Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:29]=[CH:28][C:5]([O:6][C:7]2[N:12]=[CH:11][N:10]=[C:9]([NH:13][C:14]3[CH:19]=[CH:18][C:17]([O:20][CH2:21][C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)=[CH:16][CH:15]=3)[CH:8]=2)=[C:4]([F:30])[CH:3]=1.FC1C=C(N[C:55](=[O:67])[CH2:56][C:57]([NH:59][C:60]2[CH:65]=[CH:64][C:63]([F:66])=[CH:62][CH:61]=2)=[O:58])C=CC=1OC1C=CN=C(NCCN2CCOCC2)C=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.CCN(C(C)C)C(C)C.COC1C=CC(CNC2N=C(OC3C=CC(N)=CC=3F)C=CN=2)=CC=1>CN(C=O)C>[CH2:21]([O:20][C:17]1[CH:16]=[CH:15][C:14]([NH:13][C:9]2[N:10]=[CH:11][N:12]=[C:7]([O:6][C:5]3[CH:28]=[CH:29][C:2]([NH:1][C:55](=[O:67])[CH2:56][C:57]([NH:59][C:60]4[CH:65]=[CH:64][C:63]([F:66])=[CH:62][CH:61]=4)=[O:58])=[CH:3][C:4]=3[F:30])[CH:8]=2)=[CH:19][CH:18]=1)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: O=C(CC(=O)Nc1ccc(Oc2ccnc(NCCN3CCOCC3)c2)c(F)c1)Nc1ccc(F)cc1
Reactant: Nc1ccc(Oc2cc(Nc3ccc(OCc4ccccc4)cc3)ncn2)c(F)c1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: COc1ccc(CNc2nccc(Oc3ccc(N)cc3F)n2)cc1
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=C(CC(=O)Nc1ccc(Oc2cc(Nc3ccc(OCc4ccccc4)cc3)ncn2)c(F)c1)Nc1ccc(F)cc1
Yield: 87.5 %

Procedure:
The title compound was prepared from a mixture 6-(4-amino-2-fluorophenoxy)-N-(4-(benzyloxy)phenyl)pyrimidin-4-amine (45 mg, 0.11 mmol), 3-(4-fluorophenylamino)-3-oxopropanoic acid (Compound B of Example 1, 24 mg, 0.12 mmol), TBTU (48 mg, 0.15 mmol), DIPEA (0.26 mL, 0.15 mmol), and DMF (1 mL) using a similar procedure described for the preparation of Compound C of Example 1. The crude product was triturated with isopropyl ether to give the title compound (56 mg, 88%) as a pink solid. 1H NMR (DMSO-d6) δ 10.47 (s, 1H), 10.27 (s, 1H), 9.45 (s, 1H), 8.25 (s, 1H), 7.77 (dd, 1H, J=12.7, 2.0 Hz), 7.65-7.62 (m, 2H), 7.46 (d, 4H, J=7.3 Hz), 7.40 (dd, 2H, J=7.6, 7.3 Hz), 7.37-7.29 (m, 3H), 7.17 (dd, 2H, J=9.0, 8.3 Hz), 7.00 (d, 2H, J=9.0 Hz) 6.09 (s, 1H), 5.09 (s, 2H) 3.49 (s, 2H); MS(ESI+) m/z 582.3 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[C:22]([CH3:23])=[CH:21][C:19]([NH2:20])=[C:18]([CH3:24])[CH:17]=1.Cl[C:26](Cl)([O:28][C:29](=[O:35])OC(Cl)(Cl)Cl)Cl.[CH3:37][N:38]1[CH2:43][CH2:42][N:41]([CH2:44][CH2:45]CO)[CH2:40][CH2:39]1.C(=O)(O)[O-].[Na+]>C(Cl)Cl.C(N(CC)CC)C.C1(C)C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[C:22]([CH3:23])=[CH:21][C:19]([NH:20][C:29](=[O:35])[O:28][CH2:26][CH2:45][CH2:44][N:41]2[CH2:42][CH2:43][N:38]([CH3:37])[CH2:39][CH2:40]2)=[C:18]([CH3:24])[CH:17]=1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: COc1cc2nccc(Oc3cc(C)c(N)cc3C)c2cc1OC
Reactant: CN1CCN(CCCO)CC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1cc2nccc(Oc3cc(C)c(NC(=O)OCCCN4CCN(C)CC4)cc3C)c2cc1OC
Yield: 42.1 %

