Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C@H:3]1[CH2:7][NH:6][CH2:5][C@H:4]1[NH:8][C:9]1[C:10]2[N:11]([CH:18]=[C:19]([C:21]3[CH:22]=[N:23][C:24]([CH2:27][NH:28][C:29](=[O:33])[CH2:30][O:31][CH3:32])=[CH:25][CH:26]=3)[CH:20]=2)[N:12]=[CH:13][C:14]=1[C:15]([NH2:17])=[O:16])[CH3:2].Cl[C:35]1[S:36][C:37]([C:40]#[N:41])=[CH:38][N:39]=1.C(N(C(C)C)CC)(C)C>CC(N(C)C)=O>[C:40]([C:37]1[S:36][C:35]([N:6]2[CH2:7][C@H:3]([CH2:1][CH3:2])[C@H:4]([NH:8][C:9]3[C:10]4[N:11]([CH:18]=[C:19]([C:21]5[CH:22]=[N:23][C:24]([CH2:27][NH:28][C:29](=[O:33])[CH2:30][O:31][CH3:32])=[CH:25][CH:26]=5)[CH:20]=4)[N:12]=[CH:13][C:14]=3[C:15]([NH2:17])=[O:16])[CH2:5]2)=[N:39][CH:38]=1)#[N:41]
Reactant: CC[C@H]1CNC[C@H]1Nc1c(C(N)=O)cnn2cc(-c3ccc(CNC(=O)COC)nc3)cc12
Reactant: N#Cc1cnc(Cl)s1
Solvent: CC(=O)N(C)C
Solvent: CCN(C(C)C)C(C)C
Product: CC[C@H]1CN(c2ncc(C#N)s2)C[C@H]1Nc1c(C(N)=O)cnn2cc(-c3ccc(CNC(=O)COC)nc3)cc12
Temperature: 100 °C
Reaction time: 0.25 h
Yield: 22 %

Procedure:
A mixture of 4-(((3S,4S)-4-ethylpyrrolidin-3-yl)amino)-6-(6-((2-methoxyacetamido)methyl)pyridin-3-yl)pyrrolo[1,2-b]pyridazine-3-carboxamide, 2hydroiodide from Step 5 of Example 266 (30 mg, 0.042 mmol), 2-chlorothiazole-5-carbonitrile (7.36 mg, 0.051 mmol) and diisopropylethylamine (0.052 mL, 0.297 mmol) in DMA (0.25 mL) was heated to 100° C. for 2 hr. The reaction mixture was purified via preparative LC/MS with the following conditions: Column: Waters XBridge C18, 19×150 mm, 5-μm particles; Guard Column: Waters XBridge C18, 19×10 mm, 5-μm particles; Mobile Phase A: 5:95 acetonitrile:water with 10-mM ammonium acetate; Mobile Phase B: 95:5 acetonitrile:water with 10-mM ammonium acetate; Gradient: 5-100% B over 15 minutes, then a 5-minute hold at 100% B; Flow: 20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation to afford the title compound (5.3 mg, 0.024 mmol, 22% yield). 1H NMR (500 MHz, METHANOL-d4) δ 8.80 (d, J=2.0 Hz, 1H), 8.14 (s, 1H), 8.02 (dd, J=8.2, 2.2 Hz, 1H), 7.98 (d, J=1.5 Hz, 1H), 7.69 (s, 1H), 7.39 (d, J=7.9 Hz, 1H), 7.14 (d, J=1.5 Hz, 1H), 5.07 (t, J=4.5 Hz, 1H), 4.58 (s, 2H), 4.01 (dd, J=10.9, 4.0 Hz, 1H), 3.97 (s, 2H), 3.83 (d, J=7.9 Hz, 2H), 3.46 (s, 4H), 2.79-2.66 (m, 1H), 1.77 (tq, J=14.6, 7.1 Hz, 2H), 1.04 (t, J=7.4 Hz, 3H). MS (ES+) m/z: 560.1 (M+H); LC retention time: 1.31 min (analytical LCMS Method H).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4](Br)[C:3]=1[Cl:9].C([Li])CCC.[CH3:15][S:16]SC.O>C(OCC)C>[Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([S:16][CH3:15])[C:3]=1[Cl:9]
Reactant: Clc1c(Br)cccc1Br
Reactant: CSSC
Agent: [Li]CCCC
Solvent: CCOCC
Solvent: O
Product: CSc1cccc(Br)c1Cl
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 41.1 %

