Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([C:7]2([C:12]3[N:16]([CH:17]4[CH2:33][N:21]5[C:22]6[C:27]([C:28]([CH2:29][C:30]([OH:32])=[O:31])=[C:20]5[CH2:19][CH2:18]4)=[CH:26][CH:25]=[CH:24][CH:23]=6)[N:15]=[N:14][CH:13]=3)CCCC2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[F:34]C1C=CC(CC#C)=CC=1.FC1C=CC(CCl)=CC=1.C([Si](C)(C)C)#C.[N-]=[N+]=[N-]>>[F:34][C:4]1[CH:5]=[CH:6][C:1]([CH2:7][C:12]2[N:16]([C@H:17]3[CH2:33][N:21]4[C:22]5[C:27]([C:28]([CH2:29][C:30]([OH:32])=[O:31])=[C:20]4[CH2:19][CH2:18]3)=[CH:26][CH:25]=[CH:24][CH:23]=5)[N:15]=[N:14][CH:13]=2)=[CH:2][CH:3]=1
Reactant: O=C(O)Cc1c2n(c3ccccc13)CC(n1nncc1C1(c3ccccc3)CCCC1)CC2
Reactant: C#CCc1ccc(F)cc1
Agent: C#C[Si](C)(C)C
Agent: Fc1ccc(CCl)cc1
Agent: [N-]=[N+]=[N-]
Product: O=C(O)Cc1c2n(c3ccccc13)C[C@H](n1nncc1Cc1ccc(F)cc1)CC2

Procedure:
The title compound was prepared using enantiomerically pure propyl (7-azido-6,7,8,9-tetrahydropyrido[1,2-a]indol-10-yl)acetate from EXAMPLE 6 and 1-fluoro-4-prop-2-yn-1-ylbenzene prepared from 4-fluorobenzyl chloride and ethynyltrimethylsilane described in EXAMPLE 8. EXAMPLE 28.1 and 28.2 were prepared from the chiral azide with the retention time of 10.3 and 11.5 min respectively from EXAMPLE 6. MS (+ESI) m/z: 405.1.
Reaction SMILES: [C:1]([O:6][CH2:7][CH:8]1[O:10][CH2:9]1)(=[O:5])[CH2:2][CH2:3][CH3:4].O.C(OCC1C=CC=CC=1)[C@@H]1OC1>CC(O)=O.C1COCC1>[C:1]([O:6][CH2:7][C@H:8]1[O:10][CH2:9]1)(=[O:5])[CH2:2][CH2:3][CH3:4]
Reactant: CCCC(=O)OCC1CO1
Agent: c1ccc(COC[C@H]2CO2)cc1
Solvent: C1CCOC1
Solvent: O
Solvent: CC(=O)O
Product: CCCC(=O)OC[C@@H]1CO1
Yield: 44 %

Procedure:
Using the (R,R)-(salen)Co(II) precatalyst of 1 (91 mg, 0.15 mmol, 0.005 equiv), (±)-glycidyl butyrate (4.32 g, 30.0 mmol), AcOH (32 mL, 0.6 mmol, 0.02 equiv), 0.3 mL THF, and H2O (297 mL, 16.5 mmol, 0.55 equiv) and a procedure analogous to the one outlined for 5b, (S)-glycidyl butyrate 5d (1.90 g, 13.2 mmol, 44%) was obtained as a clear oil by vacuum distillation of the reaction mixture (30° C., 0.5 torr). The product was determined to be >99% ee by conversion to and analysis of the 2-napthylsulfide (obtained by ring opening with 2-napthalenethiol in methanol using 1 equiv TEA at 0° C.; Chiralcel OD, 97:3 hexanes:EtOH, 1 mL/min, 260 nm).
Reaction SMILES: [CH:1]([Si:4]([CH:13]([CH3:15])[CH3:14])([CH:10]([CH3:12])[CH3:11])[O:5][CH2:6][C@H:7]([OH:9])[CH3:8])([CH3:3])[CH3:2].O[C:17]1[CH:18]=[C:19]([CH:24]=[C:25]([O:27][CH2:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[CH:26]=1)[C:20]([O:22][CH3:23])=[O:21].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>C1COCC1>[CH2:28]([O:27][C:25]1[CH:24]=[C:19]([CH:18]=[C:17]([O:9][C@@H:7]([CH3:8])[CH2:6][O:5][Si:4]([CH:1]([CH3:3])[CH3:2])([CH:10]([CH3:12])[CH3:11])[CH:13]([CH3:15])[CH3:14])[CH:26]=1)[C:20]([O:22][CH3:23])=[O:21])[C:29]1[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=1
Reactant: COC(=O)c1cc(O)cc(OCc2ccccc2)c1
Reactant: CC(C)[Si](OC[C@@H](C)O)(C(C)C)C(C)C
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COC(=O)c1cc(OCc2ccccc2)cc(O[C@@H](C)CO[Si](C(C)C)(C(C)C)C(C)C)c1
Temperature: 0 °C
Reaction time: 1 h
Yield: 71.4 %

