Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: N1C=CC([C:7]2[CH:15]=[C:14]([CH:16]=[O:17])[CH:13]=[C:12]3[C:8]=2[CH:9]=[N:10][N:11]3[CH2:18][O:19][CH2:20][CH2:21][Si:22]([CH3:25])([CH3:24])[CH3:23])=CC=1.[N:26]1[CH:31]=[CH:30][C:29]([CH:32]=[CH2:33])=[CH:28][CH:27]=1.C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C.CCN(C(C)C)C(C)C>C(#N)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C(OCC)(=O)C>[N:26]1[CH:31]=[CH:30][C:29](/[CH:32]=[CH:33]/[C:7]2[CH:15]=[C:14]([CH:16]=[O:17])[CH:13]=[C:12]3[C:8]=2[CH:9]=[N:10][N:11]3[CH2:18][O:19][CH2:20][CH2:21][Si:22]([CH3:25])([CH3:23])[CH3:24])=[CH:28][CH:27]=1
Reactant: C[Si](C)(C)CCOCn1ncc2c(-c3ccncc3)cc(C=O)cc21
Reactant: C=Cc1ccncc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Product: C[Si](C)(C)CCOCn1ncc2c(/C=C/c3ccncc3)cc(C=O)cc21
Temperature: 70 °C
Yield: 52.7 %

Procedure:
A solution of 4-(pyridine-4-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazole-6-carbaldehyde (50 mg, 0.14 mmol) and 4-pyridylethylene (20 μL, 0.19 mmol) in acetonitrile (1.5 mL) was purged with argon. Palladium acetate (2 mg, 0.007 mmol), tri-o-tolylphosphine (4 mg, 0.014 mmol) and DIPEA (50 μL) was added and the mixture was heated to 70° C. for 16 h. Ethyl acetate (50 mL) was added and the mixture was washed with water (2×5 mL), brine (5 mL), dried over MgSO4 and concentrated. The residue was purified by silica gel chromatography (98:2 EtOAc/MeOH) to give the title compound as a yellow solid (28 mg, 53%). MS ESI [M+H]+, calcd for [C21H25N3O2Si+H]+ 380.2; found m/z 380.2.
Reaction SMILES: [CH2:1]([O:4][C:5]1([CH3:39])[CH2:10][CH2:9][N:8]([C:11]2[N:16]3[CH:17]=[C:18]([C:20]4[CH:25]=[CH:24][CH:23]=[C:22](Br)[CH:21]=4)[N:19]=[C:15]3[C:14]([CH3:27])=[C:13]([CH3:28])[C:12]=2[C@H:29]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])[C:30]([O:32][CH3:33])=[O:31])[CH2:7][CH2:6]1)[CH:2]=[CH2:3].[F:40][C:41]1[CH:46]=[C:45]([F:47])[CH:44]=[C:43]([O:48][C@H:49]([CH2:51][CH:52]=[CH2:53])[CH3:50])[C:42]=1B1OC(=O)CN(C)CC(=O)O1.C(OC1(C)CCN(C2N3C=C(C4C=C(C5C=C(F)C(F)=CC=5O[C@H](CC=C)C)C=CC=4)N=C3C(C)=C(C)C=2[C@H](OC(C)(C)C)C(OC)=O)CC1)C=C>>[CH2:1]([O:4][C:5]1([CH3:39])[CH2:10][CH2:9][N:8]([C:11]2[N:16]3[CH:17]=[C:18]([C:20]4[CH:21]=[C:22]([C:42]5[C:43]([O:48][C@H:49]([CH2:51][CH:52]=[CH2:53])[CH3:50])=[CH:44][C:45]([F:47])=[CH:46][C:41]=5[F:40])[CH:23]=[CH:24][CH:25]=4)[N:19]=[C:15]3[C:14]([CH3:27])=[C:13]([CH3:28])[C:12]=2[C@H:29]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])[C:30]([O:32][CH3:33])=[O:31])[CH2:7][CH2:6]1)[CH:2]=[CH2:3]
Reactant: C=CCOC1(C)CCN(c2c([C@H](OC(C)(C)C)C(=O)OC)c(C)c(C)c3nc(-c4cccc(Br)c4)cn23)CC1
Reactant: C=CC[C@H](C)Oc1cc(F)cc(F)c1B1OC(=O)CN(C)CC(=O)O1
Agent: C=CCOC1(C)CCN(c2c([C@H](OC(C)(C)C)C(=O)OC)c(C)c(C)c3nc(-c4cccc(-c5cc(F)c(F)cc5O[C@@H](C)CC=C)c4)cn23)CC1
Product: C=CCOC1(C)CCN(c2c([C@H](OC(C)(C)C)C(=O)OC)c(C)c(C)c3nc(-c4cccc(-c5c(F)cc(F)cc5O[C@@H](C)CC=C)c4)cn23)CC1
Yield: 99 %