Procedure:
To a solution of 1,3-dibromo-2-chlorobenzene (3.4 g, 12.6 mmol) in dry diethyl ether (60 ml), under nitrogen, at −78° C., was added dropwise n-butyllithium (2.5 M in hexane, 5.0 ml, 12.6 mmol). The mixture was stirred for 1 h after which dimethyldisulfide (1.0 ml, 13.9 mmol) was added dropwise. The resulting mixture was stirred at −78° C. for 30 min and then brought to ambient temperature. Water (100 ml) was added and the mixture was extracted with ethylacetate (3×100 ml). The combined organic phases was dried (MgSO4), filtered and evaporated to dryness. The residue was purified by flash column chromatography (isooctane) to give the title compound (1.23 g). MS m/z (rel. intensity, 70 eV) 240 (M+, 28), 238 (M+, bp), 236 (71), 205 (29), 142 (27).
Reaction SMILES: [C:1]([C@@H:4]1[CH2:8][N:7]([C:9]2[CH:14]=[CH:13][N:12]3[N:15]=[CH:16][C:17]([C:18]([N:20](CC4C=CC(OC)=CC=4)CC4C=CC(OC)=CC=4)=[O:19])=[C:11]3[CH:10]=2)[C@@H:6]([C:39]2[CH:44]=[CH:43][CH:42]=[C:41]([F:45])[CH:40]=2)[CH2:5]1)(=[O:3])[NH2:2]>C(O)(C(F)(F)F)=O.CS(C)=O>[C:1]([C@@H:4]1[CH2:8][N:7]([C:9]2[CH:14]=[CH:13][N:12]3[N:15]=[CH:16][C:17]([C:18]([NH2:20])=[O:19])=[C:11]3[CH:10]=2)[C@@H:6]([C:39]2[CH:44]=[CH:43][CH:42]=[C:41]([F:45])[CH:40]=2)[CH2:5]1)(=[O:3])[NH2:2]
Reactant: COc1ccc(CN(Cc2ccc(OC)cc2)C(=O)c2cnn3ccc(N4C[C@@H](C(N)=O)C[C@@H]4c4cccc(F)c4)cc23)cc1
Solvent: CS(C)=O
Solvent: O=C(O)C(F)(F)F
Product: NC(=O)c1cnn2ccc(N3C[C@@H](C(N)=O)C[C@@H]3c3cccc(F)c3)cc12

Procedure:
A solution of 5-((2R,4S)-4-carbamoyl-2-(3-fluorophenyl)pyrrolidin-1-yl)-N,N-bis(4-methoxybenzyl)pyrazolo[1,5-a]pyridine-3-carboxamide (I-54) (10 mg, 0.016 mmol) in TFA (0.5 mL) was heated to 60° C. for 2 hours. The reaction was reduced to dryness and the crude material was taken up in DMSO and purified by preparative LCMS and lyophilized to give 5-((2R,4S)-4-carbamoyl-2-(3-fluorophenyl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyridine-3-carboxamide (X-26). 1H NMR (400 MHz, DMSO) δ 8.38 (d, J=7.7 Hz, 1 H), 8.26 (s, 1 H), 7.53 (s, 1 H), 7.44-7.31 (m, 1H), 7.15-7.01 (m, 2 H), 6.96 (s, 1 H), 6.31 (d, J=7.1 Hz, 1 H), 5.13 (d, J=8.0 Hz, 1 H), 3.98-3.85 (m, 1 H), 3.65-3.54 (m, 1 H), 3.20-3.07 (m, 1 H), 2.60-2.52 (m, 1 H), 2.08 (dd, J=6.9, 12.0 Hz, 1 H). MS m/z 368.1 (M+1)+.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:20])/[CH:4]=[CH:5]/[C:6]1[C:11]([C:12]#[C:13][CH2:14][CH2:15][CH2:16][CH2:17][OH:18])=[CH:10][CH:9]=[CH:8][C:7]=1[OH:19].Br[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][O:27][C:28](=[O:30])[CH3:29]>>[CH3:1][O:2][C:3](=[O:20])/[CH:4]=[CH:5]/[C:6]1[C:11]([C:12]#[C:13][CH2:14][CH2:15][CH2:16][CH2:17][OH:18])=[CH:10][CH:9]=[CH:8][C:7]=1[O:19][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][O:27][C:28](=[O:30])[CH3:29]
Reactant: CC(=O)OCCCCCBr
Reactant: COC(=O)/C=C/c1c(O)cccc1C#CCCCCO
Product: COC(=O)/C=C/c1c(C#CCCCCO)cccc1OCCCCCOC(C)=O
Yield: 77 %