Procedure:
(2R)-1-[(Triisopropylsilyl)oxy]propan-2-ol (56.1 g, 242 mmol) was added to a solution of methyl 3-hydroxy-5-{[phenylmethyl]oxy}benzoate (50 g, 194 mmol) and triphenylphosphine (63.5 g, 242 mmol) in dry THF (500 mL), at to 0° C., followed by addition of DIAD (47.6 mL, 242 mmol) over 45 minutes under an argon atmosphere. The reaction was stirred at 0° C. for 1 hour and allowed to warm up to RT over an hour then stirred at RT for 1 hour. The THF was evaporated and a mixture of ethyl acetate (80 mL) and hexane (120 mL) was added. This mixture stirred for 2 hours and filtered. The precipitate was washed with a mixture of ethyl acetate (20 mL) and hexane (180 mL) and the filtrate evaporated. The residue was purified by column chromatography, eluting with 1:20 to 1:10 ethyl acetate:hexanes, to afford the title compound (65.5 g).
Reaction SMILES: [H-].[Na+].[OH:3][C@@H:4]([CH2:15][O:16][C@@H:17]([CH3:21])[CH2:18][O:19][CH3:20])[C:5]([NH:7][C:8]1[CH:13]=[CH:12][C:11]([CH3:14])=[CH:10][N:9]=1)=[O:6].Cl[C:23]1[N:28]=[CH:27][N:26]=[C:25]2[N:29]([C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=3[Cl:38])[N:30]=[CH:31][C:24]=12>C1COCC1.C(OCC)(=O)C>[Cl:38][C:33]1[CH:34]=[CH:35][CH:36]=[CH:37][C:32]=1[N:29]1[C:25]2=[N:26][CH:27]=[N:28][C:23]([O:3][C@@H:4]([CH2:15][O:16][C@@H:17]([CH3:21])[CH2:18][O:19][CH3:20])[C:5]([NH:7][C:8]3[CH:13]=[CH:12][C:11]([CH3:14])=[CH:10][N:9]=3)=[O:6])=[C:24]2[CH:31]=[N:30]1
Reactant: COC[C@H](C)OC[C@H](O)C(=O)Nc1ccc(C)cn1
Reactant: Clc1ccccc1-n1ncc2c(Cl)ncnc21
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: COC[C@H](C)OC[C@H](Oc1ncnc2c1cnn2-c1ccccc1Cl)C(=O)Nc1ccc(C)cn1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 92 %

