Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([S:7]([CH2:10][C:11]2[CH:16]=[C:15]([F:17])[CH:14]=[C:13]([O:18][CH2:19][CH2:20]Cl)[C:12]=2[NH2:22])(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[N-:23]=[N+:24]=[N-:25].[Na+]>CS(C)=O.O>[N:23]([CH2:20][CH2:19][O:18][C:13]1[CH:14]=[C:15]([F:17])[CH:16]=[C:11]([CH2:10][S:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)(=[O:9])=[O:8])[C:12]=1[NH2:22])=[N+:24]=[N-:25]
Reactant: [N-]=[N+]=[N-]
Reactant: Nc1c(CS(=O)(=O)c2ccccc2)cc(F)cc1OCCCl
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: [N-]=[N+]=NCCOc1cc(F)cc(CS(=O)(=O)c2ccccc2)c1N
Temperature: 90 °C
Reaction time: 3 h

Procedure:
A mixture of 2-benzenesulfonylmethyl-6-(2-chloro-ethoxy)-4-fluorophenylamine (1.67 g, 4.87 mmoles) and sodium azide (0.38 g, 5.84 mmoles) in DMSO (20 mL) was stirred together in a round bottom flask under nitrogen at 90° C. for 3 hours. Reaction mixture was cooled to room temperature, diluted with water, extracted with EtOAC, washed with water (2×), brine (1×), dried over Na2SO4, and concentrated under vacuum to afford the title compound as an off white solid (1.44 g, 4.14 mmoles).
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][CH:3]=1.OS(O)(=O)=O.[CH3:16]COC(C)=O>CO>[NH2:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([O:8][CH3:16])=[O:7])=[CH:4][CH:3]=1
Reactant: CCOC(C)=O
Reactant: Nc1ccc(C(=O)O)cc1
Agent: O=S(=O)(O)O
Solvent: CO
Product: COC(=O)c1ccc(N)cc1
Yield: 93 %

Procedure:
Into a 1000 mL 3-necked round bottom flask, was placed a solution of 4-aminobenzoic acid (20 g, 145.99 mmol) in methanol (600 mL). To the above was added H2SO4 (30 mL) dropwise with stirring. The resulting solution was stirred at reflux overnight. The reaction progress was monitored by TLC (EtOAc/PE=1:5). After completion, the volatile components were removed under reduced pressure and the residue was dissolved in 300 mL of water. Adjustment of the pH to 9 was accomplished by the addition of and aqueous sat. Na2CO3 solution. The resulting solution was extracted three times with 600 mL of EtOAc and the organic layers were combined and dried over Na2SO4. Removal of the volatile components under reduced pressure afforded the crude product methyl 4-aminobenzoate (vii) (20.4 g, 93% yield) as a yellow solid which was used directly in the next step without further purification.
Reaction SMILES: Cl.[N:2]1([C:6]([C:8]2[N:9]=[CH:10][C:11]([O:14][C:15]3[CH:16]=[C:17]([CH:28]=[C:29]([O:31][C@@H:32]([CH3:42])[CH2:33][O:34][Si](C(C)(C)C)(C)C)[CH:30]=3)[C:18]([NH:20][C:21]3[CH:26]=[N:25][C:24]([CH3:27])=[CH:23][N:22]=3)=[O:19])=[N:12][CH:13]=2)=[O:7])[CH2:5][CH2:4][CH2:3]1>CO>[N:2]1([C:6]([C:8]2[N:9]=[CH:10][C:11]([O:14][C:15]3[CH:16]=[C:17]([CH:28]=[C:29]([O:31][C@@H:32]([CH3:42])[CH2:33][OH:34])[CH:30]=3)[C:18]([NH:20][C:21]3[CH:26]=[N:25][C:24]([CH3:27])=[CH:23][N:22]=3)=[O:19])=[N:12][CH:13]=2)=[O:7])[CH2:5][CH2:4][CH2:3]1
Reactant: Cc1cnc(NC(=O)c2cc(Oc3cnc(C(=O)N4CCC4)cn3)cc(O[C@@H](C)CO[Si](C)(C)C(C)(C)C)c2)cn1
Agent: Cl
Solvent: CO
Product: Cc1cnc(NC(=O)c2cc(Oc3cnc(C(=O)N4CCC4)cn3)cc(O[C@@H](C)CO)c2)cn1
Temperature: 25 °C
Reaction time: 1 h
Yield: 37.7 %