Procedure:
Using the procedure of example 63, (E)-3-[2-hydroxy-6-(6-hydroxy-1-hexynyl)phenyl]-2-propenoic acid methyl ester from the preceding example was converted into the title compound by alkylation with 5-bromopentylacetate. The product was obtained as a colorless oil in 77% yield.
Reaction SMILES: [O:1]([CH:8]1[C:16]2[C:11](=[CH:12][C:13]([C:17]([O:19]C)=[O:18])=[CH:14][CH:15]=2)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O.[OH-].[Li+]>O1CCCC1.CO.O>[O:1]([CH:8]1[C:16]2[C:11](=[CH:12][C:13]([C:17]([OH:19])=[O:18])=[CH:14][CH:15]=2)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COC(=O)c1ccc2c(c1)CCC2Oc1ccccc1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: O=C(O)c1ccc2c(c1)CCC2Oc1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 92.4 %

Procedure:
To a solution of methyl 1-phenoxy-2,3-dihydro-1H-indene-5-carboxylate (400 mg, 1.49 mmol) in tetrahydrofuran, methanol and water (3:1:1, 20 mL) was added lithium hydroxide monohydrate (377 mg, 8.98 mmol). The mixture was stirred at room temperature for 2 hours. The mixture was concentrated in vacuo and quenched with hydrochloric acid aqueous (1N, 15 mL). Then the mixture was concentrated to give 1-phenoxy-2,3-dihydro-1H-indene-5-carboxylic acid (350 mg, 92%) as white solid. LRMS (M+H)− m/z: calcd 254.09. found 254.
Reaction SMILES: OO.C([C@H]1COC(=O)N1[C:16](=[O:27])[C@@H:17]([CH2:25][OH:26])[CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)C1C=CC=CC=1.O.[OH-].[Li+].S([O-])([O-])=[O:32].[Na+].[Na+]>O.C1COCC1>[OH:26][CH2:25][C@@H:17]([CH2:18][C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1)[C:16]([OH:27])=[O:32]
Reactant: O=C1OC[C@H](Cc2ccccc2)N1C(=O)[C@@H](CO)Cc1ccccc1
Reactant: O=S([O-])[O-]
Agent: OO
Agent: [Li+]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)[C@@H](CO)Cc1ccccc1
Reaction time: 2.5 h

Procedure:
9 M of Hydrogen peroxide in water (50 mL) was added to a solution of intermediate (7c) (14.8 g, 43.6 mmol) in THF (100 mL) at 0° C. followed by the addition of aqueous 1.5 M lithium hydroxide monohydrate (58 mL). After 2.5 hours at room temperature, sodium sulfite (10 g) in water (100 mL) was added and the mixture was stirred for 30 minutes. The mixture was extracted with water (300 mL) and chloroform (2×150 mL). The aqueous layer was acidified to pH2 with aqueous 6M HCl and extracted with EtOAc (3×200 mL). The combined organic extracts were dried over Na2SO4, filtered, and concentrated in vacuo to yield intermediate (7d), which was used in the next step without further purification.
Reaction SMILES: [F:1][CH2:2][C:3]1[CH:4]=[C:5]([CH:7]=[CH:8][CH:9]=1)[NH2:6].C(=O)(O)[O-].[Na+].Cl[CH2:16][C:17]([O:19][CH3:20])=[O:18]>O>[CH3:20][O:19][C:17](=[O:18])[CH2:16][NH:6][C:5]1[CH:7]=[CH:8][CH:9]=[C:3]([CH2:2][F:1])[CH:4]=1
Reactant: COC(=O)CCl
Reactant: Nc1cccc(CF)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Product: COC(=O)CNc1cccc(CF)c1
Temperature: 90 °C
Yield: 48.1 %

