl ester (2.0 g, 36%) as an oily product.
Reaction SMILES: C(=O)([O-])[O-].[Na+].[Na+].[CH3:7][O:8][C:9](=[O:42])[NH:10][C@H:11]([C:15]([N:17]1[CH2:21][CH2:20][CH2:19][C@H:18]1[C:22]1[NH:23][CH:24]=[C:25]([C:27]2[CH:32]=[CH:31][C:30](B3OC(C)(C)C(C)(C)O3)=[CH:29][CH:28]=2)[N:26]=1)=[O:16])[CH:12]([CH3:14])[CH3:13].Br[C:44]1[CH:50]=[CH:49][C:47]([NH2:48])=[CH:46][C:45]=1[Cl:51]>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.O>[CH3:7][O:8][C:9](=[O:42])[NH:10][C@H:11]([C:15]([N:17]1[CH2:21][CH2:20][CH2:19][C@H:18]1[C:22]1[NH:23][CH:24]=[C:25]([C:27]2[CH:28]=[CH:29][C:30]([C:44]3[CH:50]=[CH:49][C:47]([NH2:48])=[CH:46][C:45]=3[Cl:51])=[CH:31][CH:32]=2)[N:26]=1)=[O:16])[CH:12]([CH3:13])[CH3:14]
Reactant: Nc1ccc(Br)c(Cl)c1
Reactant: COC(=O)N[C@H](C(=O)N1CCC[C@H]1c1nc(-c2ccc(B3OC(C)(C)C(C)(C)O3)cc2)c[nH]1)C(C)C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Product: COC(=O)N[C@H](C(=O)N1CCC[C@H]1c1nc(-c2ccc(-c3ccc(N)cc3Cl)cc2)c[nH]1)C(C)C
Temperature: 90 °C

Procedure:
Saturated aqueous sodium carbonate (0.2 mL) was added to a mixture of [(S)-2-methyl-1-((S)-2-{4-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-1H-imidazol-2-yl}-pyrrolidine-1-carbonyl)-propyl]-carbamic acid methyl ester (100 mg, 0.20 mmol), 4-bromo-3-chloroaniline (46 mg, 0.22 mmol), tetrakis(triphenylphosphine)palladium(0) (23 mg, 0.02 mmol), and water (0.3 mL). The reaction mixture was purged with nitrogen and then 1,4-dioxane (0.7 mL) was added. The reaction mixture was degassed, stirred, and heated at 90° C. overnight. Water and ethyl acetate were added; the reaction mixture was concentrated; dissolved in 1:1 acetic acid:water (1 mL) and purified by preparative HPLC. Fractions were combined, adjusted to pH 8-9 with aqueous sodium bicarbonate, and extracted with DCM. Extracts were washed with water, dried with sodium sulfate, and concentrated. The concentrate was dissolved in methanol and concentrated under vacuum to provide the title compound (m/z): [M+H]+ calcd for C26H30ClN5O3 496.20 found 496.7.
Reaction SMILES: [CH2:1]([N:3]1[C:12]2[C:7](=[CH:8][C:9]([F:14])=[C:10](F)[CH:11]=2)[C:6](=[O:15])[C:5]([C:16]([OH:18])=[O:17])=[CH:4]1)[CH3:2].CN(C)C=O.[CH3:24][NH:25][CH2:26][CH:27]1[CH2:31][CH2:30][NH:29][CH2:28]1>C(#N)C>[CH2:1]([N:3]1[C:12]2[C:7](=[CH:8][C:9]([F:14])=[C:10]([N:29]3[CH2:30][CH2:31][CH:27]([CH2:26][NH:25][CH3:24])[CH2:28]3)[CH:11]=2)[C:6](=[O:15])[C:5]([C:16]([OH:18])=[O:17])=[CH:4]1)[CH3:2]
Reactant: CNCC1CCNC1
Reactant: CCn1cc(C(=O)O)c(=O)c2cc(F)c(F)cc21
Solvent: CN(C)C=O
Solvent: CC#N
Product: CCn1cc(C(=O)O)c(=O)c2cc(F)c(N3CCC(CNC)C3)cc21
Temperature: 25 °C
Yield: 85.3 %