Procedure:
1M Hydrochloric acid (5 mL) was added to a solution of 3-{[5-(azetidin-1-ylcarbonyl)pyrazin-2-yl]oxy}-5-[((1S)-2-{[(1,1-dimethylethyl)(dimethyl)silyl]oxy}-1-methylethyl)oxy]-N-(5-methylpyrazin-2-yl)benzamide (90 mg, 0.16 mmol) in methanol (5 mL) and the mixture stirred at RT for 1 hour. The methanol was removed in vacuo, the residue adjusted to pH6 and then extracted into ethyl acetate (3×50 mL). The combined organics were washed with brine (50 mL), dried (MgSO4), and reduced in vacuo to give a yellow oil which was chromatographed on silica, eluting with 0-5% methanol in ethyl acetate, to give the desired compound as a white foam (28 mg).
Reaction SMILES: [CH:1]([C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH:6]=[CH:5][C:4]=1[O:13][CH2:14][C:15]#[N:16])=O.[CH3:17][CH:18]([CH3:34])[C:19]([NH:21][C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([CH:28]2[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]2)[CH:23]=1)=[O:20]>>[C:15]([CH2:14][O:13][C:4]1[CH:5]=[CH:6][C:7]2[C:12](=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:3]=1[CH2:1][N:31]1[CH2:32][CH2:33][CH:28]([C:24]2[CH:23]=[C:22]([NH:21][C:19](=[O:20])[CH:18]([CH3:17])[CH3:34])[CH:27]=[CH:26][CH:25]=2)[CH2:29][CH2:30]1)#[N:16]
Reactant: N#CCOc1ccc2ccccc2c1C=O
Reactant: CC(C)C(=O)Nc1cccc(C2CCNCC2)c1
Product: CC(C)C(=O)Nc1cccc(C2CCN(Cc3c(OCC#N)ccc4ccccc34)CC2)c1

Procedure:
Prepared by Procedure F and Scheme R using [(1-formyl-2-naphthyl)oxy]acetonitrile and 2-methyl-N-[3-(4-piperidinyl)phenyl]propanamide: ESMS m/e: 442.2 (M+H)+.
Reaction SMILES: [F:1][CH2:2][C:3]([N:14]1[C:18](=[O:19])[C:17]2=[CH:20][CH:21]=[CH:22][CH:23]=[C:16]2[C:15]1=[O:24])([CH2:8][C:9](=[O:13])[CH:10]=[N+]=[N-])[C:4]([O:6][CH3:7])=[O:5].[BrH:25]>CCOCC>[F:1][CH2:2][C:3]([N:14]1[C:18](=[O:19])[C:17]2=[CH:20][CH:21]=[CH:22][CH:23]=[C:16]2[C:15]1=[O:24])([CH2:8][C:9](=[O:13])[CH2:10][Br:25])[C:4]([O:6][CH3:7])=[O:5]
Reactant: Br
Reactant: COC(=O)C(CF)(CC(=O)C=[N+]=[N-])N1C(=O)c2ccccc2C1=O
Solvent: CCOCC
Product: COC(=O)C(CF)(CC(=O)CBr)N1C(=O)c2ccccc2C1=O
Reaction time: 1 h

Procedure:
A solution of methyl 2-fluoromethyl-2-phthalimido-4-oxo-5-diazo-pentanoate (1.53 g, 4.62 mmol) in ether (22.5 ml) is added dropwise and with vigorous stirring to cold (ice cooling) aqueous HBr (47%, 0.95 ml). Stirring is continued for 1 hour at room temperature. The organic phase is separated, washed with water, dried, and evaporated to give the title compound as a yellow oil (1.52 g).
Reaction SMILES: [H-].[Na+].C(O[C:6](=[O:10])[O:7][CH2:8][CH3:9])C.[C:11]([C:14]1[C:19]([Cl:20])=[CH:18][C:17]([Cl:21])=[C:16]([F:22])[CH:15]=1)(=[O:13])[CH3:12].C(O)(=O)C>CCOCC>[Cl:20][C:19]1[CH:18]=[C:17]([Cl:21])[C:16]([F:22])=[CH:15][C:14]=1[C:11]([CH2:12][C:6]([O:7][CH2:8][CH3:9])=[O:10])=[O:13]
Reactant: CC(=O)c1cc(F)c(Cl)cc1Cl
Reactant: CCOC(=O)OCC
Agent: [H-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CCOCC
Product: CCOC(=O)CC(=O)c1cc(F)c(Cl)cc1Cl
Yield: 45 %