Procedure:
3-Fluoromethyl aniline (containing 37% 3-methylaniline, 13.6 g≡68 mmol) was mixed with dry acetonitrite (10 ml), sodium bicarbonate (15.4 g, 183 mmol) and methyl chloroacetate (12 ml, 137 mmol) and heated to 90° C. under nitrogen for 14 h. The cooled reaction mixture was poured into water (100 ml) and extracted with ethyl acetate (4×100 ml). The combined organic extracts were dried (Na2SO4) and concentrated in vacuo to give an orange oil. The crude product was purified by chromatography on silica (Merck 9385, 1.5 kg) eluted with ether-hexane 1:4 to give Intermediate 54 (6.45 g, 48%) as a white crystalline solid, m.p. 47°-47.5°.
Reaction SMILES: Br[C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][C:8](=[O:19])[N:9]2[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[Cl:18])=[C:4]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=2[Cl:26])[N:3]=1.[NH2:27][CH:28]([CH2:31][OH:32])[CH2:29][OH:30].O>CN1C(=O)CCC1>[Cl:18][C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=1[N:9]1[C:10]2[C:5](=[C:4]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[Cl:26])[N:3]=[C:2]([NH:27][CH:28]([CH2:31][OH:32])[CH2:29][OH:30])[CH:11]=2)[CH:6]=[CH:7][C:8]1=[O:19]
Reactant: NC(CO)CO
Reactant: O=c1ccc2c(-c3ccccc3Cl)nc(Br)cc2n1-c1ccccc1Cl
Solvent: O
Solvent: CN1CCCC1=O
Product: O=c1ccc2c(-c3ccccc3Cl)nc(NC(CO)CO)cc2n1-c1ccccc1Cl
Yield: 23.2 %

Procedure:
7-Bromo-1,5-bis(2-chlorophenyl)[1,6]naphthyridin-2(1H)-one (38 mg, 0.085 mmol) was dissolved in NMP (2 ml) and serinol (2-amino-1,3-propanediol) (35 mg, 0.384 mmol) added, and the solution heated in a Smith creator microwave at 220° for 0.5 h. After cooling, the solution was added to water (12 ml) and extracted with dichloromethane (10 ml). The mixture was passed through a hydrophobic frit and evaporated in vacuo. The residue was purified by SPE (SiO2, 10 g) eluting with dichloromethane-methanol (98:2) to afford the title compound as a gum (9 mg, 23%).
Reaction SMILES: [CH2:1]([CH:4]1[CH:30]=[C:29]([CH3:31])[CH2:28][CH:27]([CH3:32])[CH2:26][CH:25]([O:33][CH3:34])[CH:24]2[O:35][C:20]([OH:39])([CH:21]([CH3:38])[CH2:22][CH:23]2[O:36][CH3:37])[C:19](=[O:40])[C:18](=[O:41])[N:17]2[CH:12]([CH2:13][CH2:14][CH2:15][CH2:16]2)[C:11](=[O:42])[O:10][CH:9]([C:43]([CH3:54])=[CH:44][CH:45]2[CH2:50][CH2:49][CH:48]([OH:51])[CH:47]([O:52][CH3:53])[CH2:46]2)[CH:8]([CH3:55])[CH:7]=[CH:6][C:5]1=[O:56])[CH:2]=[CH2:3].CCC(C)[BH-](C(C)CC)C(C)CC.[Li+].[Cl-].[NH4+]>O1CCCC1.C(O)(C)(C)C>[CH2:1]([CH:4]1[CH:30]=[C:29]([CH3:31])[CH2:28][CH:27]([CH3:32])[CH2:26][CH:25]([O:33][CH3:34])[CH:24]2[O:35][C:20]([OH:39])([CH:21]([CH3:38])[CH2:22][CH:23]2[O:36][CH3:37])[C:19](=[O:40])[C:18](=[O:41])[N:17]2[CH:12]([CH2:13][CH2:14][CH2:15][CH2:16]2)[C:11](=[O:42])[O:10][CH:9]([C:43]([CH3:54])=[CH:44][CH:45]2[CH2:50][CH2:49][CH:48]([OH:51])[CH:47]([O:52][CH3:53])[CH2:46]2)[CH:8]([CH3:55])[CH:7]=[CH:6][CH:5]1[OH:56])[CH:2]=[CH2:3]
Reactant: C=CCC1C=C(C)CC(C)CC(OC)C2OC(O)(C(=O)C(=O)N3CCCCC3C(=O)OC(C(C)=CC3CCC(O)C(OC)C3)C(C)C=CC1=O)C(C)CC2OC
Agent: CCC(C)[BH-](C(C)CC)C(C)CC
Agent: [Cl-]
Agent: [Li+]
Solvent: CC(C)(C)O
Solvent: C1CCOC1
Product: C=CCC1C=C(C)CC(C)CC(OC)C2OC(O)(C(=O)C(=O)N3CCCCC3C(=O)OC(C(C)=CC3CCC(O)C(OC)C3)C(C)C=CC1O)C(C)CC2OC
Reaction time: 0.67 h
Yield: 19.9 %

