Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3](=[O:18])[CH:4]([CH:10]([NH2:17])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[CH2:5][CH2:6][CH:7](Br)[CH3:8].N[C@H](C(O)=O)CC1C=C2C(C=CC=C2)=CC=1.C([O-])(O)=O.[Na+]>CN(C=O)C>[CH3:1][O:2][C:3]([C@@H:4]1[CH2:5][CH2:6][C@@H:7]([CH3:8])[NH:17][C@H:10]1[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:18]
Reactant: COC(=O)C(CCC(C)Br)C(N)c1ccccc1
Agent: N[C@@H](Cc1ccc2ccccc2c1)C(=O)O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)[C@@H]1CC[C@@H](C)N[C@H]1c1ccccc1
Temperature: 25 °C

Procedure:
(A mixture of two diastereomers and their enantiomers.) To 2-(amino-phenyl-methyl)-5-bromo-hexanoic acid methyl ester in DMF was added Nal and NaHCO3 The resultant mixture was stirred in DMF at 100° C. for 1 hour, and then was cooled to room temperature and partitioned between ether and water. The organic layer was washed with brine, dried with MgSO4, filtered and concentrated. Silica gel chromatography (97:3 CHCl3/MeOH) gave 1.63 g (90%) of the the product as an inseparable mixture of two diastereomers. 1H NMR (400 MHz, CDCl3) δ 7.17–7.32 (comp, 10H, both diastereomers), 4.47 (d, J=5.0 Hz, 1H), 3.97 (d, J=3.5 Hz, 1H), 3.45 (s, 3H), 3.38 (s, 3H), 3.02–3.08 (m, 1H), 2.92–2.99 (m, 1H), 2.75–2.85 (comp, 2H), 2.0–2.2 (comp, 2H), 1.80–2.00 (comp, 3H), 1.40–1.60 (comp, 2H), 1.20–1.30 (m, 1H), 1.20 (d, J=6.4 Hz, 3H), 1.07 (d, J=6.4 Hz, 3H); Mass spectrum m/e calcd. for M+H=234.1. Found 234.2.
Reaction SMILES: Br[C:2]1[CH:11]=[C:10]([C:12]2[CH2:13][CH2:14][N:15]([C:18]([CH3:21])([CH3:20])[CH3:19])[CH2:16][CH:17]=2)[CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][C:6](=[O:30])[N:7]2[C:22]1[C:27]([Cl:28])=[CH:26][CH:25]=[CH:24][C:23]=1[Cl:29].[F:31][C:32]1[CH:37]=[CH:36][C:35](B(O)O)=[C:34](C)[CH:33]=1>>[C:18]([N:15]1[CH2:14][CH2:13][CH:12]([C:10]2[CH:9]=[C:8]3[C:3]([CH:4]=[CH:5][C:6](=[O:30])[N:7]3[C:22]3[C:27]([Cl:28])=[CH:26][CH:25]=[CH:24][C:23]=3[Cl:29])=[C:2]([C:35]3[CH:36]=[CH:37][C:32]([F:31])=[CH:33][CH:34]=3)[CH:11]=2)[CH2:17][CH2:16]1)([CH3:19])([CH3:21])[CH3:20]
Reactant: Cc1cc(F)ccc1B(O)O
Reactant: CC(C)(C)N1CC=C(c2cc(Br)c3ccc(=O)n(-c4c(Cl)cccc4Cl)c3c2)CC1
Product: CC(C)(C)N1CCC(c2cc(-c3ccc(F)cc3)c3ccc(=O)n(-c4c(Cl)cccc4Cl)c3c2)CC1