Procedure:
To a suspension of prewashed sodium hydride (76.8 g) in ether was added 189 g of diethylcarbonate. The mixture was heated to reflux and a solution of 131.84 g of 6-acetyl-1,3-dichloro-4-fluorobenzene in 1500 ml of ether was added dropwise over 5 hours. The mixture was then refluxed 24 hours, cooled, poured onto a mixture of ice and acetic acid and extracted several times with ether. The ether extracts were combined, washed with water, dried and evaporated. The residue was purified by vacuum distillation giving 80 g of ethyl 2,4-dichloro-5-fluorobenzoylacetate.
Reaction SMILES: [CH:1]([O:4][C:5]([N:7]1[CH2:13][CH2:12][CH2:11][CH:10]([N:14]([C:30](=[O:32])[CH3:31])[CH2:15][C:16]2[CH:21]=[C:20]([C:22]([F:25])([F:24])[F:23])[CH:19]=[C:18]([C:26]([F:29])([F:28])[F:27])[CH:17]=2)[C:9]2[CH:33]=[C:34](Br)[C:35]([Cl:37])=[CH:36][C:8]1=2)=[O:6])([CH3:3])[CH3:2].[CH3:39]B(O)O.[F-].[Cs+]>O1CCOCC1>[CH:1]([O:4][C:5]([N:7]1[CH2:13][CH2:12][CH2:11][CH:10]([N:14]([C:30](=[O:32])[CH3:31])[CH2:15][C:16]2[CH:21]=[C:20]([C:22]([F:25])([F:24])[F:23])[CH:19]=[C:18]([C:26]([F:29])([F:28])[F:27])[CH:17]=2)[C:9]2[CH:33]=[C:34]([CH3:39])[C:35]([Cl:37])=[CH:36][C:8]1=2)=[O:6])([CH3:3])[CH3:2]
Reactant: CC(=O)N(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)C1CCCN(C(=O)OC(C)C)c2cc(Cl)c(Br)cc21
Reactant: CB(O)O
Agent: [Cs+]
Agent: [F-]
Solvent: C1COCCO1
Product: CC(=O)N(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)C1CCCN(C(=O)OC(C)C)c2cc(Cl)c(C)cc21
Temperature: 100 °C
Yield: 77.6 %

Procedure:
A mixture of 5-[Acetyl-(3,5-bis-trifluoromethyl-benzyl)-amino]-7-bromo-8-chloro-2,3,4,5-tetrahydro-benzo[b]azepine-1-carboxylic acid isopropyl ester (0.118 g, 0.187 mmol), methyl boronic acid (0.0340 g, 0.561 mmol) and cesium fluoride (0.0990 mg, 0.655 mmol) in dioxane (2.00 ml) was purged with nitrogen for 10 minutes. To it was added PdCl2(dppf) (0.0240 g) in one portion. The mixture was heated at 100° C. overnight. The solid was removed by filtration, washed with ethyl acetate (30.0 ml) and the filtrate was concentrated in vacuo. Purification by silica gel chromatography (gradient eluent, 0-35% ethyl acetate in hexane) provided the titled compound (0.0820 g, 77%) as white foamy solid. MS (ES+): 565 (M+H).
Reaction SMILES: [Br:1][CH2:2][C:3]([C:5]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[C:7]2([CH2:17][CH2:16][CH2:15][CH2:14]2)[CH:6]=1)=[O:4].[BH4-].[Na+]>C(O)C.O>[Br:1][CH2:2][CH:3]([C:5]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[C:7]2([CH2:17][CH2:16][CH2:15][CH2:14]2)[CH:6]=1)[OH:4]
Reactant: O=C(CBr)C1=CC2(CCCC2)c2ccccc21
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: OC(CBr)C1=CC2(CCCC2)c2ccccc21