Procedure:
The title compound from example 14 (50 mg) was dissolved in tetrahydrofuran (3 ml) and t-butanol (0.05 ml). The resulting solution was added dropwise to a stirred solution of L-Selectride (Registered Trade Mark) (0.3 ml of a 1M solution in tetrahydrofuran) under a nitrogen atmosphere at -78° C. Stirring was continued for 40 minutes, after which saturated ammonium chloride solution (5 ml) was added and the mixture extracted with ethyl acetate. After filtration of the organic phase, and removal of solvent in vacuo, chromatography on silica eluting with ether/methanol (15:1) yielded the title compound as an oil (10 mg).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1[CH:14]=[C:13]([Cl:15])[CH:12]=[CH:11][C:10]=1/[CH:16]=[CH:17]/[C:18]([OH:20])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].[F:21][C:22]1[CH:34]=[CH:33][C:25]([CH2:26][N:27]2[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]2)=[CH:24][CH:23]=1.CCN=C=NCCCN(C)C.Cl.Cl>C(Cl)Cl>[C:1]([O:5][C:6](=[O:7])[NH:8][C:9]1[CH:14]=[C:13]([Cl:15])[CH:12]=[CH:11][C:10]=1/[CH:16]=[CH:17]/[C:18]([N:30]1[CH2:29][CH2:28][N:27]([CH2:26][C:25]2[CH:33]=[CH:34][C:22]([F:21])=[CH:23][CH:24]=2)[CH2:32][CH2:31]1)=[O:20])([CH3:2])([CH3:3])[CH3:4]
Reactant: Fc1ccc(CN2CCNCC2)cc1
Reactant: CC(C)(C)OC(=O)Nc1cc(Cl)ccc1/C=C/C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Product: CC(C)(C)OC(=O)Nc1cc(Cl)ccc1/C=C/C(=O)N1CCN(Cc2ccc(F)cc2)CC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 63.3 %

Procedure:
(E)-3-(2-tert-Butoxycarbonylamino-4-chlorophenyl)-acrylic acid (150 mg, 0.5 mmol), 1-(4-fluorobenzyl)-piperazine (98 mg, 0.5 mmol) and EDCl.HCl (96 mg, 0.5 mmol) were dissolved in CH2Cl2 and stirred at room temperature for 18 hours. The reaction mixture was purified via chromatography (SiO2, EtOAc) to yield the title compound as a white foam (150 mg, 63%).
Reaction SMILES: [H-].[Na+].[Br:3][C:4]1[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][C:5]=1[C:6]([NH:8][C:9]1[CH:10]=[C:11]([CH:16]=[CH:17][C:18]=1[CH3:19])[C:12]([O:14][CH3:15])=[O:13])=[O:7].[CH2:26](Br)[CH:27]=[CH2:28]>C1COCC1>[CH2:28]([N:8]([C:6](=[O:7])[C:5]1[CH:20]=[C:21]([O:24][CH3:25])[CH:22]=[CH:23][C:4]=1[Br:3])[C:9]1[CH:10]=[C:11]([CH:16]=[CH:17][C:18]=1[CH3:19])[C:12]([O:14][CH3:15])=[O:13])[CH:27]=[CH2:26]
Reactant: COC(=O)c1ccc(C)c(NC(=O)c2cc(OC)ccc2Br)c1
Reactant: C=CCBr
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: C=CCN(C(=O)c1cc(OC)ccc1Br)c1cc(C(=O)OC)ccc1C
Temperature: 25 °C
Reaction time: 20 h