Procedure:
The title compound was prepared from 5-bromo-7-(1-tert-butyl-1,2,3,6-tetrahydropyridin-4-yl)-1-(2,6-dichlorophenyl)quinolin-2(1H)-one (INTERMEDIATE ABA5) and using 4-fluoro-2-methylphenylboronic acid as described in EXAMPLE ABA11. 1H NMR (CD3OD, 500 MHz): δ 1.252 (s, 9H), 1.734 (bs, 2H), 1.955 (bs, 2H), 2.384 (s, 3H), 2.865 (bs, 4H), 3.497 (m, 2H), 6.451 (s, 1H), 6.685 (d, J=8.5 Hz, 1H), 7.190 (m, 2H), 7.265 (m, 1H), 7.332 (d, J=8.2 Hz, 1H), 7.618 (t, J=8.2H, 1H), 7.720 (m, 2H), 7.962 (d, J=10.7 Hz, 1H. Mass spectrum (ESI): 537.2 (M+1).
Reaction SMILES: N1C=CC=CC=1[C:7]1[CH:12]=[CH:11]C=CN=1.[Cl:13][C:14]1[N:19]=[CH:18][C:17]2[CH:20]=[CH:21][NH:22][C:16]=2[CH:15]=1.C1(B(O)O)CC1.C(=O)([O-])[O-].[Na+].[Na+]>ClCCCl.[Cl-].[Na+].O.CO.C([O-])(=O)C.[Cu+2].C([O-])(=O)C.[O-]S([O-])(=O)=O.[Cu+2].CCOC(C)=O>[Cl:13][C:14]1[N:19]=[CH:18][C:17]2[CH:20]=[CH:21][N:22]([CH:11]3[CH2:12][CH2:7]3)[C:16]=2[CH:15]=1
Reactant: Clc1cc2[nH]ccc2cn1
Reactant: c1ccc(-c2ccccn2)nc1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: CCOC(C)=O
Solvent: ClCCCl
Solvent: CO
Product: Clc1cc2c(ccn2C2CC2)cn1
Temperature: 70 °C
Reaction time: 12 h
Yield: 116.5 %

Procedure:
In a 2 L round bottom flask were added copper(II) acetate (8.9 g, 49 mmol) and 2,2′-bipyridine (7.8 g, 49 mmol) in 1,2-dichloroethane (240 ml). This was heated to 70° C. Separately were suspended 6-chloro-1H-pyrrolo[3,2-c]pyridine (15 g, 98 mmol) and cyclopropylboronic acid (17 g, 200 mmol) in 1,2-dichloroethane (240 ml). To the first heated mixture was added sodium carbonate (21 g, 200 mmol), followed by the second mixture, and the resulting mixture turned from green to dark red color. The mixture was heated to 70° C. overnight. Next day, conversion was ˜50%, and another 0.25 equivalent of Cu(OAc)2 (4.5 g), 0.25 equivalent of BiPy (3.9 g), and 1.0 equivalent of cyclopropylboronic acid (8.5 g) were added. The mixture was continued to stir at 70° C. for 12 hr. After cooling to room temperature, 250 ml brine and 250 ml EtOAc were added. The layers were separated, and the aqueous layer was extracted twice with EtOAc (2×150 ml). Copper salt was filtered from organic layers, which were then dried over sodium sulfate, filtered, and concentrated to obtain the crude product as a thick black oil. Dissolved in MeOH, the crude product was loaded onto silica before silica column chromatography. Collected fractions were pooled and concentrated to give a thick yellow oil containing bi-pyridine. To this oil were added 100 ml EtOAc and 100 ml saturated aqueous CuSO4 solution. The layers were separated, and the aqueous layer was separated to remove blue copper salt. The filtrate was then extracted twice with EtOAc (2×50 ml). Combined organic layers were dried with sodium sulfate, filtered and concentrated to obtain the product 6-chloro-1-cyclopropyl-1H-pyrrolo[3,2-c]pyridine (7A, 11 g, 57%) as a light yellow solid.
Reaction SMILES: [O:1]=[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH:3]1[CH2:11][C:12]([OH:14])=[O:13].S(=O)(=O)(O)O.[CH3:20]O>O>[CH3:20][O:13][C:12](=[O:14])[CH2:11][CH:3]1[CH2:4][C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[C:2]1=[O:1]
Reactant: CO
Reactant: O=C(O)CC1Cc2ccccc2C1=O
Agent: O=S(=O)(O)O
Solvent: O
Product: COC(=O)CC1Cc2ccccc2C1=O
Reaction time: 2 h