Procedure:
3'-Bromoacetylspiro(cyclopentane-1,1'-indene) (7.5 g) in ethanol (150 ml) is stirred at about 20° C. with sodium borohydride (3.0 g) for 15 minutes. The solution is diluted with water and extracted three times with diethyl ether. The extracts are dried and the solvent removed, giving crude 2-bromo-1-[spiro(cyclopentane-1,1'-indene)-3'-yl]ethanol. This bromohydrine is dissolved in dioxane (75 ml) and dimethylamine (10 g) is added. The solution is heated in an autoclave at 90° C. for 2 hours. Evaporation of excess of dimethylamine and solvent gives an oily residue, which is treated with 2 N sodium hydroxide solution. Extraction with dichloromethane, drying of the extract and evaporation of the solvent gives the title amine as a colourless oil, which on treatment with oxalic acid in acetonitrile solution is converted to the crystalline hydrogen oxalate; m.p. 133°-134° C. after crystallization from acetonitrile.
Reaction SMILES: C(=O)(O)[O-].[Na+].Cl.[NH2:7][CH2:8][CH2:9][SH:10].[C:11]([O:15][C:16]([N:18]1[CH2:22][CH2:21][CH2:20][C@H:19]1[C:23](F)=[O:24])=[O:17])([CH3:14])([CH3:13])[CH3:12]>O.C(Cl)Cl>[C:11]([O:15][C:16]([N:18]1[CH2:22][CH2:21][CH2:20][C@H:19]1[C:23](=[O:24])[NH:7][CH2:8][CH2:9][SH:10])=[O:17])([CH3:14])([CH3:13])[CH3:12]
Reactant: NCCS
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1C(=O)F
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCC[C@H]1C(=O)NCCS
Temperature: 25 °C
Reaction time: 0.42 h

Procedure:
To a 50 mL round-bottom flask charged with a solution of sodium bicarbonate (117.0 mg, 1.39 mmol) in 6.8 mL water was added 2-aminoethanethiol hydrochloride (85.0 mg, 0.75 mmol). To this stirring solution was added dropwise over 60 seconds a solution of 25e (148.0 mg, 0.78 mmol) in 6.8 mL CH2Cl2. The reaction was vigorously stirred for 25 minutes at room temperature, then extracted twice with fresh CH2Cl2. The combined CH2Cl2 extracts were washed once with 5% aqueous HCl, once with 10% aqueous sodium bicarbonate, then once with water. The organic fraction was dried over anhydrous magnesium sulfate, filtered, and concentrated in vacuo to afford 169.2 mg (91% from 24e) of clean 26e as a pale yellow oil.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:17])[C@:4]([CH3:16])([CH2:6][C:7]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[NH:9][CH:8]=1)[NH2:5].C1NC(C(O)=O)CN(CCCP(O)(O)=O)C1.[OH-].[K+]>P([O-])([O-])([O-])=O.[Na+].[Na+].[Na+]>[CH3:1][O:2][C:3](=[O:17])[C@@:4]([CH3:16])([CH2:6][C:7]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[NH:9][CH:8]=1)[NH2:5]
Reactant: COC(=O)[C@@](C)(N)Cc1c[nH]c2ccccc12
Agent: O=C(O)C1CN(CCCP(=O)(O)O)CCN1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Product: COC(=O)[C@](C)(N)Cc1c[nH]c2ccccc12
Temperature: 25 °C
Reaction time: 2 h
Yield: 38826.2 %

Procedure:
To a suspension of (±)-α-methyltryptophan methyl ester (102.8 mg, 0.443 mmol) in 25 mL of 50 mM sodium phosphate buffer pH 6.0 was added carboxypeptidase P from Penicillium janthinellum (3.2 rag of protein). The resulting suspension was stirred at ambient temperature. After 2 h, 50% conversion was observed by HPLC (C18 column, 254 nm detection, acid tR =9.0 min and ester tR =11.9 min). The reaction was adjusted to pH 10 by the addition of 2N KOH and then was extracted with 3×25 mL ethyl acetate. The combined extracts were treated with brine, dried with magnesium sulfate, then concentrated in vacuo to yield (R)-α-methyltryptophan methyl ester (40 mg, 172 mmol, 38.8%): 1H NMR (400 MHz, CDCl3 -THS) δ8.34 (bs, 1H) , 7.61 (d, 7.9 Hz, 1H) , 7.30 (d, 8.54 Hz, 1H) , 7.16 (dd, 7.0, 7.0 Hz, 1H) , 7.10 (dd, 7.6, 7.6 Hz, 1H), 6.98 {s, 1H) , 3.64 (s, 3H), 3.29 (A of AB, JAB=14.6 Hz, 1H), 3.01 (B of AB, JAB=14.6 Hz, 1H) , 1.92 (bs, 2H), 1.45 (s, 3H); 13C NMR (100 MHz, CDCl3) δ177.85, 135.99, 128.08, 123.30, 121.91, 119.44, 119.09, 111. 07, 110.65, 59.14, 52.09, 36.38, 26.61. A portion of this (R)-α-methyl amino ester (1.6 mg, 6.89 mmol) was refluxed in 20 mL 6N HCl for 2 h then concentrated in vacuo to afford (R)-α-methyltryptophan hydrochloride (1.6 mg, 6.28 mmol, 91.1%). The enantiomeric excess of the amino acid was determined by HPLC analysis ((D)-Penicillinamine column from Phenomonex, detection 254 nm, (R)-enantiomer tR =12.4 min and (S)-enantiomer tR =14.6 min) to be >99% (R)-enantiomer.
Reaction SMILES: C([O:8][C:9]1[C:14](OC)=[CH:13][CH:12]=[CH:11][C:10]=1[C:17]1[C:18](=[O:30])[O:19][C:20]2[C:25]([C:26]=1[CH3:27])=[CH:24][CH:23]=[C:22]([O:28]C)[CH:21]=2)C1C=CC=CC=1.Cl.[C:32](O)(=[O:34])C>>[OH:8][C:9]1[CH:14]=[C:13]([O:34][CH3:32])[CH:12]=[CH:11][C:10]=1[C:17]1[C:18](=[O:30])[O:19][C:20]2[C:25]([C:26]=1[CH3:27])=[CH:24][CH:23]=[C:22]([OH:28])[CH:21]=2
Reactant: COc1ccc2c(C)c(-c3cccc(OC)c3OCc3ccccc3)c(=O)oc2c1
Reactant: CC(=O)O
Agent: Cl
Product: COc1ccc(-c2c(C)c3ccc(O)cc3oc2=O)c(O)c1
Temperature: 60 °C
Reaction time: 20 h