Procedure:
Sodium hydride (21.24 mg, 0.53 mmol) was added to (S)-2-hydroxy-3-((S)-1-methoxypropan-2-yloxy)-N-(5-methylpyridin-2-yl)propanamide (Intermediate Y5) (95 mg, 0.35 mmol) in anhydrous THF (5 mL) at 0° C. under nitrogen. The resulting solution was stirred at 0° C. for 10 minutes and then 4-chloro-1-(2-chlorophenyl)-1H-pyrazolo[3,4-d]pyrimidine (Intermediate B1) (122 mg, 0.46 mmol) in dry THF (2 mL) was added. The reaction was allowed to warm up to room temperature and stirred for 1 hour. The reaction mixture was diluted with ethyl acetate (20 mL), and washed sequentially with water (10 mL) and saturated brine (5 mL). The organic layer was dried (MgSO4) and evaporated. The crude product was purified by flash silica chromatography, eluting with 0-100% ethyl acetate in isohexane to afford the product (160 mg, 91%). 1H NMR (400 MHz, DMSO) δ 1.09 (d, 3H), 2.24 (s, 3H), 3.23 (s, 3H), 3.26-3.38 (m, 2H), 3.77-3.86 (m, 1H), 4.00-4.16 (m, 2H), 5.85-5.91 (m, 1H), 7.55-7.70 (m, 4H), 7.73-7.78 (m, 1H), 7.88 (d, 1H), 8.16-8.19 (m, 1H), 8.54 (s, 1H), 8.59 (s, 1H), 10.79 (s, 1H). m/z (ESI+) (M+H)+=497.20; HPLC tR=2.36 min.
Reaction SMILES: O=P(Cl)(Cl)[Cl:3].[O-]S([O-])(=O)=O.[Ca+2].[F:12][C:13]1[CH:18]=[C:17]([S:19]([CH3:22])(=[O:21])=[O:20])[CH:16]=[CH:15][C:14]=1[N:23]1[C:27]2[NH:28][CH:29]=[N:30][C:31](=O)[C:26]=2[CH:25]=[N:24]1.CN(C)C=O>CC(C)=O>[Cl:3][C:31]1[N:30]=[CH:29][N:28]=[C:27]2[N:23]([C:14]3[CH:15]=[CH:16][C:17]([S:19]([CH3:22])(=[O:21])=[O:20])=[CH:18][C:13]=3[F:12])[N:24]=[CH:25][C:26]=12
Reactant: CS(=O)(=O)c1ccc(-n2ncc3c(=O)nc[nH]c32)c(F)c1
Reactant: O=P(Cl)(Cl)Cl
Agent: O=S(=O)([O-])[O-]
Agent: [Ca+2]
Solvent: CN(C)C=O
Solvent: CC(C)=O
Product: CS(=O)(=O)c1ccc(-n2ncc3c(Cl)ncnc32)c(F)c1
Temperature: 130 °C
Yield: 89.7 %

Procedure:
POCl3 (379.1 g, 2.59 mol) was transferred under nitrogen to a 1 L round bottom flask fitted with a mechanical stirrer, a condenser and a tube connected above the condenser filled with a drying agent (drierite). 1-(2-Fluoro-4-methanesulfonyl-phenyl)-1,5-dihydro-pyrazolo[3,4-d]pyrimidin-4-one (4) (100 g, 0.324 mol) was added to the reaction vessel, the contents were stirred, and a slurry was obtained. Dimethylformamide (DMF; 9.43 g, 0.129 mol) was added, and the reaction mixture was heated to reflux (oil bath set at 130° C.). After refluxing for 3 h, an additional amount of DMF (9.43 g, 0.129 mol) was added. The resulting mixture was refluxed for another 2 h and then gradually cooled to 55° C. Subsequently, acetone (270 mL) was added. The mixture was further cooled to 23° C. and a precipitate was obtained, which was isolated by filtration. The filtrate was quenched by slow dropwise addition into ice water (1.5 L) with stirring. During the quench, the internal temperature was kept at 0° C. or below by cooling with an ice-salt bath. Product 4-chloro-1-(2-fluoro-4-methanesulfonyl-phenyl)-1H-pyrazolo[3,4-d]pyrimidine (7) crystallized out of the quenched mixtures was isolated by filtration. The solids from both filtrations were combined and washed with water (2×500 mL), 10% aqueous NaHCO3 (2×500 mL), and water (2×500 mL) until the filtrate was neutral. The washed solids were vacuum dried overnight at room temperature and dissolved in methylene chloride (600 mL). The resulting mixture was filtered to remove any residual starting material (4). Hexane (200 mL) was added to the filtrate and methylene chloride was removed by rotary evaporation under reduced pressure. Product crystallized from the hexane solution and was filtered to obtain (7) (95 g; 90%). HPLC analysis, 99.26% (purity, by peak area); 1H NMR (Bruker 400 MHz, CDCl3) δ 8.88 (s, 1H, Ar—H), 8.46 (s, 1H, Ar—H), 7.96 (m, 3H, Ar—H), 3.14 (s, 3H, —SO2CH3); mass spec. (electrospray), m/z 327 (M+H).
Reaction SMILES: C[O:2][C:3](=[O:31])[CH2:4][O:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[N:12]([C:14](=[O:30])[C:15]1[CH:20]=[CH:19][C:18]([Cl:21])=[C:17]([C:22]2[CH:23]=[N:24][C:25]([Cl:29])=[CH:26][C:27]=2[CH3:28])[CH:16]=1)[CH3:13].[Li+].[OH-]>C1COCC1>[Cl:21][C:18]1[CH:19]=[CH:20][C:15]([C:14]([N:12]([CH3:13])[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[O:5][CH2:4][C:3]([OH:31])=[O:2])=[O:30])=[CH:16][C:17]=1[C:22]1[CH:23]=[N:24][C:25]([Cl:29])=[CH:26][C:27]=1[CH3:28]
Reactant: COC(=O)COc1ccccc1N(C)C(=O)c1ccc(Cl)c(-c2cnc(Cl)cc2C)c1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Product: Cc1cc(Cl)ncc1-c1cc(C(=O)N(C)c2ccccc2OCC(=O)O)ccc1Cl
Temperature: 25 °C