Procedure:
4-[(6,7-Dimethoxy-4-quinolyl)oxy]-2,5-dimethylaniline (50 mg) was added to toluene (5 ml), and triethylamine (0.5 ml), and the mixture was heated under reflux to prepare a solution. A solution of triphosgene (68 mg) in methylene chloride was then added thereto, and the mixture was heated under reflux for 10 min. Next, 3-(4-methylpiperazino)-1-propanol (36 mg) was added thereto, and the mixture was further stirred with heating under reflux for 3 hr. A saturated aqueous sodium bicarbonate solution was added to stop the reaction, and the reaction solution was then extracted with chloroform, and the extract was washed with water and saturated brine in that order. The extract was dried over sodium sulfate and was then concentrated. The residue was purified on a column using chloroform/methanol to give the title compound (33 mg, yield 36%).
Reaction SMILES: [C:1]1([CH:7]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:8]([OH:10])=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C([Li])CCC.Cl[CH2:23][C:24]([CH3:26])=[CH2:25].Cl>O1CCCC1.CCCCCC.CCOCC>[C:1]1([C:7]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)([CH2:25][C:24]([CH3:26])=[CH2:23])[C:8]([OH:10])=[O:9])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C(O)C(c1ccccc1)c1ccccc1
Reactant: C=C(C)CCl
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCOCC
Solvent: CCCCCC
Product: C=C(C)CC(C(=O)O)(c1ccccc1)c1ccccc1
Reaction time: 0.25 h
Yield: 114.9 %

Procedure:
A solution of diphenylacetic acid (14 g, 66 mmol.) in 150 mL of tetrahydrofuran was stirred at 0° C. under argon while 55.5 mL of a 2.5 M solution of n-butyllithium in hexane was added dropwise. After 15 minutes, 3-chloro-2-methylpropene (6.51 mL, 66 mmol.) was added in one portion. After 10 minutes, 25 mL of 4N hydrochloric acid was added, along with ether (250 mL). The layers were separated, the organic layer was washed with water (2×100 mL), brine (2×100 mL) dried (MgSO4), and filtered. Concentration afforded 20.2 g (99%) of a yellow oil. 1H NMR (CDCl3)δ 7.4-7.2 (m, 10H), 4.7 (s, IH), 4.6 (s, lH), 3.2 (s, 2H), 1.4 (s, 3H).
Reaction SMILES: Cl.[Cl:2][C:3]1[C:8]([NH2:9])=[C:7]([Cl:10])[CH:6]=[CH:5][C:4]=1[OH:11].[OH-].[K+].S(OC)(O[CH3:18])(=O)=O.O>CC(C)=O>[Cl:2][C:3]1[C:4]([O:11][CH3:18])=[CH:5][CH:6]=[C:7]([Cl:10])[C:8]=1[NH2:9]
Reactant: Nc1c(Cl)ccc(O)c1Cl
Reactant: COS(=O)(=O)OC
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CC(C)=O
Solvent: O
Product: COc1ccc(Cl)c(N)c1Cl