Procedure:
A solution of 3-(2-benzyloxy-3-methoxyphenyl)-7-methoxy-4-methyl-chromen-2-one (0.98 g, 2.44 mmol), prepared as in Example 4, in glacial acetic acid (8 mL) was treated with concentrated hydrochloric acid (3.5 mL) and the mixture stirred and heated to 60° C. for about 20 hours. Reaction monitoring by mass spectrum and thin layer chromatography revealed the presence of the starting material, so additional acetic acid (4 mL) and hydrochloric acid (3 mL) were added and stirring and heating continued for another 20 hours. The reaction mixture was then evaporated to dryness in vacuum and the residue diluted with water. The precipitated crystalline pinkish, solid, crude title compound was isolated by filtration, washed with water and dried. The resulting product was triturated with ether, filtered and washed with additional ether to yield the title product as a solid.
Reaction SMILES: [CH2:1]([NH2:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[C:10]1[C:11]2[CH:24]=[C:23]([C:25]([F:28])([F:27])[F:26])[S:22][C:12]=2[N:13]=[C:14]([C:16]2[CH:21]=[CH:20][N:19]=[CH:18][CH:17]=2)[N:15]=1>>[N:19]1[CH:20]=[CH:21][C:16]([C:14]2[N:15]=[C:10]([NH:8][CH2:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)[C:11]3[CH:24]=[C:23]([C:25]([F:27])([F:26])[F:28])[S:22][C:12]=3[N:13]=2)=[CH:17][CH:18]=1
Reactant: FC(F)(F)c1cc2c(Cl)nc(-c3ccncc3)nc2s1
Reactant: NCc1ccccc1
Product: FC(F)(F)c1cc2c(NCc3ccccc3)nc(-c3ccncc3)nc2s1

Procedure:
With the procedure of Example 1, the reaction of benzylamine with 4-chloro-2-(pyridin-4-yl)-6-trifluoromethyl-thieno-[2,3-d]-pyrimidine yields 2-(pyridin-4-yl)-4-benzylamino-6-trifluoromethyl-thieno-[2,3-d]-pyrimidine.
Reaction SMILES: [NH2:1][CH2:2][C@@H:3]1[C@H:8]([CH3:9])[CH2:7][CH2:6][CH2:5][N:4]1[C:10]([C:12]1[CH:17]=[C:16]([Cl:18])[CH:15]=[CH:14][C:13]=1[C:19]1[N:24]=[CH:23][CH:22]=[CH:21][N:20]=1)=[O:11].Br[C:26]1[CH:31]=[CH:30][C:29]([Cl:32])=[CH:28][N:27]=1>>[Cl:18][C:16]1[CH:15]=[CH:14][C:13]([C:19]2[N:20]=[CH:21][CH:22]=[CH:23][N:24]=2)=[C:12]([C:10]([N:4]2[CH2:5][CH2:6][CH2:7][C@@H:8]([CH3:9])[C@H:3]2[CH2:2][NH:1][C:26]2[CH:31]=[CH:30][C:29]([Cl:32])=[CH:28][N:27]=2)=[O:11])[CH:17]=1
Reactant: C[C@@H]1CCCN(C(=O)c2cc(Cl)ccc2-c2ncccn2)[C@@H]1CN
Reactant: Clc1ccc(Br)nc1
Product: C[C@@H]1CCCN(C(=O)c2cc(Cl)ccc2-c2ncccn2)[C@@H]1CNc1ccc(Cl)cn1