Procedure:
(2-{[4-Chloro-3-(6-chloro-4-methyl-pyridin-3-yl)-benzoyl]-methyl-amino}-phenoxy)-acetic acid methyl ester (10 mg, 0.02 mmol) was dissolved in THF (300 μL) and 1M LiOH (100 μL) was added. The mixture was stirred at room temperature until LCMS indicated that starting material was completely consumed. The mixture was diluted with EtOAc and acidified with 1N HCl. The organic layer was concentrated, dissolved in MeOH and purified by prep LCMS to yield (2-{[4-chloro-3-(6-chloro-4-methyl-pyridin-3-yl)-benzoyl]-methyl-amino}-phenoxy)-acetic acid 4-1. MS [M+H]+: 445.0; tR=6.75 min, (method 2)
Reaction SMILES: [OH:1][C:2]1[CH:17]=[CH:16][C:5]([C:6]([O:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[O:7])=[CH:4][CH:3]=1.C1(B(O)O)C=CC=CC=1.C=O.[C:29](O)(=[O:32])CC>C1C=CC=CC=1.O>[OH:1][C:2]1[CH:17]=[CH:16][C:5]([C:6]([O:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[O:7])=[CH:4][C:3]=1[CH2:29][OH:32]
Reactant: CCC(=O)O
Reactant: O=C(OCc1ccccc1)c1ccc(O)cc1
Agent: C=O
Agent: OB(O)c1ccccc1
Solvent: c1ccccc1
Solvent: O
Product: O=C(OCc1ccccc1)c1ccc(O)c(CO)c1
Yield: 287.2 %

Procedure:
A solution of 27.4 g (0.12 mole) of benzyl 4-hydroxybenzoate, 14.7 g (0.12 mole) of benzeneboronic acid, 6 g (0.135 mole) of paraformaldehyde and 0.9 ml (12 mmoles) of propionic acid in 600 ml of anhydrous benzene is heated at reflux for 12 hours using a Dean-Stark reactor to separate the water formed. The reaction medium is poured into bicarbonated water and extracted with ethyl ether. The organic phase is decanted, washed with water, dried on magnesium sulfate and evaporated. The resulting residue is purified by chromatography on a silica column eluted with dichloromethane. After evaporation of the solvent, 8.9 g (30% yield) of the expected product having a melting point of 109°-110° C. are obtained.
Reaction SMILES: P(Cl)(Cl)([Cl:3])=O.O=[C:7]1[NH:11][C:10]2[CH:12]=[CH:13][CH:14]=[C:15]([C:16]([O:18][CH3:19])=[O:17])[C:9]=2[NH:8]1.O.C(=O)(O)[O-].[Na+]>C(OCC)(=O)C.C1COCC1>[Cl:3][C:7]1[NH:11][C:10]2[CH:12]=[CH:13][CH:14]=[C:15]([C:16]([O:18][CH3:19])=[O:17])[C:9]=2[N:8]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: COC(=O)c1cccc2[nH]c(=O)[nH]c12
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: COC(=O)c1cccc2[nH]c(Cl)nc12
Temperature: 85 °C
Reaction time: 4 h
Yield: 70.9 %

Procedure:
Phosphorus oxychloride (8.5 g, 55.6 mmol) was added to methyl 2-oxo-2,3-dihydro-1H-benzimidazole-4-carboxylate (1.03 g, 5.36 mmol) (reference: WO 2006/116412 A2), and the mixture was stirred at 85° C. for four hours. The reaction solution was diluted with ethyl acetate and THF, slowly added to cold water and neutralized with sodium bicarbonate. The separated organic layer was washed with brine and dried over anhydrous sodium sulfate. Following concentration under reduced pressure, the residue was dissolved in toluene and the insoluble matter was removed. Concentration under reduced pressure gave 800 mg of the title compound as an oily substance. The resulting compound was used for the next reaction without purification.
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[Br:5][C:6]1[C:7]([O:27]C)=[C:8]([C:13]([CH2:16][S:17]([C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([Cl:26])[CH:21]=2)(=[O:19])=[O:18])=[CH:14][CH:15]=1)[C:9]([O:11][CH3:12])=[O:10].CN(C)C1C=CC=CC=1>C(Cl)Cl>[Br:5][C:6]1[C:7]([OH:27])=[C:8]([C:13]([CH2:16][S:17]([C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([Cl:26])[CH:21]=2)(=[O:19])=[O:18])=[CH:14][CH:15]=1)[C:9]([O:11][CH3:12])=[O:10]
Reactant: COC(=O)c1c(CS(=O)(=O)c2cccc(Cl)c2)ccc(Br)c1OC
Agent: [Al+3]
Agent: [Cl-]
Solvent: CN(C)c1ccccc1
Solvent: ClCCl
Product: COC(=O)c1c(CS(=O)(=O)c2cccc(Cl)c2)ccc(Br)c1O
Yield: 82.9 %