Procedure:
To a solution of (1-Oxo-indan-2-yl)-acetic acid (Step 1, 2.00 g) in methanol (10 mL) at 0° C. was added sulphuric acid (2 mL). The solution was stirred for 2 h and then diluted with water (50 mL) and extracted with ethyl acetate. The combined organic layers were washed with sat. sodium hydrogenocarbonate, dried and concentrated to give (1-Oxo-indan-2-yl)-acetic acid methyl ester (pale yellow oil, 2.15 g, quantitative). C12H12O3; MW: 204.23; LCMS (method A) RT 1.40 min; ES 227 (25%, MNa+), 205 (25%, MH+), 173 (100%); IR: 2952, 1734, 1710, 1608, 1436 cm−1; 1H NMR (400 MHz, CDCl3) 7.78 (1H, d), 7.61 (1H, t), 7.47 (1H, d), 7.39 (1H, t), 3.70 (3H, s), 3.47 (1H, dd), 2.95-3.08 (2H, m), 2.89 (1H, dd), 2.63 (1H, dt) ppm. The compound was used without further purification for the next step
Reaction SMILES: [O:1]=[C:2]([NH:19][CH2:20][C:21]#[CH:22])[C@@H:3]([NH:11][C:12](=[O:18])[O:13][C:14]([CH3:17])([CH3:16])[CH3:15])[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1>CC#N.[Au](Cl)(Cl)Cl>[CH3:22][C:21]1[O:1][C:2]([C@@H:3]([NH:11][C:12](=[O:18])[O:13][C:14]([CH3:17])([CH3:16])[CH3:15])[CH2:4][C:5]2[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=2)=[N:19][CH:20]=1
Reactant: C#CCNC(=O)[C@H](Cc1ccccc1)NC(=O)OC(C)(C)C
Agent: Cl[Au](Cl)Cl
Solvent: CC#N
Product: Cc1cnc([C@H](Cc2ccccc2)NC(=O)OC(C)(C)C)o1
Temperature: 50 °C
Reaction time: 8 h
Yield: 73.6 %

Procedure:
To a solution of (S)-tert-butyl (1-oxo-3-phenyl-1-(prop-2-yn-1-ylamino)propan-2-yl)carbamate (95 mg, 0.31 mmol) in MeCN (1.6 mL) was added gold (III) chloride (9.5 mg, 0.031 mmol). The resulting reaction mixture was stirred at 50° C. overnight and then purified directly using flash chromatography (gradient from 0% to 100% EtOAc/hexanes) to give the title compound (69 mg, 73%) as a colorless oil. %). 1H NMR (CDCl3) δ 7.37-7.17 (m, 3H), 7.05 (d, J=6.4 Hz, 2H), 6.63 (s, 1H), 5.12 (br s, 2H), 3.33-3.01 (m, 2H), 2.27 (d, J=1.1 Hz, 3H), 1.49-1.34 (m, 9H); MS (ESI+) m/z 303.3 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([CH3:8])[N:5]=[C:4](O)[CH:3]=1.P(Cl)(Cl)([Cl:12])=O>CN(C=O)C>[Cl:12][C:4]1[N:5]=[C:6]([CH3:8])[N:7]=[C:2]([NH2:1])[CH:3]=1
Reactant: Cc1nc(N)cc(O)n1
Reactant: O=P(Cl)(Cl)Cl
Solvent: CN(C)C=O
Product: Cc1nc(N)cc(Cl)n1
Temperature: 80 °C

Procedure:
6-Amino-2-methylpyrimidin-4-ol (5 g) was suspended in phosphorous oxychloride (50 ml) and heated at 80° C. for 1 hour. A few drops of DMF was added and the reaction heated to 105° C. for 3 hours to give an orange solution. The reaction was cooled, concentrated in vacuo and azeotroped with toluene. The residue was cautiously partitioned between ethyl acetate and ice-cold saturated aqueous sodium bicarbonate solution. The organic layer was separated, washed with water and brine, dried and concentrated in vacuo to afford 6-chloro-2-methylpyrimidin-4-amine as a yellow solid which was used without further purification (3 g, 68%); NMR Spectrum (300 MHz, CDCl3) 2.50 (s, 3H), 5.00 (br s, 2H), 6.30 (s, 1H); Mass Spectrum MH++CH3CN 185. 6-Chloro-2-methylpyrimidin-4-amine (2.45 g) was suspended in 1-methylpiperazine (24 ml) and the reaction heated at 140° C. for 20 minutes in a microwave reactor. The reaction was cooled and concentrated in vacuo. The residue was dissolved in methanol and neutralised with polymer-bound carbonate resin for 1 hour, then filtered and concentrated to give an orange solid that was triturated with ethyl acetate to give 2-methyl-6-(4-methylpiperazin-1-yl)pyrimidin-4-amine as a cream solid (2.64 g, 81%); NMR Spectrum (300 MHz, CDCl3) 2.20 (s, 3H), 2.30 (s, 3H), 2.40 (m, 4H), 3.50 (m, 4H), 4.40 (br s, 2H), 5.40 (s, 1H); Mass Spectrum MH+ 208.
Reaction SMILES: [CH:1]([N:4]1[C:12]2[C:7](=[CH:8][C:9]([OH:13])=[CH:10][CH:11]=2)[C:6]([C:14]2[CH:19]=[CH:18][N:17]=[CH:16][CH:15]=2)=[C:5]1[CH3:20])([CH3:3])[CH3:2].[CH2:21]([O:23][C:24](=[O:29])[C:25](Br)([CH3:27])[CH3:26])[CH3:22]>>[CH2:21]([O:23][C:24](=[O:29])[C:25]([O:13][C:9]1[CH:8]=[C:7]2[C:12](=[CH:11][CH:10]=1)[N:4]([CH:1]([CH3:3])[CH3:2])[C:5]([CH3:20])=[C:6]2[C:14]1[CH:19]=[CH:18][N:17]=[CH:16][CH:15]=1)([CH3:27])[CH3:26])[CH3:22]
Reactant: Cc1c(-c2ccncc2)c2cc(O)ccc2n1C(C)C
Reactant: CCOC(=O)C(C)(C)Br
Product: CCOC(=O)C(C)(C)Oc1ccc2c(c1)c(-c1ccncc1)c(C)n2C(C)C