Procedure:
To a solution of 2,4-dichloro-3-aminophenol hydrochloride (GLSynthesis, 7.70 g, 35.9 mmol, 1.0 eq.) in acetone is added powdered potassium hydroxide 85% (9.48 g, 143.6 mmol, 4.0 eq.) in small portions. Then, dimethyl sulfate (5.13 ml, 53.9 mmol, 1.5 eq.) is added at such a rate that the internal temperature does not rise above 30° C. After 1 h stirring at room temperature water (50 ml) is added and stirring is continued for another hour. The solvent is evaporated and the residue is distributed between ethyl acetate (150 ml) and water (100 ml). The organic layer is isolated, dried over Na2SO4 and evaporated to give a yellow oil. Kugelrohr distillation affords the desired product as a colorless oil: b.p. 150° C./0.3 mbar, HPLC: tR=5.61 min (purity: 90%, gradient A), 400 MHz 1H-NMR (CDCl3) δ: 3.87 (s, 3H, OMe), 4.49 (br s, 2H, NH2), 6.30 (d, 1H, Ar—H4), 7.11 (d, 1H, Ar—H5).
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]([N:27]2[N:31]=[CH:30][CH:29]=[N:28]2)=[C:6]([CH:26]=1)[C:7]([NH:9][C@H:10]1[CH2:14][CH2:13][CH2:12][C@@H:11]1[NH:15][C:16]1[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][N:17]=1)=[O:8].Cl.[F:33]C(F)(F)C1C=CC(N[C@H]2CCC[C@@H]2N)=NC=1.FC1C(N2N=CC=N2)=C(C=CC=1)C(O)=O>>[F:33][C:4]1[C:5]([N:27]2[N:28]=[CH:29][CH:30]=[N:31]2)=[C:6]([CH:26]=[CH:2][CH:3]=1)[C:7]([NH:9][C@H:10]1[CH2:14][CH2:13][CH2:12][C@@H:11]1[NH:15][C:16]1[CH:21]=[CH:20][C:19]([C:22]([F:24])([F:25])[F:23])=[CH:18][N:17]=1)=[O:8]
Reactant: O=C(N[C@H]1CCC[C@@H]1Nc1ccc(C(F)(F)F)cn1)c1cc(Cl)ccc1-n1nccn1
Reactant: N[C@H]1CCC[C@@H]1Nc1ccc(C(F)(F)F)cn1
Agent: Cl
Agent: O=C(O)c1cccc(F)c1-n1nccn1
Product: O=C(N[C@H]1CCC[C@@H]1Nc1ccc(C(F)(F)F)cn1)c1cccc(F)c1-n1nccn1

Procedure:
Prepared according to the procedure for 5-chloro-2-(2H-1,2,3-triazol-2-yl)-N-[(1S,2S)-2-{[5-(trifluoromethyl)pyridin-2-yl]amino}cyclopentyl]benzamide (Example 97) from (1S,2S)-1-N-[5-(trifluoromethyl)pyridin-2-yl]cyclopentane-1,2-diamine hydrochloride (Intermediate 1; 50 mg, 0.20 mmol) and 3-fluoro-2-(2H-1,2,3-triazol-2-yl)benzoic acid (CAS number 1293284-51-1; 42 mg, 0.20 mmol) to afford the title compound.
Reaction SMILES: [C:1](Cl)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:10]([O:14][C:15]([N:17]1[CH2:22][CH:21]([N:23]2[C:32]3[CH:31]=[CH:30][CH:29]=[C:28]([Cl:33])[C:27]=3[C:26]3=[N:34][O:35][C:36]([CH3:37])=[C:25]3[C:24]2=[O:38])[CH2:20][CH:19]([CH2:39][NH2:40])[CH2:18]1)=[O:16])([CH3:13])([CH3:12])[CH3:11].CCN(CC)CC.C(Cl)(Cl)Cl>C(Cl)Cl.CN(C1C=CN=CC=1)C>[C:10]([O:14][C:15]([N:17]1[CH2:22][CH:21]([N:23]2[C:32]3[CH:31]=[CH:30][CH:29]=[C:28]([Cl:33])[C:27]=3[C:26]3=[N:34][O:35][C:36]([CH3:37])=[C:25]3[C:24]2=[O:38])[CH2:20][CH:19]([CH2:39][NH:40][C:1](=[O:8])[C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[CH2:18]1)=[O:16])([CH3:13])([CH3:12])[CH3:11]
Reactant: O=C(Cl)c1ccccc1
Reactant: Cc1onc2c1c(=O)n(C1CC(CN)CN(C(=O)OC(C)(C)C)C1)c1cccc(Cl)c21
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: Cc1onc2c1c(=O)n(C1CC(CNC(=O)c3ccccc3)CN(C(=O)OC(C)(C)C)C1)c1cccc(Cl)c21
Temperature: 25 °C
Yield: 52.6 %