Procedure:
The title compound was prepared following the same general protocol as described for Example A44 using ((2S,3R)-2-(aminomethyl)-3-methylpiperidin-1-yl)(5-chloro-2-(pyrimidin-2-yl)phenyl)methanone and 2-bromo-5-chloropyridine. MS (ESI) 456 (M+H).
Reaction SMILES: [C:1]1([PH:7][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:14][O:15][C:16]1[CH:25]=[C:24]2[C:19]([CH:20]=[CH:21][C:22](OS(C(F)(F)F)(=O)=O)=[C:23]2[C:26]2[C:35]3[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=3)[C:29]([NH:36][C@@H:37]([C:39]3[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=3)[CH3:38])=[N:28][N:27]=2)=[CH:18][CH:17]=1.N12CCN(CC1)CC2>CN(C)C=O>[C:8]1([P:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[C:22]2[CH:21]=[CH:20][C:19]3[C:24](=[CH:25][C:16]([O:15][CH3:14])=[CH:17][CH:18]=3)[C:23]=2[C:26]2[C:35]3[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=3)[C:29]([NH:36][C@@H:37]([C:39]3[CH:40]=[CH:41][CH:42]=[CH:43][CH:44]=3)[CH3:38])=[N:28][N:27]=2)[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: COc1ccc2ccc(OS(=O)(=O)C(F)(F)F)c(-c3nnc(N[C@H](C)c4ccccc4)c4ccccc34)c2c1
Reactant: c1ccc(Pc2ccccc2)cc1
Agent: C1CN2CCN1CC2
Solvent: CN(C)C=O
Product: COc1ccc2ccc(P(c3ccccc3)c3ccccc3)c(-c3nnc(N[C@H](C)c4ccccc4)c4ccccc34)c2c1
Temperature: 120 °C
Reaction time: 0.5 h
Yield: 59.5 %

Procedure:
A solution of NiCl2(dppe) (0.22 g, 0.42 mmol) in N,N-dimethylformamide (10 ml) was treated with diphenylphosphine (1.5 ml, 8.4 mmol) at 23° C. The resulting dark red solution was stirred at 120° C. for 30 min. Then a solution of trifluoromethanesulfonic acid 7-methoxy-1-[4-((R)-1-phenyl-ethylamino)-phthalazin-1-yl]-naphthalen-2-yl ester (2.3 g, 4.2 mmol) and 1,4-diazabicyclo[2.2.2]octane (DABCO, 1.9 g, 17 mmol) in N,N-dimethylformamide (13 ml) was added via a syringe, the flask was washed with N,N-dimethylformamide (2 ml). The resulting green solution was stirred at 120° C. for 17 hrs. The mixture was concentrated under reduced pressure (20 mbar, 70° C. bath temperature). The residue was purified by flash chromatography on silica gel (toluene→toluene/EtOAc 5:1) to give 1.5 g (2.5 mmol) of the title compound as an off-white solid as a 1.7:1 (1st diastereomer: 2nd diastereomer) mixture of diastereomers.
Reaction SMILES: [CH2:1]([C:5]1[CH:10]=[CH:9][C:8]([C@@H:11]([O:15][C:16]2[CH:40]=[CH:39][C:19]([C:20]([C:22]3[CH:23]=[C:24]([CH2:31][CH2:32][CH2:33][C:34]([O:36]CC)=[O:35])[N:25]4[C:30]=3[CH:29]=[CH:28][CH:27]=[CH:26]4)=[O:21])=[CH:18][CH:17]=2)[CH2:12][CH2:13][CH3:14])=[CH:7][CH:6]=1)[CH:2]([CH3:4])[CH3:3].[OH-].[Na+].C(OCC)(=O)C.Cl>C(O)C.O1CCOCC1>[CH2:1]([C:5]1[CH:6]=[CH:7][C:8]([C@@H:11]([O:15][C:16]2[CH:17]=[CH:18][C:19]([C:20]([C:22]3[CH:23]=[C:24]([CH2:31][CH2:32][CH2:33][C:34]([OH:36])=[O:35])[N:25]4[C:30]=3[CH:29]=[CH:28][CH:27]=[CH:26]4)=[O:21])=[CH:39][CH:40]=2)[CH2:12][CH2:13][CH3:14])=[CH:9][CH:10]=1)[CH:2]([CH3:4])[CH3:3]
Reactant: CCC[C@H](Oc1ccc(C(=O)c2cc(CCCC(=O)OCC)n3ccccc23)cc1)c1ccc(CC(C)C)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: CCO
Solvent: C1COCCO1
Product: CCC[C@H](Oc1ccc(C(=O)c2cc(CCCC(=O)O)n3ccccc23)cc1)c1ccc(CC(C)C)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 86.8 %