Procedure:
Prepared from (S)-methyl 2-(5-(4-(allyloxy)-4-methylpiperidin-1-yl)-2-(3-bromophenyl)-7,8-dimethylimidazo[1,2-a]pyridin-6-yl)-2-(tert-butoxy)acetate and (S)-2-(2,4-difluoro-6-(pent-4-en-2-yloxy)phenyl)-6-methyl-1,3,6,2-dioxazaborocane-4,8-dione in 99% yield following the same procedure as (S)-methyl 2-(5-(4-(allyloxy)-4-methylpiperidin-1-yl)-2-(4′,5′-difluoro-2′-((S)-pent-4-en-2-yloxy)-[1,1′-biphenyl]-3-yl)-7,8-dimethylimidazo[1,2-a]pyridin-6-yl)-2-(tert-butoxy)acetate. LCMS (ESI, M+1): 716.4.
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7](Cl)[CH:8]=2)[N:3]=1.[CH3:13][O:14][C:15]1[CH:22]=[CH:21][CH:20]=[CH:19][C:16]=1[CH2:17][NH2:18].[NH2:23][CH2:24][C:25]1[CH:26]=[N:27][CH:28]=[CH:29][CH:30]=1>>[CH3:13][O:14][C:15]1[CH:22]=[CH:21][CH:20]=[CH:19][C:16]=1[CH2:17][NH:18][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([NH:23][CH2:24][C:25]3[CH:26]=[N:27][CH:28]=[CH:29][CH:30]=3)[CH:8]=2)[N:3]=1
Reactant: Clc1ccc2nc(Cl)ccc2c1
Reactant: COc1ccccc1CN
Reactant: NCc1cccnc1
Product: COc1ccccc1CNc1ccc2cc(NCc3cccnc3)ccc2n1

Procedure:
The title compound, MS: m/e=371.0 (M+H+), was prepared in accordance with the general method of example 1 from 2,6-dichloroquinoline, 2-methoxybenzylamine and 3-(aminomethyl)pyridine.
Reaction SMILES: [C:1]([S:4][CH:5]1[CH2:10][CH2:9][N:8](C(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[CH2:7]/[C:6]/1=[CH:30]\[C:31]1[N:35]([CH2:36][CH2:37][CH2:38][C:39]([O:41][CH2:42][CH3:43])=[O:40])[N:34]=[N:33][CH:32]=1)(=[O:3])[CH3:2].[F:44][C:45]([F:50])([F:49])[C:46]([OH:48])=[O:47]>ClCCl>[F:44][C:45]([F:50])([F:49])[C:46]([OH:48])=[O:47].[C:1]([S:4][CH:5]1[CH2:10][CH2:9][NH:8][CH2:7]/[C:6]/1=[CH:30]\[C:31]1[N:35]([CH2:36][CH2:37][CH2:38][C:39]([O:41][CH2:42][CH3:43])=[O:40])[N:34]=[N:33][CH:32]=1)(=[O:3])[CH3:2]
Reactant: CCOC(=O)CCCn1nncc1/C=C1\CN(C(c2ccccc2)(c2ccccc2)c2ccccc2)CCC1SC(C)=O
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCOC(=O)CCCn1nncc1/C=C1\CNCCC1SC(C)=O
Temperature: 25 °C