Procedure:
Add benzoyl chloride (0.11 mL, 0.98 mmol) to a solution of 3-aminomethyl-5-(9-chloro-3-methyl-4-oxo-5H-isoxazolo[4,3-c]quinolin-5-yl)-piperidine-1-carboxylic acid tert-butyl ester (0.4 g, 0.89 mmol) in CH2Cl2 (10 mL). Add Et3N (0.4 mL, 2.67 mmol) and DMAP (5 mg, cat.). Stir 4 H at room temperature then add CHCl3. Wash 2× with sat. aq NaHCO3, wash 2× with 1N HCl, wash 2× with brine, dry over Na2SO4, filter and concentrate to dryness. Purify by radial chromatography using a MeOH/CHCl3 gradient as eluant. Purify again via radial chromatography using an EtOAc/hexane gradient as eluant and concentrate to dryness to afford the title compound (0.258 g, 53%) as a white foam as a mixture of cis isomers. MS(IS) 551.3 (M+). Purify via chiral HPLC (Chiralcel OD 4.6×250 mm. Eluant: 35% IPA, 65% heptane. Flow: 1.0 mL/min. UV: 240 nM). Chromatography affords isomer 1 of the title compound (59 mg, 23%) as a white solid. MS(IS) 551.3 (M+); Rt=7.0 min. Chromatography affords isomer 2 of the title compound (124 mg, 48%) as a white solid. MS(IS) 551.3; Rt=15.0 min.
Reaction SMILES: [C:1]([O:4][CH2:5][CH2:6][O:7][CH2:8][CH2:9][C:10]([C:12]1[CH:24]=[CH:23][C:15]([CH2:16][C:17]2[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=2)=[CH:14][CH:13]=1)=[O:11])(=[O:3])[CH3:2].B.[Na].O.Cl>C(O)C.C(OCC)(=O)C>[C:1]([O:4][CH2:5][CH2:6][O:7][CH2:8][CH2:9][CH:10]([C:12]1[CH:24]=[CH:23][C:15]([CH2:16][C:17]2[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=2)=[CH:14][CH:13]=1)[OH:11])(=[O:3])[CH3:2]
Reactant: CC(=O)OCCOCCC(=O)c1ccc(Cc2cccnc2)cc1
Agent: B
Agent: Cl
Agent: [Na]
Solvent: CCO
Solvent: O
Solvent: CCOC(C)=O
Product: CC(=O)OCCOCCC(O)c1ccc(Cc2cccnc2)cc1
Yield: 82.7 %

Procedure:
In 27 ml of ethanol was dissolved 2.70 g of 3-[p-[3-(2-acetoxyethyl)oxypropionyl]benzyl]pyridine, and to the resulting solution was added 0.34 g of sodium boron hydride in portions with ice-cooling over 30 minutes, after which the resulting mixture was subjected to reaction at the same temperature for one hour. To the reaction mixture were added 30 ml of iced water and 20 ml of ethyl acetate, and then, the pH thereof was adjusted to 2.0 with 2N hydrochloric acid. The aqueous layer was separated, and 30 ml of ethyl acetate was added thereto, after which the pH thereof was adjusted to 7 with sodium hydrogencarbonate. The organic layer was separated, washed with 10 ml of water, and then dried over anhydrous magnesium sulfate. The solvent was removed by distillation to obtain 2.25 g (yield 82.7%) of colorless, oily 3-[p-[3-(2-acetoxyethyl)oxy-1-hydroxypropyl]benzyl]pyridine.
Reaction SMILES: C([O:8][C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[NH:14][C:13]([C:18]([N:20]1[CH2:25][CH2:24][N:23]([CH3:26])[CH2:22][CH2:21]1)=[O:19])=[CH:12]2)C1C=CC=CC=1>C(O)C.C(OC(=O)C)C.[Pd]>[OH:8][C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[NH:14][C:13]([C:18]([N:20]1[CH2:25][CH2:24][N:23]([CH3:26])[CH2:22][CH2:21]1)=[O:19])=[CH:12]2
Reactant: CN1CCN(C(=O)c2cc3cc(OCc4ccccc4)ccc3[nH]2)CC1
Agent: [Pd]
Solvent: CCO
Solvent: CCOC(C)=O
Product: CN1CCN(C(=O)c2cc3cc(O)ccc3[nH]2)CC1
Yield: 22.9 %