Procedure:
The above compound was prepared from 1-isopropyl-2-methyl-3-(4-pyridyl)-1H-indole-5-ol and 2-bromo-2-methylpropanoic acid ethylester using a procedure analogous to that of Example 10.
Reaction SMILES: COC1C=CC(C[N:8]2[C:12]3=[N:13][CH:14]=[CH:15][C:16]([O:17][C:18]4[CH:23]=[CH:22][C:21]([NH:24][C:25]([C:27]5[C:32](=[O:33])[N:31]([C:34]6[CH:39]=[CH:38][C:37]([F:40])=[CH:36][CH:35]=6)[N:30]=[CH:29][CH:28]=5)=[O:26])=[CH:20][C:19]=4[F:41])=[C:11]3[C:10]([N:42]3[CH2:47][CH2:46][N:45](C(OC(C)(C)C)=O)[CH2:44][CH2:43]3)=[N:9]2)=CC=1.C(O)(C(F)(F)F)=O>>[F:41][C:19]1[CH:20]=[C:21]([NH:24][C:25]([C:27]2[C:32](=[O:33])[N:31]([C:34]3[CH:35]=[CH:36][C:37]([F:40])=[CH:38][CH:39]=3)[N:30]=[CH:29][CH:28]=2)=[O:26])[CH:22]=[CH:23][C:18]=1[O:17][C:16]1[CH:15]=[CH:14][N:13]=[C:12]2[NH:8][N:9]=[C:10]([N:42]3[CH2:43][CH2:44][NH:45][CH2:46][CH2:47]3)[C:11]=12
Reactant: COc1ccc(Cn2nc(N3CCN(C(=O)OC(C)(C)C)CC3)c3c(Oc4ccc(NC(=O)c5ccnn(-c6ccc(F)cc6)c5=O)cc4F)ccnc32)cc1
Solvent: O=C(O)C(F)(F)F
Product: O=C(Nc1ccc(Oc2ccnc3[nH]nc(N4CCNCC4)c23)c(F)c1)c1ccnn(-c2ccc(F)cc2)c1=O
Temperature: 60 °C
Reaction time: 8 h
Yield: 87.3 %

Procedure:
A 50 mL round-bottomed flask was charged with tert-butyl 4-(1-(4-methoxybenzyl)-4-(2-fluoro-4-(1-(4-fluorophenyl)-6-oxo-1,6-dihydropyridazine-5-carboxamido)phenoxy)-1H-pyrazolo[3,4-b]pyridin-3-yl)piperazine-1-carboxylate (56.8 mg, 0.0743 mmol) and CF3COOH (5 mL). The reaction mixture was stirred at 60° C. overnight. The solvent was removed and the residue was purified by silica gel chromatography (DCM/7 M NH3 in MeOH from 50/1 to 10/1, v/v) to afford product (35.3 mg, 87.3%). LRMS (APCI pos): >99% purity, 254 nm, m/e 545 (M+1). 1H NMR (400 MHz, CDCl3) δ 11.83 (s, 1H), 8.41 (d, 1H), 8.24 (m, 2H), 7.90 (dd, 1H), 7.60 (m, 2H), 7.41 (d, 1H), 7.24 (m, 3H), 6.21 (d, 1H), 3.46 (m, 4H), 3.04 (m, 4H).
Reaction SMILES: [CH2:1]([N:3]([CH2:7][CH3:8])[CH2:4][CH2:5][OH:6])[CH3:2].[Br:9][C:10]1[CH:11]=[C:12]2[C:17](=[CH:18][CH:19]=1)[N:16]=[N:15][C:14]([C:20](Cl)=[O:21])=[CH:13]2>O1CCCC1>[Br:9][C:10]1[CH:11]=[C:12]2[C:17](=[CH:18][CH:19]=1)[N:16]=[N:15][C:14]([C:20]([O:6][CH2:5][CH2:4][N:3]([CH2:7][CH3:8])[CH2:1][CH3:2])=[O:21])=[CH:13]2
Reactant: O=C(Cl)c1cc2cc(Br)ccc2nn1
Reactant: CCN(CC)CCO
Solvent: C1CCOC1
Product: CCN(CC)CCOC(=O)c1cc2cc(Br)ccc2nn1