Procedure:
To a solution of (E)-4-(acetylsulfanyl)-3-({1-[3-(ethoxycarbonyl)propyl]-1H-1,2,3-triazol-5-yl}methylidene)-1-(triphenylmethyl)piperidine (7.45 g) in dichloromethane (80 ml) was added trifluoroacetic acid (2.86 ml) with stirring at room temperature. After the resulting mixture was stirred at room temperature for one hour, solvents were removed under reduced pressure. The residue was purified by silica gel chromatography using dichloromethane and methanol (10:1) as the eluent to afford the title compound (5.39 g, including impurities) as an orange-coloured oil.
Reaction SMILES: [CH3:1][C:2]([CH3:34])([CH3:33])[C@H:3]([NH:8][C:9]([C:11]1[N:12]=[C:13]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[N:14]2[CH2:19][CH2:18][N:17](C(OC(C)(C)C)=O)[CH2:16][C:15]=12)=[O:10])[C:4]([NH:6][CH3:7])=[O:5].C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH3:1][C:2]([CH3:34])([CH3:33])[C@H:3]([NH:8][C:9]([C:11]1[N:12]=[C:13]([C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=2)[N:14]2[CH2:19][CH2:18][NH:17][CH2:16][C:15]=12)=[O:10])[C:4]([NH:6][CH3:7])=[O:5]
Reactant: CNC(=O)[C@@H](NC(=O)c1nc(-c2ccccc2)n2c1CN(C(=O)OC(C)(C)C)CC2)C(C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CNC(=O)[C@@H](NC(=O)c1nc(-c2ccccc2)n2c1CNCC2)C(C)(C)C
Reaction time: 8 h
Yield: 84.6 %

Procedure:
Compound 1 (150 mg, 0.32 mmol) was dissolved in DCM and TFA (0.25 mL, 3.20 mmol) was added. The resulting mixture was stirred overnight. The mixture was concentrated, diluted with DCM and washed with saturated NaHCO3 solution. The filtrate was dried anhydrous Na2SO4, filtered and concentrated. The residue was purified by normal phase chromatography, eluting with 0-30% 1M methanolic ammonia/dichloromethane to give desired product, Compound 2 as a white solid (0.10 g, 85%). MS: m/z 370.2 [M+H]+. 1H-NMR (400 MHz, CD3OD) δ:1.05 (s, 9H), 2.76 (s, 3H), 3.16 (m, 2H), 4.11 (m, 2H), 4.37 (m, 3H), 7.53 (m, 3H), 7.71 (m, 2H).
Reaction SMILES: Br[CH:2]([CH:6]([CH2:9]Br)[CH2:7][CH3:8])[C:3]([OH:5])=[O:4].[CH:11]([NH2:24])([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>C(#N)C>[C:18]1([CH:11]([C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)[N:24]2[CH2:9][CH:6]([CH2:7][CH3:8])[CH:2]2[C:3]([OH:5])=[O:4])[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: NC(c1ccccc1)c1ccccc1
Reactant: CCC(CBr)C(Br)C(=O)O
Solvent: CC#N
Product: CCC1CN(C(c2ccccc2)c2ccccc2)C1C(=O)O

Procedure:
19.5 g of 2A and 29 g of benzhydrylamine in acetonitrile were stirred and refluxed for 48 hours. The resulting mixture was cooled, filtered free of insoluble amine salt and the filtrate evaporated to dryness. The residue, which was a complex mixture of product, was partially purified using a column of silica gel and petroleum ether/ethyl acetate as the eluent. The first fast-running products to emerge were collected and evaporated to dryness, leaving the benzyl ester of 1-diphenylmethyl-2-carboxy-3-ethylazetidine (2B) as the major component (65% by NMR) of the crude residual mixture.
Reaction SMILES: [Cl:1][C:2]1[CH:34]=[CH:33][C:5]([CH2:6][NH:7][C:8](=[O:32])[N:9]([CH2:30][CH3:31])[CH2:10][C:11]2[CH:16]=[C:15]([C:17]([F:20])([F:19])[F:18])[CH:14]=[CH:13][C:12]=2B2OC(C)(C)C(C)(C)O2)=[CH:4][CH:3]=1.[CH3:35][O:36][C:37](=[O:57])[CH2:38][C:39]1[CH:44]=[C:43]([C:45]([F:48])([F:47])[F:46])[CH:42]=[C:41](OS(C(F)(F)F)(=O)=O)[CH:40]=1>>[CH3:35][O:36][C:37](=[O:57])[CH2:38][C:39]1[CH:40]=[C:41]([C:12]2[CH:13]=[CH:14][C:15]([C:17]([F:19])([F:18])[F:20])=[CH:16][C:11]=2[CH2:10][N:9]([CH2:30][CH3:31])[C:8]([NH:7][CH2:6][C:5]2[CH:4]=[CH:3][C:2]([Cl:1])=[CH:34][CH:33]=2)=[O:32])[CH:42]=[C:43]([C:45]([F:47])([F:46])[F:48])[CH:44]=1
Reactant: COC(=O)Cc1cc(OS(=O)(=O)C(F)(F)F)cc(C(F)(F)F)c1
Reactant: CCN(Cc1cc(C(F)(F)F)ccc1B1OC(C)(C)C(C)(C)O1)C(=O)NCc1ccc(Cl)cc1
Product: CCN(Cc1cc(C(F)(F)F)ccc1-c1cc(CC(=O)OC)cc(C(F)(F)F)c1)C(=O)NCc1ccc(Cl)cc1