Procedure:
To a solution of ethyl 4-[1-[4-[(S)-1-(4-isobutylphenyl)butoxy]benzoyl]indolizin-3-yl]butyrate (282 mg) in ethanol (3 ml) and 1,4-dioxane (3 ml) was added 1N aqueous solution of sodium hydroxide (2 ml). The mixture was stirred at room temperature for 2 hours, and then poured into a mixture of ethyl acetate and 0.5N hydrochloric acid. The organic layer was separated, washed with water and brine, dried over magnesium sulfate and evaporated to give 4-[1-[4-[(S)-1-(4-isobutylphenyl)butoxy]benzoyl]- indolizin-3-yl]butyric acid (232 mg) as powder.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][NH:5][C:4](=[O:8])[C:3]=1[N+:9]([O-:11])=[O:10].[C:12]([O:16][C:17](=[O:24])[NH:18][C@@H:19]([CH2:22][SH:23])[CH2:20][OH:21])([CH3:15])([CH3:14])[CH3:13]>CCO>[C:12]([O:16][C:17](=[O:24])[NH:18][C@@H:19]([CH2:22][S:23][C:2]1[CH:7]=[CH:6][NH:5][C:4](=[O:8])[C:3]=1[N+:9]([O-:11])=[O:10])[CH2:20][OH:21])([CH3:15])([CH3:13])[CH3:14]
Reactant: O=c1[nH]ccc(Cl)c1[N+](=O)[O-]
Reactant: CC(C)(C)OC(=O)N[C@H](CO)CS
Solvent: CCO
Product: CC(C)(C)OC(=O)N[C@H](CO)CSc1cc[nH]c(=O)c1[N+](=O)[O-]
Yield: 69.2 %

Procedure:
A solution of 4-chloro-3-nitropyridin-2(1H)-one (1.61 g, 9.2 mmol) (or any other suitable activated aromatic compound) and TEA (2 ml, 14.4 mmol) in etanol (15 mL) stirred at 0° C., was treated with a solution of tert-butyl[(2R)-1-hydroxy-3-sulfanylpropan-2-yl]carbamate (42, 2.073 g, 10 mmol) in ethanol (10 mL+5 ml rinse) added from syringe. The final mixture was stirred at room temperature for 22 h (became a thick yellow suspension). Filtered, the cake washed with pentane and dried under vacuum, to afford the title compound (2.20 g, 69% yield) as a yellow solid, MS: m/z=368.1 (MNa+).
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:20]3[CH:21]=[N:22][NH:23][CH:24]=3)=[CH:7][N:8]2[S:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)(=[O:13])=[O:12])=[CH:4][CH:3]=1.[CH:25]([S:27]([CH3:30])(=[O:29])=[O:28])=[CH2:26].CCN(CC)CC>CO>[F:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:20]3[CH:24]=[N:23][N:22]([CH2:26][CH2:25][S:27]([CH3:30])(=[O:29])=[O:28])[CH:21]=3)=[CH:7][N:8]2[S:11]([C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)(=[O:12])=[O:13])=[CH:4][CH:3]=1
Reactant: O=S(=O)(c1ccccc1)n1cc(-c2cn[nH]c2)c2ccc(F)cc21
Reactant: C=CS(C)(=O)=O
Solvent: CO
Solvent: CCN(CC)CC
Product: CS(=O)(=O)CCn1cc(-c2cn(S(=O)(=O)c3ccccc3)c3cc(F)ccc23)cn1
Temperature: 130 °C
Yield: 57.7 %