Procedure:
A solution of 2-diethylaminoethanol (1.4 g.) in dry tetrahydrofuran (15 ml.) was added to a solution of 6-bromocinnolin-3-yl carbonyl chloride (1.07 g.) in dry tetrahydrofuran (15 ml.). The resulting solution was heated under reflux for 2 hours, and the solvent was then evaporated in vacuo. The solid residue was dissolved in water (50 ml.), the solution extracted with ethyl acetate (3× 100 ml.), and the combined extracts dried (MgSO4). The solution was evaporated to a small volume, petroleum ether (b.p. 60°-80° C.; 50 ml.) was added, the resulting mixture was filtered to give, as the solid residue, 2-diethylaminoethyl 6-bromocinnolin-3-yl carboxylate, m.p. 90°-93° C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:9]2[C:17]3[C:12](=[CH:13][CH:14]=[C:15]([O:18][CH3:19])[CH:16]=3)[C:11](=[O:20])[CH:10]=2)[CH:5]=[C:6]([F:8])[CH:7]=1.[Br:21]Br>C(Cl)Cl.O>[Br:21][C:10]1[C:11](=[O:20])[C:12]2[C:17]([C:9]=1[C:4]1[CH:3]=[C:2]([F:1])[CH:7]=[C:6]([F:8])[CH:5]=1)=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=2
Reactant: COc1ccc2c(c1)C(c1cc(F)cc(F)c1)=CC2=O
Reactant: BrBr
Solvent: O
Solvent: ClCCl
Product: COc1ccc2c(c1)C(c1cc(F)cc(F)c1)=C(Br)C2=O
Temperature: 25 °C
Reaction time: 3 h
Yield: 95.6 %

Procedure:
To a solution of 3-(3,5-difluorophenyl)-5-methoxy-1H-inden-1-one (810 mg, 2.98 mmol) obtained in Step 2 in CH2Cl2 (10 mL) at 0° C. was added dropwise a solution of Br2 (571 mg, 3.57 mmol) in CH2Cl2 (3 mL). The mixture was stirred for 3 h at room temperature. The reaction was diluted with H2O (10 mL) and extracted with CH2Cl2. The extracts were washed with H2O and brine, dried over MgSO4, and concentrated in vacuo. The residue was purified by silica gel column chromatography (CH2Cl2/hexanes) to afford the desired product (1.0 g, 95%).
Reaction SMILES: [Cl:1][C:2]1[CH:29]=[CH:28][C:5]([CH2:6][N:7]2[C:12](=[O:13])[C:11]([C:14](O)=[O:15])=[N:10][N:9]([C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([NH:23][C:24](=[O:26])[CH3:25])[CH:18]=3)[C:8]2=[O:27])=[CH:4][CH:3]=1.C(N(C(C)C)CC)(C)C.ClC(OCC)=O.[BH4-].[Na+]>C1COCC1.O>[Cl:1][C:2]1[CH:29]=[CH:28][C:5]([CH2:6][N:7]2[C:12](=[O:13])[C:11]([CH2:14][OH:15])=[N:10][N:9]([C:17]3[CH:18]=[C:19]([NH:23][C:24](=[O:26])[CH3:25])[CH:20]=[CH:21][CH:22]=3)[C:8]2=[O:27])=[CH:4][CH:3]=1
Reactant: CC(=O)Nc1cccc(-n2nc(C(=O)O)c(=O)n(Cc3ccc(Cl)cc3)c2=O)c1
Agent: CCOC(=O)Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CC(=O)Nc1cccc(-n2nc(CO)c(=O)n(Cc3ccc(Cl)cc3)c2=O)c1
Reaction time: 1 h
Yield: 8.7 %