Procedure:
Aluminium chloride (0.7 g) was added to a stirred solution of methyl 3-bromo-6-(3-chlorobenzenesulphonylmethyl)-2-methoxybenzoate (Intermediate 68, 0.76 g) and N,N-dimethylaniline (1.27 g) in DCM (8 ml) and the resultant mixture was stirred for 30 minutes. The mixture was partitioned between ethyl acetate and hydrochloric acid (1M) and the organic layer was washed with sodium bicarbonate (saturated aqueous solution), dried (Na2SO4) and filtered. The filtrate was evaporated to dryness and the residue was triturated with ether. The solid was collected by filtration to give methyl 3-bromo-6-(3-chlorobenzenesulphonylmethyl)-2-hydroxybenzoate (0.61 g) as a white solid.
Reaction SMILES: [C:1](Cl)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH:10][CH:11]1[CH:25]([N:26]2[CH2:31][CH2:30][CH:29]([CH3:32])[CH2:28][CH2:27]2)[C:24]2=[CH:33][CH:21]([O:22][C:23]2=[O:34])[CH:20]2[CH:16]([O:17][C:18](=[O:36])[CH:19]2[CH3:35])[CH2:15][C:14]2([CH3:37])[CH:12]1[O:13]2.C(OC1C(N2CCC(C)CC2)C2=CC(OC2=O)C2C(OC(=O)C2C)CC2(C)C1O2)(=O)C>N1C=CC=CC=1>[CH3:35][CH:19]1[C:18](=[O:36])[O:17][CH:16]2[CH:20]1[CH:21]1[CH:33]=[C:24]([CH:25]([N:26]3[CH2:31][CH2:30][CH:29]([CH3:32])[CH2:28][CH2:27]3)[CH:11]([O:10][C:1]([C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)=[O:8])[CH:12]3[C:14]([CH3:37])([CH2:15]2)[O:13]3)[C:23](=[O:34])[O:22]1
Reactant: O=C(Cl)c1ccccc1
Reactant: CC1CCN(C2C3=CC(OC3=O)C3C(CC4(C)OC4C2O)OC(=O)C3C)CC1
Agent: CC(=O)OC1C(N2CCC(C)CC2)C2=CC(OC2=O)C2C(CC3(C)OC13)OC(=O)C2C
Solvent: c1ccncc1
Product: CC1CCN(C2C3=CC(OC3=O)C3C(CC4(C)OC4C2OC(=O)c2ccccc2)OC(=O)C3C)CC1
Reaction time: 2 h
Yield: 50.4 %

Procedure:
Benzoyl chloride (400 μmol; 46 μl) is added to a solution of the compound of Example 9 (100 μmol; 40 mg) in pyridine (0.5 ml). The reaction mass is stirred for 2 hours then treated in the same manner as for the preparation of the compound of Example 17. 25 mg of product is obtained in the form of a white powder. Melting point: 234° C.
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[C:3]1[CH:10]=[CH:9][C:6]([CH2:7][NH2:8])=[CH:5][CH:4]=1.[O:13]=[C:14]1[NH:18][C:17](=[O:19])[CH:16]([C:20]2[CH:21]=[CH:22][C:23]([O:29][CH3:30])=[C:24]([CH:28]=2)[C:25](O)=[O:26])[S:15]1.P(C#N)(OCC)(OCC)=O.C(N(CC)CC)C>CN(C=O)C.O>[F:1][C:2]([F:11])([F:12])[C:3]1[CH:10]=[CH:9][C:6]([CH2:7][NH:8][C:25](=[O:26])[C:24]2[CH:28]=[C:20]([CH:16]3[S:15][C:14](=[O:13])[NH:18][C:17]3=[O:19])[CH:21]=[CH:22][C:23]=2[O:29][CH3:30])=[CH:5][CH:4]=1
Reactant: NCc1ccc(C(F)(F)F)cc1
Reactant: COc1ccc(C2SC(=O)NC2=O)cc1C(=O)O
Agent: CCOP(=O)(C#N)OCC
Solvent: O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COc1ccc(C2SC(=O)NC2=O)cc1C(=O)NCc1ccc(C(F)(F)F)cc1
Yield: 53.3 %