Procedure:
Prepared according to the procedure described in Example 1, Step 4, using the following starting materials: 3-(4-chloro-benzyl)-1-ethyl-1-[2-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-5-trifluoromethyl-benzyl]-urea and (3-trifluoromethanesulfonyloxy-5-trifluoromethyl-phenyl)-acetic acid methyl ester.
Reaction SMILES: [FH:1].C(Cl)Cl.[CH3:5][N:6]=[C:7]=[O:8].[CH2:9]([N:11]([CH2:14][CH3:15])[S:12]Cl)[CH3:10]>C(N(CC)CC)C>[CH3:5][N:6]([S:12][N:11]([CH2:14][CH3:15])[CH2:9][CH3:10])[C:7]([F:1])=[O:8]
Reactant: CN=C=O
Reactant: CCN(CC)SCl
Reactant: F
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCN(CC)SN(C)C(=O)F
Reaction time: 1 h
Yield: 62.9 %

Procedure:
Anhydrous hydrogen fluoride (3.0 g, 0.15 mole) was added to 150 ml of methylene chloride at -10° C. Then 8.6 g of methylisocyanate was added, followed by 20.9 g (0.15 mole) of N,N-diethylaminosulfenyl chloride at 0° C. Triethylamine (15.2 g) was then added at 0° C. over a 15-minute period, and the mixture was stirred at +5° C. for 1 hour. The mixture was then extracted with water (100 ml), saturated sodium bicarbonate solution, and water again. After drying (MgSO4), the solvent was removed in vacuo, and the crude residue was vacuum distilled to give 17 g of N-methyl-N-(diethylaminosulfenyl)carbamoyl fluoride, b.p. 57° C./0.8 mm (62.9 percent yield).
Reaction SMILES: [OH:1][CH2:2][C:3]1([CH3:15])[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:4]1.O[C:17]1[C:18]([C:23]([O:25][CH2:26][CH3:27])=[O:24])=[N:19][CH:20]=[CH:21][CH:22]=1.ClC1C=C(O)C=NC=1>>[C:11]([O:10][C:8]([N:5]1[CH2:6][CH2:7][C:3]([CH2:2][O:1][C:17]2[C:18]([C:23]([O:25][CH2:26][CH3:27])=[O:24])=[N:19][CH:20]=[CH:21][CH:22]=2)([CH3:15])[CH2:4]1)=[O:9])([CH3:14])([CH3:13])[CH3:12]
Reactant: CCOC(=O)c1ncccc1O
Reactant: CC1(CO)CCN(C(=O)OC(C)(C)C)C1
Agent: Oc1cncc(Cl)c1
Product: CCOC(=O)c1ncccc1OCC1(C)CCN(C(=O)OC(C)(C)C)C1

Procedure:
The title compound was prepared according to the procedure described in Step 1 of EXAMPLE 29 using tert-butyl 3-(hydroxymethyl)-3-methylpyrrolidine-1-carboxylate and ethyl 3-hydroxypicolinate instead of (R)-tert-butyl 2-(hydroxymethyl)pyrrolidine-1-carboxylate and 5-chloropyridin-3-ol.
Reaction SMILES: [OH:1][C:2]1([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.[CH2:14]([N:21]1[CH2:26][C:25]([C:35]2[CH:40]=[CH:39][C:38]([Cl:41])=[C:37]([Cl:42])[CH:36]=2)([CH2:27][CH2:28][CH2:29]OS(C)(=O)=O)[CH2:24][O:23][C:22]1=[O:43])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.[I-].[K+].[ClH:46]>CN(C=O)C.CCOCC>[OH2:1].[ClH:41].[CH2:14]([N:21]1[CH2:26][C:25]([C:35]2[CH:40]=[CH:39][C:38]([Cl:41])=[C:37]([Cl:42])[CH:36]=2)([CH2:27][CH2:28][CH2:29][N:5]2[CH2:6][CH2:7][C:2]([OH:1])([C:8]3[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=3)[CH2:3][CH2:4]2)[CH2:24][O:23][C:22]1=[O:43])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.[CH2:14]([N:21]1[CH2:26][C:25]([CH2:27][CH2:28][CH2:29][N:5]2[CH2:6][CH2:7][C:2]([C:8]3[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=3)([OH:1])[CH2:3][CH2:4]2)([C:35]2[CH:40]=[CH:39][C:38]([Cl:41])=[C:37]([Cl:42])[CH:36]=2)[CH2:24][O:23][C:22]1=[O:43])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.[ClH:46]
Reactant: CS(=O)(=O)OCCCC1(c2ccc(Cl)c(Cl)c2)COC(=O)N(Cc2ccccc2)C1
Reactant: OC1(c2ccccc2)CCNCC1
Agent: Cl
Agent: [I-]
Agent: [K+]
Solvent: CCOCC
Solvent: CN(C)C=O
Product: O
Product: O=C1OCC(CCCN2CCC(O)(c3ccccc3)CC2)(c2ccc(Cl)c(Cl)c2)CN1Cc1ccccc1