Procedure:
A mixture of 6-fluoro-1-(phenylsulfonyl)-3-(1H-pyrazol-4-yl)-1H-indole (Intermediate 5; 210 mg; 0.62 mmol), methyl vinyl sulfone (654 mg; 6.16 mmol) and Et3N (0.26 mL; 1.85 mmol) in methanol (15 mL) was heated at 130° C. for 0.5 h in a microwave reactor. The reaction mixture was cooled to r.t., concentrated to give a residue which was triturated with MeOH (2 mL) to afford 160 mg (58%) of the title product as a white solid.
Reaction SMILES: Cl.[NH2:2][C@H:3]1[CH2:7][CH2:6][C@H:5]([NH:8][C:9]([C:11]2[C:15]3[N:16]=[CH:17][N:18]=[C:19]([C:20]4[CH:25]=[C:24]([CH:26]([F:28])[F:27])[CH:23]=[CH:22][C:21]=4[O:29][CH2:30][CH:31]4[CH2:33][CH2:32]4)[C:14]=3[NH:13][C:12]=2[CH3:34])=[O:10])[CH2:4]1.[C:35](Cl)(=[O:38])[CH2:36][CH3:37]>>[CH:31]1([CH2:30][O:29][C:21]2[CH:22]=[CH:23][C:24]([CH:26]([F:28])[F:27])=[CH:25][C:20]=2[C:19]2[C:14]3[NH:13][C:12]([CH3:34])=[C:11]([C:9]([NH:8][C@H:5]4[CH2:6][CH2:7][C@H:3]([NH:2][C:35](=[O:38])[CH2:36][CH3:37])[CH2:4]4)=[O:10])[C:15]=3[N:16]=[CH:17][N:18]=2)[CH2:33][CH2:32]1
Reactant: Cc1[nH]c2c(-c3cc(C(F)F)ccc3OCC3CC3)ncnc2c1C(=O)N[C@H]1CC[C@H](N)C1
Reactant: CCC(=O)Cl
Agent: Cl
Product: CCC(=O)N[C@H]1CC[C@H](NC(=O)c2c(C)[nH]c3c(-c4cc(C(F)F)ccc4OCC4CC4)ncnc23)C1

Procedure:
Starting from N-[(1S,3S)-3-aminocyclopentyl]-4-[2-(cyclopropylmethoxy)-5-(difluoromethyl)phenyl]-6-methyl-5H-pyrrolo[3,2-d]pyrimidine-7-carboxamide hydrochloride (example D.f64) and commercially available propionyl chloride the title compound is obtained as colorless solid.
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9]([F:12])([F:11])[F:10])=[CH:4][CH:3]=1.C([Mg]Cl)(C)C.[Cl-].[Li+].[F:20][C:21]1[C:22](/[CH:27]=[N:28]/[S@:29]([C:31]([CH3:34])([CH3:33])[CH3:32])=[O:30])=[N:23][CH:24]=[CH:25][CH:26]=1>C1COCC1>[F:20][C:21]1[C:22]([C@H:27]([C:2]2[CH:7]=[CH:6][C:5]([O:8][C:9]([F:12])([F:11])[F:10])=[CH:4][CH:3]=2)[NH:28][S@:29]([C:31]([CH3:34])([CH3:33])[CH3:32])=[O:30])=[N:23][CH:24]=[CH:25][CH:26]=1
Reactant: CC(C)(C)[S@](=O)/N=C/c1ncccc1F
Reactant: FC(F)(F)Oc1ccc(I)cc1
Agent: CC(C)[Mg]Cl
Agent: [Cl-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CC(C)(C)[S@](=O)N[C@@H](c1ccc(OC(F)(F)F)cc1)c1ncccc1F
Reaction time: 0.17 h

Procedure:
1-Iodo-4-(trifluoromethoxy)benzene (1.00 g, 3.47 mmol) was dissolved in dry THF (10 mL) and cooled in an ice bath. Isopropylmagnesium chloride, lithium chloride complex (14% solution in THF, Aldrich, 3.07 mL, 2.82 mmol) was added, and the mixture was stirred for 10 min. A solution of (S,E)-N-((3-fluoropyridin-2-yl)methylene)-2-methylpropane-2-sulfinamide (0.643 g, 2.82 mmol) in dry THF (10 mL) was added and the reaction was stirred. After 50 minutes, the reaction was quenched by addition of saturated aqueous NH4Cl (10 mL). H2O (100 mL) and EtOAc (150 mL) were added, and the phases were mixed and separated. The organic layer was dried with MgSO4 and evaporated to dryness under reduced pressure. Purification using silica chromatography (hexane to EtOAc gradient) gave the desired (S)—N—((S)-(3-fluoropyridin-2-yl)(4-(trifluoro-methoxy)phenyl)methyl)-2-methylpropane-2-sulfinamide.