Procedure:
To a solution of 4-trifluoromethylbenzylamine (71.9 g) in DMF (1 L) were added 5-(2,4-dioxothiazolidin-5-yl)-2-methoxybenzoic acid (98.7 g), diethyl cyanophosphate (94.7 g) and triethylamine (63 ml) under cooling with ice and stirring, and the mixture was stirred for 15 minutes as it was. Thereafter, it was stirred for 7 hours at room temperature. The reaction mixture was poured into water, which was extracted with ethyl acetate and, after washing with water, dried over anhydrous sodium sulfate. This was concentrated under reduced pressure and the residue was dissolved into ethanol. After treating with activated charcoal, this was filtered through celite and water was added to the filtrate. The crystals deposited were collected by filtration and dried to obtain 83.6 g (53%) of aimed compound as colorless powder. Melting point: 168.0~169.0° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:39]=[CH:40][C:41]=1[Cl:42])[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([C@H:13]2[CH2:38][O:37][C:16]3=[CH:17][C:18]4[CH2:19][C@@H:20]([C:34](O)=[O:35])[N:21]([C@H:25]([C:28]5[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=5)[CH2:26][CH3:27])[CH2:22][C:23]=4[CH:24]=[C:15]3[O:14]2)=[CH:9][CH:8]=1.Cl.C[O:45][C:46](=[O:63])[C@@H:47]([NH2:62])[CH2:48][C:49]1[CH:54]=[CH:53][C:52]([C:55]2[CH:60]=[CH:59][C:58]([Cl:61])=[CH:57][CH:56]=2)=[CH:51][CH:50]=1>>[Cl:61][C:58]1[CH:59]=[CH:60][C:55]([C:52]2[CH:53]=[CH:54][C:49]([CH2:48][C@H:47]([NH:62][C:34]([C@@H:20]3[CH2:19][C:18]4[CH:17]=[C:16]5[O:37][CH2:38][C@H:13]([C:10]6[CH:9]=[CH:8][C:7]([O:6][CH2:5][C:4]7[CH:39]=[CH:40][C:41]([Cl:42])=[C:2]([Cl:1])[CH:3]=7)=[CH:12][CH:11]=6)[O:14][C:15]5=[CH:24][C:23]=4[CH2:22][N:21]3[C@H:25]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[CH2:26][CH3:27])=[O:35])[C:46]([OH:45])=[O:63])=[CH:50][CH:51]=2)=[CH:56][CH:57]=1
Reactant: CC[C@@H](c1ccccc1)N1Cc2cc3c(cc2C[C@H]1C(=O)O)OC[C@H](c1ccc(OCc2ccc(Cl)c(Cl)c2)cc1)O3
Reactant: COC(=O)[C@@H](N)Cc1ccc(-c2ccc(Cl)cc2)cc1
Agent: Cl
Product: CC[C@@H](c1ccccc1)N1Cc2cc3c(cc2C[C@H]1C(=O)N[C@@H](Cc1ccc(-c2ccc(Cl)cc2)cc1)C(=O)O)OC[C@H](c1ccc(OCc2ccc(Cl)c(Cl)c2)cc1)O3

Procedure:
The title compound (16 mg) was prepared from (3S,8S)-3-[4-(3,4-dichloro-benzyloxy)-phenyl]-7-((S)-1-phenyl-propyl)-2,3,6,7,8,9-hexahydro-[1,4]dioxino[2,3-g]isoquinoline-8-carboxylic acid (30 mg) and (S)-2-amino-3-(4′-chloro-biphenyl-4-yl)-propionic acid methyl ester hydrochloride according to General Procedures L and B. LCMS (m/z): 862.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH2:11][C:12]([O:14][CH3:15])=[O:13].[Cu][C:17]#[N:18].CCOC(C)=O>CN1C(=O)CCC1>[C:17]([C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH2:11][C:12]([O:14][CH3:15])=[O:13])#[N:18]
Reactant: COC(=O)Cc1c[nH]c2ccc(Br)cc12
Reactant: N#C[Cu]
Solvent: CCOC(C)=O
Solvent: CN1CCCC1=O
Product: COC(=O)Cc1c[nH]c2ccc(C#N)cc12
Yield: 46.7 %