Procedure:
According to Scheme 7 Step 5: To a solution of 11(D) (380 mg, 0.92 mmol),) and diisopropylethylamine (189 μL, 1.1 mmol) in THF (10 mL) at 0° C. under nitrogen atmosphere was added ethyl chloroformate (101 μL, 1.06 mmol) dropwise. The reaction mixture was stirred for 1 h then treated dropwise with a solution of sodium borohydride (90 mg, 2.38 mmol) in water (2 mL). The mixture was stirred overnight at room temperature and quenched slowly with a saturated solution of NaHCO3 (100 mL). The aqueous layer was extracted thrice with CH2Cl2 (100 mL). The organic layers were combined, dried over MgSO4, filtered and concentrated under reduced pressure to afford a yellow solid. The crude solid was purified by flash chromatography with silica gel (Merck Flashmart prepacked column 20 g SiO2) using CH2Cl2/MeOH 97/3 as eluant to afford N-(3-(4-(4-chlorobenzyl)-6-(hydroxymethyl)-3,5-dioxo-4,5-dihydro-1,2,4-triazin-2(3H)-yl)phenyl)acetamide 11(E) (32 mg, 9%) as a white solid.
Reaction SMILES: Br[CH:2]1[C:10]2([CH2:15][CH2:14][N:13]([C:16]([O:18][CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)=[O:17])[CH2:12][CH2:11]2)[CH2:9][C:8]2[C:4](=[N:5][N:6]([C:26]([CH3:29])([CH3:28])[CH3:27])[CH:7]=2)[CH:3]1[O:30]C.CC(C)([O-])C.[K+].Cl>O1CCCC1.O>[C:26]([N:6]1[CH:7]=[C:8]2[C:4]([C:3](=[O:30])[CH2:2][C:10]3([CH2:9]2)[CH2:15][CH2:14][N:13]([C:16]([O:18][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[O:17])[CH2:12][CH2:11]3)=[N:5]1)([CH3:29])([CH3:27])[CH3:28]
Reactant: COC1c2nn(C(C)(C)C)cc2CC2(CCN(C(=O)OCc3ccccc3)CC2)C1Br
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)n1cc2c(n1)C(=O)CC1(CCN(C(=O)OCc3ccccc3)CC1)C2
Reaction time: 0.5 h
Yield: 70.1 %

Procedure:
Benzyl 6-bromo-2-tert-butyl-7-methoxy-2,4,6,7-tetrahydrospiro[indazole-5,4′-piperidine]-1′-carboxylate (150 mg, 0.31 mmol) was dissolved in 5 mL tetrahydrofuran and treated with potassium tert-butoxide (0.61 mL, 0.61 mmol, 1 M tetrahydrofuran) and stirred for 30 minutes. Aqueous 2 N HCl (5 mL) was added and the mixture was stirred for 15 minutes at room temperature. The mixture was then diluted with 50 mL water and extracted with ethyl acetate (50 mL). The organic layer was dried over sodium sulfate, filtered and concentrated. The residue was purified by flash column chromatography (10-80% ethyl acetate/heptanes) to yield 86 mg (71%) of the title compound as a clear oil. +ESI (M+H) 396.5; 1H NMR (400 MHz, CDCl3, δ): 7.38 (s, 1 H), 7.27-7.35 (m, 5 H), 5.11 (s, 2 H), 3.48 (t, J=5.8 Hz, 4 H), 2.71 (s, 2 H), 2.57 (s, 2 H), 1.57-1.66 (m, 9 H), 1.47-1.59 (m, 4 H).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH2:14][CH:15]([CH3:17])[CH3:16])[C:9]([O:11][CH2:12][CH3:13])=[O:10])=[CH:4][C:3]=1[O:18][CH2:19][CH:20]1[CH2:22][CH2:21]1.C1C(=O)N([Br:30])C(=O)C1>C(Cl)(Cl)(Cl)Cl.O>[NH2:1][C:2]1[C:3]([O:18][CH2:19][CH:20]2[CH2:22][CH2:21]2)=[CH:4][C:5]([CH:8]([CH2:14][CH:15]([CH3:17])[CH3:16])[C:9]([O:11][CH2:12][CH3:13])=[O:10])=[CH:6][C:7]=1[Br:30]
Reactant: O=C1CCC(=O)N1Br
Reactant: CCOC(=O)C(CC(C)C)c1ccc(N)c(OCC2CC2)c1
Solvent: ClC(Cl)(Cl)Cl
Solvent: O
Product: CCOC(=O)C(CC(C)C)c1cc(Br)c(N)c(OCC2CC2)c1
Temperature: 25 °C
Yield: 72.3 %