Procedure:
This compound is prepared by the procedure described in step D of EXAMPLE 8 from 1.6 g of 4-hydroxy-4-phenylpiperidine, 2 g of the compound obtained in step C of EXAMPLE 8 and 0.75 g of potassium iodide in 10 ml of DMF. The residue is chromatographed on silica H using DCM and then a DCM/MeOH mixture (96/4; v/v) as the eluent. The product obtained is taken up with a saturated solution of gaseous HCl in ether and the precipitate formed is wrung to give 1.34 g of the expected product. M.p=125° C.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:15])[C:5]1[CH:10]=[CH:9][C:8](F)=[C:7]([N+:12]([O-:14])=[O:13])[CH:6]=1)[CH3:2].CN(C=O)C.C(=O)([O-])[O-].[K+].[K+].[NH2:27][CH:28]([CH2:31][CH3:32])[CH2:29][CH3:30]>O>[CH2:1]([O:3][C:4](=[O:15])[C:5]1[CH:10]=[CH:9][C:8]([NH:27][CH:28]([CH2:31][CH3:32])[CH2:29][CH3:30])=[C:7]([N+:12]([O-:14])=[O:13])[CH:6]=1)[CH3:2]
Reactant: CCC(N)CC
Reactant: CCOC(=O)c1ccc(F)c([N+](=O)[O-])c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)c1ccc(NC(CC)CC)c([N+](=O)[O-])c1
Reaction time: 2 h
Yield: 99.8 %

Procedure:
To a solution of 25.0 g of 4-fluoro-3-nitro-benzoic acid ethyl ester in 100 ml of abs. DMF was added 24.3 g of potassium carbonate, followed by 11.6 g of 3-aminopentane. After 2 h at rt, the mixture was poured into water, and extracted with ethyl acetate three times. The combined organic phases were dried over magnesium sulphate and concentrated to yield 32.8 g (100%) of 4-(1-Ethyl-propylamino)-3-nitro-benzoic acid ethyl ester as a yellow oil.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([F:37])=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([CH2:14][N:15]([CH2:31][C@@H:32]([OH:36])[C:33]([OH:35])=[O:34])[NH:16][C:17]([C:19]3[NH:23][C:22](=[O:24])[N:21]([C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=4)[N:20]=3)=[O:18])=[CH:10][CH:9]=2)[CH:7]=1.[C:38](=[O:46])([O:42][CH:43]([CH3:45])[CH3:44])[O:39][CH2:40]Cl.[Na+].[I-].CC1C=CC=C(C)N=1>CN(C=O)C.O>[CH:43]([O:42][C:38]([O:39][CH2:40][O:34][C:33](=[O:35])[C@H:32]([OH:36])[CH2:31][N:15]([CH2:14][C:11]1[CH:10]=[CH:9][C:8]([C:6]2[CH:7]=[C:2]([Cl:1])[CH:3]=[CH:4][C:5]=2[F:37])=[CH:13][CH:12]=1)[NH:16][C:17]([C:19]1[NH:23][C:22](=[O:24])[N:21]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[N:20]=1)=[O:18])=[O:46])([CH3:45])[CH3:44]
Reactant: O=C(NN(Cc1ccc(-c2cc(Cl)ccc2F)cc1)C[C@@H](O)C(=O)O)c1nn(-c2ccccc2)c(=O)[nH]1
Reactant: CC(C)OC(=O)OCCl
Agent: [I-]
Agent: [Na+]
Solvent: Cc1cccc(C)n1
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)OC(=O)OCOC(=O)[C@H](O)CN(Cc1ccc(-c2cc(Cl)ccc2F)cc1)NC(=O)c1nn(-c2ccccc2)c(=O)[nH]1
Temperature: 25 °C
Reaction time: 8 h
Yield: 6 %