Procedure:
A mixture of the product of Example 5, (5-Benzyloxy-1H-indol-2-yl)-(4-methyl-piperazin-1-yl)-methanone (0.2 g) in a mixture of ethanol (3 mL) and ethylacetate (5 mL) was treated with 10% palladium on carbon (approximately 0.025 g) and hydrogenated at atmospheric pressure for 2 h. The reaction mixture was filtered through a pad of Celite and the residue washed with methanol. The solvent in the combined filtrates was removed under reduced pressure, and the residue was purified via silica gel chromatography (3-10% 2 M ammonia in methanol/dichloromethane) to afford the title compound (0.034 g, 23%). 1H NMR (400 MHz, CD3OD): δ 7.20 (d, J=8.0 Hz, 1H), 6.90 (m, 1H), 6.75 (dd, J=4, 8 Hz, 1H), 6.54 (m,1H), 3.80 (br.m, 4H), 2.44 (m, 4H), 2.27 (s, 3H). MS (electrospray): exact mass calculated for C14H17N3O2, 259.13; m/z found, 260.0 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:16]2[C@:15]34[CH2:17][CH2:18][N:19](C(OCC(Cl)(Cl)Cl)=O)[C@@H:9]([C@:10]3(C(OCC(Cl)(Cl)Cl)=O)[CH2:11][CH2:12][C:13](=[O:28])[CH2:14]4)[CH2:8][C:7]=2[CH:6]=[CH:5][CH:4]=1.[NH4+].[Cl-].C([OH:41])C>[Zn]>[OH:41][C@:10]12[C@@H:9]3[NH:19][CH2:18][CH2:17][C@:15]1([C:16]1[C:3]([O:2][CH3:1])=[CH:4][CH:5]=[CH:6][C:7]=1[CH2:8]3)[CH2:14][C:13](=[O:28])[CH2:12][CH2:11]2
Reactant: CCO
Reactant: COc1cccc2c1[C@]13CCN(C(=O)OCC(Cl)(Cl)Cl)[C@H](C2)[C@]1(C(=O)OCC(Cl)(Cl)Cl)CCC(=O)C3
Agent: [Cl-]
Agent: [NH4+]
Agent: [Zn]
Product: COc1cccc2c1[C@]13CCN[C@H](C2)[C@]1(O)CCC(=O)C3
Reaction time: 0.5 h
Yield: 53 %

Procedure:
To a mixture of 2.9 g (4.54 mmol) 4-methoxy-N,14-bis(2,2,2-trichloroethoxycarbonyl)-morphinan-6-one in 130 ml ethanol were added 15 g (280.4 mmol) NH4Cl and this mixture was stirred and refluxed. During 0.5 h 12 g (177 mg) activated zinc powder were added portionwise and the resulting mixture was refluxed for 1 h. After cooling and filtration, the filtrate was evaporated. The residue was dissolved in water, basified with saturated NaHCO3 solution and extracted with CHCl3. The organic layer was washed with brine, dried and evaporated to give an oil which was crystallized with isopropyl ether to yield 690 mg (53%) 14-hydroxy-4-methoxymorphinan-6-one, m.p. 137°-139°, [α]D26 --66.5°. (C 1.08, CHCl3).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[N:9]=[C:8]1[C:13]3[N:18]([CH2:19][C:7]1=[CH:6]2)[C:17](=[O:20])[C:16]([CH3:21])=[C:15]([CH:22]([O:25][C:26](=[O:36])[CH2:27][NH:28]C(OC(C)(C)C)=O)[CH2:23][CH3:24])[CH:14]=3)#[N:2].C(C(O)=O)(F)(F)F.O>>[NH2:28][CH2:27][C:26]([O:25][CH:22]([C:15]1[CH:14]=[C:13]2[N:18]([CH2:19][C:7]3[C:8]2=[N:9][C:10]2[C:5]([CH:6]=3)=[CH:4][C:3]([C:1]#[N:2])=[CH:12][CH:11]=2)[C:17](=[O:20])[C:16]=1[CH3:21])[CH2:23][CH3:24])=[O:36]
Reactant: CCC(OC(=O)CNC(=O)OC(C)(C)C)c1cc2n(c(=O)c1C)Cc1cc3cc(C#N)ccc3nc1-2
Solvent: O
Solvent: O=C(O)C(F)(F)F
Product: CCC(OC(=O)CN)c1cc2n(c(=O)c1C)Cc1cc3cc(C#N)ccc3nc1-2