Procedure:
To a slurry of NaH (680 mg [60% dispersion in oil]) in THF (250 ml) at 0° C. was added methyl 3-[(2-bromo-5-methoxybenzoyl)amino]-4-methylbenzoate (5.36 g) portionwise. The reaction was stirred for 30 minutes at room temperature when allyl bromide (1.6 ml) was added dropwise and the solution was stirred for a further 20 hours at room temperature. The reaction mixture was quenched with water and then concentrated. The residue was dissolved in ethyl acetate and washed with water (×2), brine, dried (magnesium sulfate) and concentrated. The residue was purified by column chromatography on a silica column eluting using a gradient of iso-hexane to 50% ethyl acetate/iso-hexane to yield methyl 3-[allyl(2-bromo-5-methoxybenzoyl)amino]-4-methylbenzoate as a colourless oil (4.88 g); Mass Spectrum: M+H+ 417.
Reaction SMILES: Cl[C:2]1[CH:11]=[C:10]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=[CH:9]2)[C:3]=1[C:12](OC)=O.C([NH:20][S:21]([C:24]1[CH:29]=[CH:28][C:27](B(O)O)=[CH:26][CH:25]=1)(=[O:23])=[O:22])(C)(C)C.C([O-])([O-])=O.[Na+].[Na+]>C1(C)C=CC=CC=1.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>[C:12]1([C:3]2[C:4]3[C:10]([CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=3)=[CH:11][C:2]=2[C:27]2[CH:26]=[CH:25][C:24]([S:21]([NH2:20])(=[O:22])=[O:23])=[CH:29][CH:28]=2)[CH:10]=[CH:11][CH:2]=[CH:3][CH:4]=1
Reactant: COC(=O)c1c(Cl)cc2cccccc1-2
Reactant: CC(C)(C)NS(=O)(=O)c1ccc(B(O)O)cc1
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: Cc1ccccc1
Product: NS(=O)(=O)c1ccc(-c2cc3cccccc-3c2-c2ccccc2)cc1
Temperature: 0 °C
Yield: 277.5 %

Procedure:
Methyl 2-(4-t -butylaminosulfonylphenyl) azulene-1-carboxylate: To a solution of methyl 2-chloroazulene-1-carboxylate (0.50 g) in toluene (20.0 ml) was added 4-t-butylaminosulfonyl-phenylboronic acid (0.87 g), tetrakis(triphenylphosphine)palladium (0) (0.12 g), and 2M aqueous Na2CO3 (4.5 ml), and the reaction mixture was heated under reflux for 16 hr. The mixture was poured into ice-water, followed by extracted with EtOAc. The combined EtOAc extracts were washed with water and brine, dried over Na2SO4, and concentrated. The crude product was purified by SiO2 column chromatography (CHCl3 /EtOAc, 100:1) to give the title compound (1.13 g) as violet crystals; mp 169°-170° C.
Reaction SMILES: Cl.[NH2:2][CH:3]([CH:7]([C:15]1[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=1)[C:8]1[CH:13]=[CH:12][C:11]([F:14])=[CH:10][CH:9]=1)[C:4]([OH:6])=[O:5].[OH-].[Na+].[C:24]1([CH2:30][C:31](Cl)=[O:32])[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.Cl>C(OCC)(=O)C>[C:24]1([CH2:30][C:31]([NH:2][CH:3]([CH:7]([C:8]2[CH:9]=[CH:10][C:11]([F:14])=[CH:12][CH:13]=2)[C:15]2[CH:16]=[CH:17][C:18]([F:21])=[CH:19][CH:20]=2)[C:4]([OH:6])=[O:5])=[O:32])[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: O=C(Cl)Cc1ccccc1
Reactant: NC(C(=O)O)C(c1ccc(F)cc1)c1ccc(F)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Product: O=C(Cc1ccccc1)NC(C(=O)O)C(c1ccc(F)cc1)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 79.8 %