Procedure:
To a stirred solution of ethyl 2-(4-amino-3-(cyclopropylmethoxy)phenyl)-4-methylpentanoate (1.65 g, 5.4 mmol) in dry CCl4 (60 mL), NBS (0.96 g, 5.4 mmol) was added at 0° C. The reaction mixture was allowed to stir for 3 at room temperature to complete the reaction. The reaction mixture was diluted with water, extracted with DCM (2×50 mL), the combined organic solvents was dried over Na2SO4, filtered and concentrated in vacuo. The crude reaction mixture was purified by column chromatography to yield ethyl 2-(4-amino-3-bromo-5-(cyclopropylmethoxy)phenyl)-4-methylpentanoate (1.5 g) as a yellow solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([CH3:9])=[CH:7][C:6]([CH:10]([OH:12])[CH3:11])=[C:5]([CH3:13])[CH:4]=1.[Cr](O[Cr]([O-])(=O)=O)([O-])(=O)=O.[NH+]1C=CC=CC=1.[NH+]1C=CC=CC=1>ClCCl>[CH3:1][O:2][C:3]1[C:8]([CH3:9])=[CH:7][C:6]([C:10](=[O:12])[CH3:11])=[C:5]([CH3:13])[CH:4]=1
Reactant: COc1cc(C)c(C(C)O)cc1C
Agent: O=[Cr](=O)([O-])O[Cr](=O)(=O)[O-]
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Product: COc1cc(C)c(C(C)=O)cc1C
Yield: 73.9 %

Procedure:
A solution of 0.8 g (4.1 mmol) of 1-(4-methoxy-2,5-dimethylphenyl)ethanol obtained in Step 1 in 30 mL of dichloromethane was reacted with 3.0 g (8.2 mmol) of pyridinium dichromate at room temperature for 2 hours with stirring, followed by filtration through celite. The organic layer was dried over anhydrous magnesium sulfate, filtered and concentrated in a vacuum to afford 1-(4-methoxy-2,5-dimethylphenyl)ethanone as a brown oil (0.54 g, yield: 69%).
Reaction SMILES: O[C:2]1[N:3]=[C:4]2[NH:11][C@:10]([CH3:16])([C:12]([F:15])([F:14])[F:13])[CH2:9][N:5]2[C:6](=[O:8])[CH:7]=1.P(Cl)(Cl)([Cl:19])=O>ClCCCl>[Cl:19][C:2]1[N:3]=[C:4]2[NH:11][C@:10]([CH3:16])([C:12]([F:15])([F:14])[F:13])[CH2:9][N:5]2[C:6](=[O:8])[CH:7]=1
Reactant: C[C@@]1(C(F)(F)F)Cn2c(nc(O)cc2=O)N1
Reactant: O=P(Cl)(Cl)Cl
Solvent: ClCCCl
Product: C[C@@]1(C(F)(F)F)Cn2c(nc(Cl)cc2=O)N1
Temperature: 70 °C
Reaction time: 2 h

Procedure:
To a suspension of 5.6 g of (2S)-7-hydroxy-2-methyl-2-(trifluoromethyl)-2,3-dihydroimidazo[1,2-a]pyrimidin-5(1H)-one in 100 mL of 1,2-dichloroethane, are added at room temperature and under an argon atmosphere, 11 mL of phosphorus oxychloride. The resulting mixture is then heated to 70° C. After two hours of stirring and after monitoring with LC/MS, the reaction is completed. After cooling, the reaction mixture is dry evaporated under reduced pressure. The obtained residue is taken up with 5 mL of cold water and 200 mL of ethyl acetate. On the obtained mixture, 32% soda is added up to a pH=6. The organic phase is then separated and then dried on magnesium sulphate, filtered and concentrated under reduced pressure in order to obtain 6 g of (2S)-7-chloro-2-methyl-2-(trifluoromethyl)-2,3-dihydroimidazo[1,2-a]pyrimidin-5(1H)-one including the following characteristics:
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]#[N:9])=[C:6]([Cl:10])[N:5]=[C:4]([C:11]([OH:13])=O)[CH:3]=1.Cl.Cl.Cl.[N:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[C:23]1[S:24][C:25]([CH2:28][N:29]2[CH2:34][CH2:33][CH:32]([CH2:35][NH2:36])[CH2:31][CH2:30]2)=[CH:26][N:27]=1.F[P-](F)(F)(F)(F)F.N1(O[P+](N2CCCC2)(N2CCCC2)N2CCCC2)C2C=CC=CC=2N=N1.C(=O)(O)[O-].[Na+]>CN(C)C=O.ClCCl.C(OCC)(=O)C.C(N(CC)CC)C>[NH2:1][C:2]1[C:7]([C:8]#[N:9])=[C:6]([Cl:10])[N:5]=[C:4]([C:11]([NH:36][CH2:35][CH:32]2[CH2:33][CH2:34][N:29]([CH2:28][C:25]3[S:24][C:23]([C:18]4[CH:19]=[CH:20][CH:21]=[CH:22][N:17]=4)=[N:27][CH:26]=3)[CH2:30][CH2:31]2)=[O:13])[CH:3]=1
Reactant: N#Cc1c(N)cc(C(=O)O)nc1Cl
Reactant: NCC1CCN(Cc2cnc(-c3ccccn3)s2)CC1
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Agent: O=C([O-])O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: N#Cc1c(N)cc(C(=O)NCC2CCN(Cc3cnc(-c4ccccn4)s3)CC2)nc1Cl
Temperature: 25 °C