Procedure:
A mixture of 1.00 g (3.95 mmole) 1-ethyl-6,7-difluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid, 10 ml N,N-dimethylformamide, 75 ml acetonitrile, and 1.35 g (11.85 mmole) of N-methyl-3-pyrrolidinemethanamine were refluxed overnight The reaction was cooled to room temperature and filtered. The precipitate was washed with water, ethanol/ether (1:3), and finally with ether until dry to give 1.17 g of 1-ethyl-6-fluoro-1,4-dihydro-7-[3-[(methylamino)methyl]-1-pyrrolidinyl]-4-oxo-3-quinolinecarboxylic acid, mp 247°-250° C.
Reaction SMILES: N#N.Br[C:4]1[N:5]=[C:6]([CH3:13])[S:7][C:8]=1[NH:9][C:10](=[O:12])[CH3:11].C([O-])([O-])=O.[Cs+].[Cs+].CN[C@@H]1CCCC[C@H]1NC.[CH3:30][C:31]1[N:32]=[C:33]([CH2:36][CH2:37][CH3:38])[NH:34][CH:35]=1>CN(C=O)C.[Cu]I>[CH3:13][C:6]1[S:7][C:8]([NH:9][C:10](=[O:12])[CH3:11])=[C:4]([N:34]2[CH:35]=[C:31]([CH3:30])[N:32]=[C:33]2[CH2:36][CH2:37][CH3:38])[N:5]=1
Reactant: CC(=O)Nc1sc(C)nc1Br
Reactant: CCCc1nc(C)c[nH]1
Agent: [Cu]I
Agent: CN[C@@H]1CCCC[C@H]1NC
Agent: N#N
Solvent: CN(C)C=O
Product: CCCc1nc(C)cn1-c1nc(C)sc1NC(C)=O
Temperature: 90 °C
Reaction time: 8 h
Yield: 12.7 %

Procedure:
A flask (backfilled with N2) was charged with N-(4-bromo-2-methylthiazol-5-yl)acetamide (400 mg, 1.7 mmol), CuI(324 mg, 1.7 mmol) and Cs2CO3 (1.6 g, 5.1 mmol). Trans-N,N′-dimethylcyclohexane-1,2-diamine (CAS: 61798-24-1, 242 mg, 1.7 mmol) and 4-methyl-2-propyl-1H-imidazole (230 mg, 1.9 mmol) in DMF (9.0 mL) were added and the mixture was stirred at 90° C. overnight. After the mixture was cooled to room temperature, the mixture was filtered through a syringe filter (washed with DMF). The filtrate was purified by prep-HPLC to give 60 mg of the pure title compound.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH3:9].[Cl:10][SiH:11]([Cl:13])[Cl:12]>[Cl-].C([P+](CCCC)(CCCC)CCCC)CCC>[CH2:2]([Si:11]([Cl:13])([Cl:12])[Cl:10])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH3:9]
Reactant: Cl[SiH](Cl)Cl
Reactant: CCCCCCCCCl
Agent: CCCC[P+](CCCC)(CCCC)CCCC
Agent: [Cl-]
Product: CCCCCCCC[Si](Cl)(Cl)Cl
Yield: 85.2 %

Procedure:
In the same apparatus and procedure as Example 1 above, 0.20 g (0.68 mmol) of tetrabutylphosphonium chloride, 1.00 g (6.73 mmol) of 1-chlorooctane and 2.71 g (20.0 mmol) of trichlorosilane were reacted at 170° C. for 2 hrs. The resulting mixture was distilled to give 1.42 g of n-octyltrichlorosilane (yield; 85%).