Procedure:
Step H (2): To a solution of methyl 2-(5-bromo-1H-indol-3-yl)acetate (134 mg, 0.5 mmol) in NMP (1.0 mL) was added copper(I) cyanide (54 mg, 0.6 mmol). The reaction mixture was microwaved at 180° C. for 1.5 h. More copper (I) cyanide (54 mg, 0.6 mmol) was added, and the mixture was microwaved again at 180° C. for 2 h. 100 mL of EtOAc was added, and the reaction mixture was washed with 1.0 N HCl and H2O. The organic layer was dried and the residue was purified by flash chromatography to give 50 mg of the methyl 2-(5-cyano-1H-indol-3-yl)acetate (yield 47%). MS (ESI) (M+H)+=215.16. 1H NMR (500 MHz, CDCl3) δ ppm 3.73 (s, 3 H) 3.77 (s, 2 H) 7.26 (d, J=2.14 Hz, 1 H) 7.37 (d, J=8.24 Hz, 1 H) 7.40 (dd, J=8.24, 1.22 Hz, 1 H) 7.95 (s, 1 H) 8.54 (s, 1 H).
Reaction SMILES: [OH-:1].[Na+].[F:3][C:4]([F:20])([F:19])[C:5]1[CH:10]=[C:9]([C:11]([F:14])([F:13])[F:12])[CH:8]=[C:7]([N+:15]([O-:17])=[O:16])[C:6]=1Cl.ClCl.O>CO>[F:3][C:4]([F:20])([F:19])[C:5]1[CH:10]=[C:9]([C:11]([F:14])([F:13])[F:12])[CH:8]=[C:7]([N+:15]([O-:17])=[O:16])[C:6]=1[OH:1]
Reactant: O=[N+]([O-])c1cc(C(F)(F)F)cc(C(F)(F)F)c1Cl
Reactant: [OH-]
Agent: ClCl
Agent: [Na+]
Solvent: CO
Solvent: O
Product: O=[N+]([O-])c1cc(C(F)(F)F)cc(C(F)(F)F)c1O

Procedure:
To a solution of 168 g (4 moles +5% excess) of sodium hydroxide in 1000 ml methanol there were added portionwise, at 50°-65°C internal temperature, 586 g (2 moles) 2,4-bis-trifluoromethyl-6-nitrochlorobenzene; the reaction mixture, after completion of addition (about 1 hour) of the reactive chlorine compound, was boiled under reflux for one hour. After cooling, 700 ml of water were added to the mixture and unreacted starting materials were extracted once with 400 ml methylene chloride. The aquous phase was separated off, distinct acidification was effected with 20%-strength sulfuric acid; the 2,4-bis-trifluoromethyl-6-nitrophenol which separated was taken up in methylene chloride. The organic phase was dried over sodium sulfate. The 2,4-bis-trifluoromethyl-6-nitro-phenol remaining behind after methylene chloride had been distilled off was subjected to vacuum distillation. 480 g (87%) of the boiling pont 105°-106°C/20 mm Hg were obtained; refractive index nD20 : 1.4580.
Reaction SMILES: Br[CH2:2][CH:3]1[O:8][C:7]2=[CH:9][S:10][CH:11]=[C:6]2[O:5][CH2:4]1.[C:12]([O-:20])(=[O:19])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.[NH4+].CS(C)=O>O>[C:12]([O:20][CH2:2][CH:3]1[CH2:4][O:5][C:6]2=[CH:11][S:10][CH:9]=[C:7]2[O:8]1)(=[O:19])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: BrCC1COc2cscc2O1
Reactant: O=C([O-])c1ccccc1
Agent: [NH4+]
Solvent: CS(C)=O
Solvent: O
Product: O=C(OCC1COc2cscc2O1)c1ccccc1
Temperature: 25 °C
Yield: 71.1 %