Procedure:
An aqueous solution (188 mL) of 2-amino-3,3-bis(4-fluorophenyl)propanoic acid hydrochloride (21.50 g, 68.9 mmol) was adjusted to pH 12.2 with 1M aqueous sodium hydroxide solution (154.2 g). Phenylacetyl chloride (10.8 mL, 81.7 mmol) was added dropwise at 0-10° C. while adjusting the mixture to pH 11-12 with 1M aqueous sodium hydroxide solution, and the mixture was stirred at room temperature for 3 hrs. Ethyl acetate (400 mL) was added to the reaction mixture, and the mixture was adjusted to pH 1.1 with concentrated hydrochloric acid and partitioned. The obtained organic layer was warmed to 40° C. and hexane (525 mL) was added. The mixture was cooled in an ice bath to allow solid precipitation. The solid was collected by filtration and dried to give the title compound (21.75 g).
Reaction SMILES: [C:1]([O:5][C:6](=[O:21])[N:7]([CH2:11][C:12]1[CH:17]=[CH:16][C:15]([Cl:18])=[C:14]([CH:19]=O)[CH:13]=1)[CH2:8][CH2:9][F:10])([CH3:4])([CH3:3])[CH3:2].[CH:22]1([NH2:25])[CH2:24][CH2:23]1.[BH4-].[Na+]>CO>[C:1]([O:5][C:6](=[O:21])[N:7]([CH2:11][C:12]1[CH:17]=[CH:16][C:15]([Cl:18])=[C:14]([CH2:19][NH:25][CH:22]2[CH2:24][CH2:23]2)[CH:13]=1)[CH2:8][CH2:9][F:10])([CH3:4])([CH3:3])[CH3:2]
Reactant: NC1CC1
Reactant: CC(C)(C)OC(=O)N(CCF)Cc1ccc(Cl)c(C=O)c1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CC(C)(C)OC(=O)N(CCF)Cc1ccc(Cl)c(CNC2CC2)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 88 %

Procedure:
A mixture of (4-chloro-3-formyl-benzyl)-(2-fluoro-ethyl)-carbamic acid tert-butyl ester (850 mg, 2.69 mmol) and cyclopropylamine (0.290 mL, 4.05 mmol) in MeOH (27 mL) was heated to reflux for 4 h. The mixture was allowed to cool to rt, and NaBH4 (153 mg, 4.40 mmol) was added in portions. The mixture was stirred for 1 h. The solvents were removed under reduced pressure, and EtOAc was added. The resulting mixture was washed with aq. sat. NaHCO3 and brine. The org. layer was dried over MgSO4, filtered, and the solvents were removed under reduced pressure. Purification of the crude by FC (CH2Cl2/MeOH 95:5) yielded the title compound (845 mg, 88%). LC-MS: tR=0.76 min; ES+: 357.19.
Reaction SMILES: [CH2:1]([O:19][CH2:20][CH:21]([O:43][C:44]([N:46]1[CH2:51][CH2:50][O:49][CH2:48][CH2:47]1)=[O:45])[CH2:22][O:23]C(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18]>C(O)(=O)C>[CH2:1]([O:19][CH2:20][CH:21]([O:43][C:44]([N:46]1[CH2:51][CH2:50][O:49][CH2:48][CH2:47]1)=[O:45])[CH2:22][OH:23])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18]
Reactant: CCCCCCCCCCCCCCCCCCOCC(COC(c1ccccc1)(c1ccccc1)c1ccccc1)OC(=O)N1CCOCC1
Solvent: CC(=O)O
Product: CCCCCCCCCCCCCCCCCCOCC(CO)OC(=O)N1CCOCC1
Temperature: 100 °C
Yield: 73.6 %

Procedure:
The glycerol compound (2.7 g) obtained in Example 42 was dissolved in 30 ml of 80% acetic acid, and the solution was heated at 100° C. for an hour. The solvent was then distilled off and the residue was purified by silica gel column chromatography to give 1.3 g of the above-identified compound melting at 48°-49° C.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([NH:7][S:8]([C:11]2[CH:12]=[C:13]3[C:17](=[CH:18][CH:19]=2)[NH:16][C:15](=[O:20])[CH2:14]3)(=[O:10])=[O:9])[CH:2]=1.[N:21]1([CH2:26][CH2:27][O:28][C:29]2[CH:30]=[C:31]3[C:35](=[CH:36][CH:37]=2)[NH:34][C:33]([CH:38]=O)=[CH:32]3)[CH2:25][CH2:24][CH2:23][CH2:22]1>>[N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([NH:7][S:8]([C:11]2[CH:12]=[C:13]3[C:17](=[CH:18][CH:19]=2)[NH:16][C:15](=[O:20])[C:14]3=[CH:38][C:33]2[NH:34][C:35]3[C:31]([CH:32]=2)=[CH:30][C:29]([O:28][CH2:27][CH2:26][N:21]2[CH2:25][CH2:24][CH2:23][CH2:22]2)=[CH:37][CH:36]=3)(=[O:10])=[O:9])[CH:2]=1
Reactant: O=Cc1cc2cc(OCCN3CCCC3)ccc2[nH]1
Reactant: O=C1Cc2cc(S(=O)(=O)Nc3cccnc3)ccc2N1
Product: O=C1Nc2ccc(S(=O)(=O)Nc3cccnc3)cc2C1=Cc1cc2cc(OCCN3CCCC3)ccc2[nH]1