Procedure:
To a solution of (R)-3-[N-(5′-chloro-2′-fluorobiphenyl-4-ylmethyl)-N′-(5-oxo-1-phenyl-4,5-dihydro-1H-[1,2,4]triazole-3-carbonyl)hydrazino]-2-hydroxypropionic acid (200 mg, 335 μmol) in dry DMF (6 mL) was added chloromethyl isopropyl carbonate (76 mg, 503 μmol), NaI (101 mg, 670 μmol) and 2,6-dimethylpyridine (143 mg, 1.3 mmol) in portions at room temperature. The resulting mixture was stirred at room temperature for 8 hours. Water (12 mL) was added and the mixture was extracted with EtOAc (3×10 mL). The combined organic layers were dried over anhydrous Na2SO4 and concentrated in vacuo. The residue was purified by column chromatography ((PE:EtOAc=1:1) to yield the title compound as a white solid (12.8 mg). LC-MS: 641.9 [M+H]+. 1H NMR (DMSO-d6, 400 MHz) δ 1.21 (d, J=6.2 Hz, 6H), 3.21-3.28 (m, 2H), 4.12-4.30 (m, 2H), 4.40-4.52 (m, 1H), 4.77-4.79 (m, 1H), 5.68-5.76 (m, 2H), 7.41-7.45 (m, 1H), 7.50-7.87 (m, 9H), 7.90 (d, J=7.7 Hz, 2H), 9.98 (s, 1H), 12.76 (s, 1H).
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[C:11]1[C:12]2[C:17]([CH:18]=[C:19]3[C:24]=1[CH:23]=[CH:22][CH:21]=[CH:20]3)=[CH:16][CH:15]=[CH:14][CH:13]=2.[Br:25]N1C(=O)CCC1=O.O>CN(C)C=O>[Br:25][C:18]1[C:19]2[C:24]([C:11]([C:2]3[CH:3]=[CH:4][C:5]4[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=4)[CH:1]=3)=[C:12]3[C:17]=1[CH:16]=[CH:15][CH:14]=[CH:13]3)=[CH:23][CH:22]=[CH:21][CH:20]=2
Reactant: c1ccc2cc(-c3c4ccccc4cc4ccccc34)ccc2c1
Reactant: O=C1CCC(=O)N1Br
Solvent: CN(C)C=O
Solvent: O
Product: Brc1c2ccccc2c(-c2ccc3ccccc3c2)c2ccccc12
Temperature: 25 °C
Reaction time: 7 h
Yield: 99 %

Procedure:
23.1 g of 9-(naphthalene-2-yl) anthracene was dispersed into 250 ml of DMF (dimethylformamide), and then 14.9 g of NBS (N-bromosuccinimide) in DMF solution (150 ml) was dropped therein. After stirred at room temperature for 7 hours, it was left over a night. 200 ml of water was added thereto, and then the crystal precipitated was separated by filtration. Subsequently it was washed by ethanol adequately, followed by drying, and 28.8 g of 9-bromo-10-(naphthalene-2-yl)anthracene of beige color crystal was obtained (Yield: 99%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:8]2[N:12](CCOC[Si](C)(C)C)[N:11]=[CH:10][C:9]=2[NH:21][C:22]([C:24]2[CH:25]=[N:26][N:27]3[CH:32]=[CH:31][CH:30]=[N:29][C:28]=23)=[O:23])[CH:5]=[CH:6][CH:7]=1.Cl>C(O)C.O>[Br:1][C:2]1[CH:3]=[C:4]([C:8]2[NH:12][N:11]=[CH:10][C:9]=2[NH:21][C:22]([C:24]2[CH:25]=[N:26][N:27]3[CH:32]=[CH:31][CH:30]=[N:29][C:28]=23)=[O:23])[CH:5]=[CH:6][CH:7]=1
Reactant: C[Si](C)(C)COCCn1ncc(NC(=O)c2cnn3cccnc23)c1-c1cccc(Br)c1
Agent: Cl
Solvent: CCO
Solvent: O
Product: O=C(Nc1cn[nH]c1-c1cccc(Br)c1)c1cnn2cccnc12
Temperature: 70 °C
Reaction time: 6 h
Yield: 57.6 %