Procedure:
The title compound was prepared according to the procedure in Example 3B except using (±)-2-cyano-8-methyl-7-[1-[[[[(1,1-dimethylethoxy)carbonyl]amino]acetyl]oxy]propyl]indolizino[1,2-b]quinolin-9(11H)-one. 1H NMR (DMSO-d6) d 8.81 (d, J=1.5 Hz, 1H), 8.77 (s, 1H), 8.27 (d, J=8.9 Hz, 1H), 8.13 (dd, J=8.9, 1.8 Hz, 1H), 7.24 (s, 1H), 5.91 (apparent br t, J=6.7 Hz, 1H), 5.29 (s, 2H), 3.98 (br s, 2H), 2.26 (s, 3H), 2.05-1.81 (m, 2H), 0.96 (t, J=7.4 Hz, 3H). Anal. Calcd for C22H20N4O3.3/2 CF3CO2H.H2O: C, 52.00; H, 4.10; N, 9.70. Found: C, 52.04; H, 4.32; N, 9.73.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][N:10]([CH2:18][C@@H:19]([C:21]2[CH:26]=[CH:25][CH:24]=[C:23]([Cl:27])[CH:22]=2)[OH:20])[C:11](=[O:17])[O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[CH:4][CH:3]=1.[CH3:28][O:29][C:30]([C:32]1[CH:37]=[CH:36][C:35](B(O)O)=[C:34]([CH3:41])[CH:33]=1)=[O:31].C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.C(OCC)(=O)C.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>[C:13]([O:12][C:11]([N:10]([CH2:18][C@@H:19]([C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([Cl:27])[CH:22]=1)[OH:20])[CH2:9][CH2:8][C:5]1[CH:6]=[CH:7][C:2]([C:35]2[CH:36]=[CH:37][C:32]([C:30]([O:29][CH3:28])=[O:31])=[CH:33][C:34]=2[CH3:41])=[CH:3][CH:4]=1)=[O:17])([CH3:16])([CH3:15])[CH3:14]
Reactant: COC(=O)c1ccc(B(O)O)c(C)c1
Reactant: CC(C)(C)OC(=O)N(CCc1ccc(Br)cc1)C[C@H](O)c1cccc(Cl)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Solvent: CCOC(C)=O
Product: COC(=O)c1ccc(-c2ccc(CCN(C[C@H](O)c3cccc(Cl)c3)C(=O)OC(C)(C)C)cc2)c(C)c1
Temperature: 80 °C
Reaction time: 2 h
Yield: 69.4 %

Procedure:
To a solution of tert-butyl [2-(4-bromophenyl)ethyl]-[(2R)-2-(3-chlorophenyl)-2-hydroxyethyl]carbamate (400 mg) in 1,2-dimethoxyethane (6 ml) was added (4-methoxycarbonyl-2-methylphenyl)boronic acid (171 mg), tetrakis(triphenylphosphine)palladium (55 mg) and aqueous solution of sodium carbonate (2M, 0.92 ml), and the mixture was stirred at 80° C. for 2 hours under nitrogen. The mixture was diluted with ethyl acetate and water. The organic layer was separated, washed with brine, dried over magnesium sulfate and evaporated under reduced pressure. The residue was purified by column chromatography on silica gel (hexane/ethyl acetate=2/1) to give methyl 4′-[2-[(tert-butoxycarbonyl)[(2R)-2-(3-chlorophenyl)-2-hydroxyethyl]-amino]ethyl]-2-methyl-1,1′-biphenyl-4-carboxylate (320 mg).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5](/[CH:13]=[CH:14]/[C:15]([OH:17])=O)[CH:6]=[CH:7][C:8]=1[S:9](=[O:12])(=[O:11])[NH2:10].S(Cl)(Cl)=O.[Cl:22][C:23]1[CH:24]=[C:25]([NH2:29])[CH:26]=[CH:27][CH:28]=1.C(N(C(C)C)CC)(C)C>C1COCC1>[Cl:22][C:23]1[CH:24]=[C:25]([NH:29][C:15](=[O:17])/[CH:14]=[CH:13]/[C:5]2[CH:6]=[CH:7][C:8]([S:9](=[O:11])(=[O:12])[NH2:10])=[C:3]([O:2][CH3:1])[CH:4]=2)[CH:26]=[CH:27][CH:28]=1
Reactant: COc1cc(/C=C/C(=O)O)ccc1S(N)(=O)=O
Reactant: Nc1cccc(Cl)c1
Solvent: O=S(Cl)Cl
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: COc1cc(/C=C/C(=O)Nc2cccc(Cl)c2)ccc1S(N)(=O)=O
Yield: 26.5 %