Procedure:
2-Oxo-2,3-dihydro-1H-indole-5-sulfonic acid pyridin-3-ylamide was condensed with 5-(2-pyrrolidin-1-yl-ethoxy)-1H-indole-2-carbaldehyde to give the title compound.
Reaction SMILES: C(O)(C(F)(F)F)=O.[Cl:8][C:9]1[CH:28]=[CH:27][C:12]([CH2:13][CH:14]([CH2:19][C:20]([O:22]C(C)(C)C)=[O:21])[C:15]([O:17][CH3:18])=[O:16])=[CH:11][CH:10]=1>C(Cl)Cl>[Cl:8][C:9]1[CH:10]=[CH:11][C:12]([CH2:13][CH:14]([C:15]([O:17][CH3:18])=[O:16])[CH2:19][C:20]([OH:22])=[O:21])=[CH:27][CH:28]=1
Reactant: COC(=O)C(CC(=O)OC(C)(C)C)Cc1ccc(Cl)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COC(=O)C(CC(=O)O)Cc1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 5 h
Yield: 99 %

Procedure:
TFA (15 mL) was added dropwise to a solution of 4-tert-butyl 1-methyl 2-(4-chlorobenzyl)succinate (1.91 g, 6.1 mmol) in DCM (30 mL) at 0° C. The reaction mixture was then warmed to room temperature and stirred for 5 hours. The reaction was then concentrated to dryness to give 3-(4-chlorobenzyl)-4-methoxy-4-oxobutanoic acid as a syrup (1.55 g, 95%), which was used without further purification.
Reaction SMILES: [H-].[Na+].[CH2:3]([O:10][C:11]1[N:16]=[C:15]([NH2:17])[C:14]([F:18])=[CH:13][N:12]=1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[N:19]#[C:20]Br>C1COCC1.C(=O)(O)[O-].[Na+]>[CH2:3]([O:10][C:11]1[N:16]=[C:15]([NH:17][C:20]#[N:19])[C:14]([F:18])=[CH:13][N:12]=1)[C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: N#CBr
Reactant: Nc1nc(OCc2ccccc2)ncc1F
Agent: O=C([O-])O
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: N#CNc1nc(OCc2ccccc2)ncc1F
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 77.3 %

Procedure:
To a mixture of sodium hydride (0.65 g, 0.27 mol) in dry THF (10 mL), was added 2-benzyloxy-5-fluoro-pyrimidin-4-yl amine (2.0 g, 0.009 mol) dissolved in THF (15 mL) at room temperature under nitrogen. The mixture was allowed to stir at room temperature for 30 min and then cyanogen bromide (1.45 g, 0.0136 mol) in THF (10 ml) was added to the reaction mixture and allowed stir at room temperature for 16 h. The reaction was diluted with sat. sodium bicarbonate (2×5 mL) and extracted with EtOAc (3×40 mL). The organic phase was dried over Na2SO4, and concentrated to a give a crude solid which was recrystallized by adding minimum quantity of ethyl acetate and hexane until solution became turbid. The solvent was decanted and a gummy brown solid was obtained. The gummy brown solid was rinsed with Et2O (2×10 mL) and allowed to stand in Et2O while stirring for 1 h, until a free solid formed. The resulting solid was filtered and dried to give the title compound (1.7 g, 77%) as a pale brown solid: mp 150-152 dec.; 1H NMR (300 MHz, DMSO-d6) δ 7.80 (bs, 1H), 7.43 (m, 5H), 5.20 (s, 2H); MS (EI) m/z 245 (M)+.