Procedure:
To a solution of N-(5-(3-bromophenyl)-1-(2-((trimethylsilyl)methoxy)ethyl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide (742 mg, 1.45 mmol) in 20 mL of ethanol was added HCl (1.0 mL of a 6 M solution in water, 6 mmol). The reaction mixture was then stirred at 70° C. for 6 hours. After cooling to room temperature a light yellow precipitate formed, which was isolated by filtration and washed with methanol and diethyl ether. The filtrate was reduced in volume, and more solid product filtered. The combined collected solids were dried under vacuum to yield 320 mg (58%) of N-(5-(3-bromophenyl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide. LCMS (ESI) m+H=383.0; 1H NMR (400 MHz, DMSO-d6) δ13.01 (s, 1H), 9.93 (s, 1H), 9.33 (dd, 1H), 8.83 (dd, 1H), 8.66 (d, 1H), 8.26 (s, 1H), 7.57 (d, 1H), 7.47 (t, 1H), 7.28 (dd, 1H).
Reaction SMILES: [CH:1]1([NH:8][C:9]([NH:11][C:12]2[CH:17]=[C:16](B3OC(C)(C)C(C)(C)O3)[CH:15]=[CH:14][C:13]=2[F:27])=[O:10])[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.FC(F)(F)S(O[C:34]1[C:35]([CH3:45])=[N:36][C:37]2[C:42]([CH:43]=1)=[CH:41][N:40]=[C:39]([Cl:44])[CH:38]=2)(=O)=O.C([O-])([O-])=O.[K+].[K+]>O1CCOCC1.O.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>[Cl:44][C:39]1[CH:38]=[C:37]2[C:42]([CH:43]=[C:34]([C:16]3[CH:15]=[CH:14][C:13]([F:27])=[C:12]([NH:11][C:9]([NH:8][CH:1]4[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7]4)=[O:10])[CH:17]=3)[C:35]([CH3:45])=[N:36]2)=[CH:41][N:40]=1
Reactant: CC1(C)OB(c2ccc(F)c(NC(=O)NC3CCCCCC3)c2)OC1(C)C
Reactant: Cc1nc2cc(Cl)ncc2cc1OS(=O)(=O)C(F)(F)F
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: [K+]
Solvent: O
Solvent: C1COCCO1
Product: Cc1nc2cc(Cl)ncc2cc1-c1ccc(F)c(NC(=O)NC2CCCCCC2)c1
Temperature: 60 °C
Yield: 142.5 %

Procedure:
Sparge a suspension of 1-cycloheptyl-3-(2-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)urea (0.420 g, 1.116 mmol), 7-chloro-2-methyl-1,6-naphthyridin-3-yl trifluoromethanesulfonate (0.438 g, 1.339 mmol) and K2CO3 (0.463 g, 3.35 mmol) in dioxane (4 mL) and H2O (1 mL) with Ar, add Pd(PPh3)4 (0.064 g, 0.056 mmol) and heat at 60° C. for 3 h. Concentrate the mixture to dryness and purify via silica gel chromatography (EtOAc/Hex) to afford the title compound (679 mg, 61%) as a white solid. MS(ESI) m/z: 427.1 (M+H+).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:21])[CH:5]([CH2:9][C:10]1[CH:15]=[CH:14][N:13]=[C:12]([NH:16]C(=O)C)[C:11]=1[F:20])[C:6](=O)[CH3:7])[CH3:2].[C:22]1(C=C[CH:27]=[C:25](O)[CH:24]=1)[OH:23].[CH3:30][S:31]([OH:34])(=[O:33])=[O:32].O>C(OCC)(=O)C.C(O)C>[CH3:30][S:31]([OH:34])(=[O:33])=[O:32].[F:20][C:11]1[C:12]([NH2:16])=[N:13][CH:14]=[CH:15][C:10]=1[CH2:9][C:5]1[C:4](=[O:21])[O:3][C:1]2[CH:2]=[C:22]([OH:23])[CH:24]=[CH:25][C:27]=2[C:6]=1[CH3:7]
Reactant: CCOC(=O)C(Cc1ccnc(NC(C)=O)c1F)C(C)=O
Reactant: Oc1cccc(O)c1
Agent: CS(=O)(=O)O
Solvent: CCO
Solvent: CCOC(C)=O
Solvent: O
Product: Cc1c(Cc2ccnc(N)c2F)c(=O)oc2cc(O)ccc12
Temperature: 25 °C
Reaction time: 16 h
Yield: 60.9 %