Procedure:
4-Amino-6-chloro-5-cyanopicolinic acid (1.053 g, prepared according to the reported preparation in Zhao, Hongyu, et al.; J. Med. Chem. 2006, 49(15), 4455-4458), the compound prepared in Example 214 (2.12 g), (benzotriazol-1-yloxy)tripyrrolidinophosphonium hexafluorophosphate (3.33 g) and triethylamine (7.43 mL) were suspended in N,N-dimethylformamide (100 mL) and stirred at room temperature over weekend. The reaction mixture was poured onto saturated aqueous sodium bicarbonate solution and ethyl acetate. The organics were washed with brine, dried over magnesium sulfate, filtered and concentrated under reduced pressure to afford the crude material. The crude material was slurried with dichloromethane and the desired material precipitated out of solution. The solids was filtered and washed with dichloromethane to afford clean material. The filtrate was concentrated under reduced pressure and purified by flash column chromatography (gradient elution: 100% ethyl acetate to 96.5% ethyl acetate, 2.5% triethylamine 1% methanol) to afford pure material, which was combined with the triturated material to give the title compound (1.69 g), with the following physical data.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:9]=[C:10](I)[CH:11]=1)[C:5]([O:7][CH3:8])=[O:6].[C:13](B1OC(C)(C)C(C)(C)O1)([CH3:15])=[CH2:14].C(NC(C)C)(C)C.C(=O)(O)[O-].[Na+]>C(#N)C.O.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C1C=C(S([O-])(=O)=O)C=C(P(C2C=CC=C(S([O-])(=O)=O)C=2)C2C=CC=C(S([O-])(=O)=O)C=2)C=1.[Na+].[Na+].[Na+]>[Br:1][C:2]1[CH:3]=[C:4]([CH:9]=[C:10]([C:13]([CH3:15])=[CH2:14])[CH:11]=1)[C:5]([O:7][CH3:8])=[O:6]
Reactant: C=C(C)B1OC(C)(C)C(C)(C)O1
Reactant: COC(=O)c1cc(Br)cc(I)c1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])O
Solvent: O
Solvent: CC#N
Solvent: CC(C)NC(C)C
Product: C=C(C)c1cc(Br)cc(C(=O)OC)c1
Temperature: 80 °C
Reaction time: 2.5 h
Yield: 91.4 %

Procedure:
To a solution of methyl 3-bromo-5-iodobenzoate (2.50 g, 7.33 mmol) in acetonitrile (22.0 mL) and water (7.33 mL) was 2-isopropenyl-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (1.378 mL, 7.33 mmol), palladium(II) acetate (41.0 mg, 0.183 mmol), 3,3′3″-phosphinidynetris(benzenesulfonic acid)trisodium salt (313 mg, 0.550 mmol) and diisopropylamine (2.61 mL, 18.33 mmol) and the mixture was heated to 80° C. After 2.5 h, the reaction was allowed to cool to ambient temperature and saturated aqueous sodium bicarbonate was added. The mixture was extracted with ethyl acetate (3×). The combined organic extracts were washed with brine, dried over magnesium sulfate, filtered and concentrated. Purification by silica gel chromatography (100% hexanes→80% hexanes/ethyl acetate) gave the title compound (1.71 g).