Procedure:
In a 100 mL round bottom flask 9.00 g (0.0382 mol) 2-(bromomethyl)-2,3-dihydrothieno[3,4-b][1,4]dioxine, 6.39 g (0.0459 mol) ammonium benzoate, and 55 g DMSO were combined. A reflux condenser was equipped and the reaction was heated to 100 C overnight. After cooling to room temperature, the reaction mixture was poured into water and the product was extracted with methylene chloride. The organic fractions were combined and the solvent removed under reduced pressure. Purification by column chromatography provided 7.5 g (71% yield) of a white solid whose structure was confirmed by 1H/13C NMR and LC-MS.
Reaction SMILES: [C:1]([O:5][C:6]([CH2:8][CH2:9][C@H:10]([NH:33]C(OCC1C=CC=CC=1)=O)[C:11]([NH:13][C@@H:14]([CH2:22][CH2:23][C:24]([O:26][CH2:27][CH2:28][Si:29]([CH3:32])([CH3:31])[CH3:30])=[O:25])[C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])=[O:12])=[O:7])([CH3:4])([CH3:3])[CH3:2]>CC(O)C.[Pd]>[NH2:33][C@@H:10]([CH2:9][CH2:8][C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])[C:11]([NH:13][C@@H:14]([CH2:22][CH2:23][C:24]([O:26][CH2:27][CH2:28][Si:29]([CH3:30])([CH3:32])[CH3:31])=[O:25])[C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])=[O:12]
Reactant: CC(C)(C)OC(=O)CC[C@H](NC(=O)OCc1ccccc1)C(=O)N[C@@H](CCC(=O)OCC[Si](C)(C)C)C(=O)OC(C)(C)C
Agent: [Pd]
Solvent: CC(C)O
Product: CC(C)(C)OC(=O)CC[C@H](N)C(=O)N[C@@H](CCC(=O)OCC[Si](C)(C)C)C(=O)OC(C)(C)C
Reaction time: 1 h
Yield: 93.9 %

Procedure:
The product of step 7G (1.09 g) was dissolved in 2-propanol (75 mL) with 10% palladium on carbon (300 mg) and hydrogenated on a Parr shaker at 45 psi for one hour. The reaction mixture was filtered on a bed of Celite, washed with 2-propanol, and concentrated to yield the product (803 mg, 94%) as a clear oil. LRMS (ES): 489.5 [M+H]+, 977.7 [2M+H]+. 1HNMR (600.1343 MHz, CDCl3): 7.78 (m, 1H), 4.53 (m, 1H), 4.22 (m, 2H), 3.53 (m, 1H), 1.80–2.41 (m, 10H), 1.43 (s, 18H), 1.01 (m, 2H), 0.02 (s, 9H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[C@H:9]1[CH2:13][CH2:12][CH2:11][N:10]1[C:14]1[CH:15]=[CH:16][C:17]2[N:18]([C:20]([NH2:23])=[CH:21][N:22]=2)[N:19]=1.[C:24]([N:31]1[CH:35]=[CH:34]N=[CH:32]1)(N1C=CN=C1)=[O:25].N1CC[O:39][CH2:38]C1>C(Cl)Cl>[F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[C@H:9]1[CH2:13][CH2:12][CH2:11][N:10]1[C:14]1[CH:15]=[CH:16][C:17]2[N:18]([C:20]([NH:23][C:24]([N:31]3[CH2:35][CH2:34][O:39][CH2:38][CH2:32]3)=[O:25])=[CH:21][N:22]=2)[N:19]=1
Reactant: Nc1cnc2ccc(N3CCC[C@@H]3c3cc(F)ccc3F)nn12
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: C1COCCN1
Solvent: ClCCl
Product: O=C(Nc1cnc2ccc(N3CCC[C@@H]3c3cc(F)ccc3F)nn12)N1CCOCC1
Reaction time: 2 h
Yield: 78.6 %

Procedure:
To a DCM (1.9 mL) solution of (R)-6-(2-(2,5-difluorophenyl)pyrrolidin-1-yl)imidazo[1,2-b]pyridazin-3-amine (Preparation B; 72 mg, 0.19 mmol) was added 1,1′-carbonyldiimidazole (CDI) (47 mg, 0.29 mmol) at ambient temperature in one portion. After stirring for 2 hours, morpholine (34 mg, 0.39 mmol) was added in one portion. The reaction was stirred for another hour before it was concentrated, then directly purified by reverse-phase column chromatography, eluting with 5 to 60% acetonitrile/water to yield (R)—N-(6-(2-(2,5-difluorophenyl)pyrrolidin-1-yl)imidazo[1,2-b]pyridazin-3-yl)morpholine-4-carboxamide as a solid (64 mg, 77% yield). MS (apci) m/z=429.1 (M+H).