Procedure:
Under a nitrogen atmosphere, the oily product of step 3 (2.70 g) was dissolved in ethyl acetate (5.47 mL), resorcinol (1.32 g, 12.0 mmol) and methanesulfonic acid (8.20 mL, 126 mmol) were added while stirring at room temperature, and after warming to 50° C., the mixture was stirred for 4 hours. The reaction mixture was cooled to room temperature and allowed to stand for 16 hours, water (2.7 mL) was then added, and the mixture was stirred at 80° C. for 7 hours. The reaction mixture was again cooled to room temperature and allowed to stand for 16 hours, and after the mixture was warmed to 70° C., seed crystals (27.4 mg) were added. Water (5.5 mL) was then added, the mixture was stirred for 1 hour, ethanol (13.7 mL) was further added, and the mixture was stirred for 30 minutes. It was then cooled to 25° C., ethanol (38.2 mL) was added, and the mixture was stirred for 30 minutes. The precipitated crystals were collected by filtration, washed twice with ethanol (16.4 mL), and dried under reduced pressure to obtain the title compound (2.20 g).
Reaction SMILES: [CH3:1][N:2]1[CH2:6][C@H:5](O)[CH2:4][C@H:3]1[CH2:8][O:9][C:10]1[CH:11]=[N:12][CH:13]=[CH:14][CH:15]=1.CCN(S(F)(F)[F:22])CC.C(Cl)[Cl:26]>>[ClH:26].[ClH:26].[F:22][C@@H:5]1[CH2:6][N:2]([CH3:1])[C@H:3]([CH2:8][O:9][C:10]2[CH:11]=[N:12][CH:13]=[CH:14][CH:15]=2)[CH2:4]1
Reactant: CN1C[C@H](O)C[C@H]1COc1cccnc1
Reactant: CCN(CC)S(F)(F)F
Reactant: ClCCl
Product: CN1C[C@@H](F)C[C@H]1COc1cccnc1
Product: Cl
Temperature: -78 °C
Reaction time: 4 h

Procedure:
A 100 mg (0.5 mmol) sample of 3-((trans-1-methyl-4-hydroxy-2(S)-pyrrolidinyl)methoxy)pyridine, from Example 23 above, above was dissolved in 10 mL of methylene chloride and cooled to -78° C. To this was added 0.165 mL (1.25 mmol) of DAST, and the mixture was stirred for 4 hours while allowing the reaction mixture to warm to room temperature. The reaction was quenched by addition of satd NaHCO3 solution, and the mixture was extracted with chloroform. The solvent was removed, and the residue was purified by chromatography on silica gel, eluting with 20:1 CHCl3 :methanol, to give 30 mg of title compound.
Reaction SMILES: [CH2:1]([CH:3]1[CH2:12][CH2:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[NH:4]1)[CH3:2].C([O:15][CH:16]=[C:17]([C:23](OCC)=O)[C:18]([O:20]CC)=[O:19])C.O>[OH-].[Na+]>[CH2:1]([CH:3]1[N:4]2[C:5]3[C:6](=[CH:7][CH:8]=[CH:9][C:10]=3[CH2:11][CH2:12]1)[C:16](=[O:15])[C:17]([C:18]([OH:20])=[O:19])=[CH:23]2)[CH3:2]
Reactant: CCOC=C(C(=O)OCC)C(=O)OCC
Reactant: CCC1CCc2ccccc2N1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CCC1CCc2cccc3c(=O)c(C(=O)O)cn1c23
Temperature: 115 °C

Procedure:
Following the procedure set forth in Example 1, 2-ethyltetrahydroquinoline is mixed with diethyl ethoxymethylenemalonate and heated to 125° to 130° C. for 2 hours. Polyphosphoric acid is added, and the mixture is heated at 115° C. for 1 hour. The mixture is poured into water, neutralized with 40 percent sodium hydroxide, and the product is isolated and saponified in 10 percent sodium hydroxide solution. The solution is neutralized, and the solid product, 6,7-dihydro-5-ethyl-1-oxo-1H,5H-benzo[ij]quinolizine-2-carboxylic acid, is isolated by filtration.