Procedure:
A solution of (E)-3-(3-methoxy-4-sulfamoyl-phenyl)-acrylic acid (0.291 g, 1.13 mmol) and thionyl chloride (0.100 mL, 1.36 mmol) in dry THF (15 mL) was stirred at reflux temperature for 1 h. Then a further aliquot of thionyl chloride (0.050 mL, 0.68 mmol) was added and the mixture was stirred at reflux temperature for additional 2 hrs. The mixture was then concentrated under reduced pressure, taken up with dry THF (3 mL) and added dropwise to a solution of 3-chloro-phenylamine (0.109 mL, 1.03 mmol) and diisopropylethylamine (0.705 mL, 4.12 mmol) in dry THF (13 mL). After stirring at RT for 16 hrs, the reaction mixture was concentrated under reduced pressure, taken up with DCM and washed with aqueous sodium hydrogencarbonate, and brine. The organic layer was then dried over sodium sulphate and evaporated. The resulting raw material was purified by column chromatography over silica gel (eluant DCM/acetone 9/1) to give 100 mg of the title (E)-N-(3-chloro-phenyl)-3-(3-methoxy-4-sulfamoyl-phenyl)-acrylamide as a white powder.
Reaction SMILES: [OH:1][CH2:2][C@H:3]1[CH2:20][N:7]2[CH2:8][CH2:9][N:10]([C:12]3[CH:17]=[CH:16][C:15]([F:18])=[CH:14][C:13]=3[NH2:19])[CH2:11][C@@H:6]2[CH2:5][CH2:4]1.[F:21][C:22]1[CH:27]=[CH:26][C:25](O)=[CH:24][CH:23]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>C1COCC1>[F:21][C:22]1[CH:27]=[CH:26][C:25]([O:1][CH2:2][C@H:3]2[CH2:20][N:7]3[CH2:8][CH2:9][N:10]([C:12]4[CH:17]=[CH:16][C:15]([F:18])=[CH:14][C:13]=4[NH2:19])[CH2:11][C@@H:6]3[CH2:5][CH2:4]2)=[CH:24][CH:23]=1
Reactant: Oc1ccc(F)cc1
Reactant: Nc1cc(F)ccc1N1CCN2C[C@H](CO)CC[C@H]2C1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: Nc1cc(F)ccc1N1CCN2C[C@H](COc3ccc(F)cc3)CC[C@H]2C1
Temperature: 25 °C
Reaction time: 96 h
Yield: 30.6 %

Procedure:
A solution of 4.12 g (14.8 mmol) of (7R,9aS)-7-hydroxymethyl-2-(2-amino-4-fluorophenyl)-2,3,4,6,7,8,9,9a-octahydro-1H-pyrido[1,2-a]pyrazine, 2.48 g (22.2 mmol) of 4-fluorophenol and 4.65 g (17.7 mmol) of triphenylphosphine in 225 mL of THF was treated with 2.79 mL (17.7 mmol) of diethyl azodicarboxylate and stirred at room temperature for 4 days. The solvent was evaporated, the residue dissolved in 1:1 ethyl acetate:ethyl ether and the solution treated with HCl(g) in ether until precipitation ceased. The mixture was filtered and the solid washed repeatedly with ethyl acetate. The solid was dissolved in a mixture of chloroform and 1M sodium hydroxide, the layers separated, and the organic phase was dried (magnesium sulfate), filtered and evaporated. Purification by flash silica gel chromatography with 60:40 ethyl acetate:hexane gave 1.69 g (30%) of the title compound. mp (—HCl) 144-149° C. HRMS calcd for C21H25F2N3O: 373.1966, found: 373.1958.
Reaction SMILES: [NH2:1][CH:2]([C:5]([N:7]1[CH2:11][C@H:10]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C@@H:9]([O:18][C@@H:19]([C:21]2[CH:26]=[C:25]([C:27]([F:30])([F:29])[F:28])[CH:24]=[C:23]([C:31]([F:34])([F:33])[F:32])[CH:22]=2)[CH3:20])[CH2:8]1)=[O:6])[CH2:3][OH:4].C(N(CC)CC)C.[C:42](Cl)(Cl)=[O:43]>C(Cl)Cl.C1(C)C=CC=CC=1>[F:33][C:31]([F:34])([F:32])[C:23]1[CH:22]=[C:21]([C@H:19]([O:18][C@@H:9]2[C@@H:10]([C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=3)[CH2:11][N:7]([C:5]([CH:2]3[CH2:3][O:4][C:42](=[O:43])[NH:1]3)=[O:6])[CH2:8]2)[CH3:20])[CH:26]=[C:25]([C:27]([F:28])([F:29])[F:30])[CH:24]=1
Reactant: O=C(Cl)Cl
Reactant: C[C@@H](O[C@H]1CN(C(=O)C(N)CO)C[C@@H]1c1ccccc1)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C[C@@H](O[C@H]1CN(C(=O)C2COC(=O)N2)C[C@@H]1c1ccccc1)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Temperature: 0 °C
Reaction time: 8 h

Procedure:
To a solution of 15 mg (0.03 mmol) 2-amino-3-[(3R,4S)-3-({(1R)-1-[3,5-bis(trifluoromethyl)phenyl]ethyl}oxy)-4-phenylpyrrolidin-1-yl]-3-oxopropan-1-ol (Example 5) in 3 mL methylene chloride was added 0.011 mL (0.08 mmol) triethylamine. The resulting mixture was cooled to 0° C. and 0.015 mL (0.03 mmol) of a 2M solution of phosgene in toluene was added by syringe. The reaction mixture was stirred at RT for 8 hr and the volatiles were removed under vacuum. The dark yellow residue was purified by prep TLC eluting with methylene chloride/methanol (95/5) to afford the title compound. 1H-NMR (CDCl3) rotamers: δ: 1.43 (d, 3H, 6.5 Hz), 3.30-4.13 (m, 7H), 4.40-4.70 (m, 3H), 7.00-7.10 (m, 2H), 7.20-7.30 (m, 3H), 7.55 (s, 2H), 7.60 (s, 1H), 7.75, 7.77 (2s, 1H)ppm. MS: 517.0 (MH+) observed.
Reaction SMILES: [I-].[CH3:2][S+](C)(C)=O.[H-].[Na+].[F:9][C:10]1[CH:11]=[C:12]2[C:16](=[CH:17][CH:18]=1)[NH:15][C:14](=[O:19])/[C:13]/2=[CH:20]\[C:21]1[CH:29]=[C:28]2[C:24]([C:25]([I:30])=[N:26][NH:27]2)=[CH:23][CH:22]=1>C1COCC1>[F:9][C:10]1[CH:11]=[C:12]2[C:16](=[CH:17][CH:18]=1)[NH:15][C:14](=[O:19])[C@:13]12[CH2:2][C@H:20]1[C:21]1[CH:29]=[C:28]2[C:24]([C:25]([I:30])=[N:26][NH:27]2)=[CH:23][CH:22]=1
Reactant: C[S+](C)(C)=O
Reactant: O=C1Nc2ccc(F)cc2/C1=C/c1ccc2c(I)n[nH]c2c1
Agent: [H-]
Agent: [I-]
Agent: [Na+]
Solvent: C1CCOC1
Product: O=C1Nc2ccc(F)cc2[C@]12C[C@H]2c1ccc2c(I)n[nH]c2c1
Temperature: 50 °C
Reaction time: 7 h
Yield: 53.9 %

Procedure:
Trimethylsulfoxonium iodide (173.8 mg, 0.789 mmol) was added to a suspension of sodium hydride (94.76 mg, 4.12 mmol) (60% dispersion in oil) in THF (4.0 mL) at room temperature. The mixture was stirred for 15 min after which time a solution of (Z)-5-fluoro-3-((3-iodo-1H-indazol-6-yl)methylene)indolin-2-one (160 mg, 0.394 mmol) in THF (2.4 mL) was added. The solution was stirred at 50° C. for 7 h prior to quenching the reaction mass over 10% NH4Cl solution (15 mL) at room temperature. The product was extracted using ethyl acetate (15 mL×2) and the organic layer was dried over Na2SO4 and evaporated in vacuo. Trituration with hexane (5 mL) gave the title compound as a cream solid (89 mg, 54%). 1H NMR (400 MHz, DMSO-d6) δ 13.50 (s, 1H), 10.65 (s, 1H), 7.50 (s, 1H), 7.31 (d, 1H, J=8.4 Hz), 7.00 (d, 1H, J=8.4 Hz), 6.85-6.81 (m, 2H), 5.81 (d, 1H, J=8.4 Hz), 3.22 (m, 1H), 2.43 (m, 1H), 2.01 (m, 1H); MS ESI 420.0 [M+H]+, calcd for [C17H11FIN3O+H]+ 420.0.