Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:3]1[CH:7]=[C:6]([NH:8][C:9]2[N:10]=[CH:11][C:12]3[N:17]=[N:16][N:15]([C:18]4[CH:23]=[CH:22][C:21]([C:24](O)([CH3:26])[CH3:25])=[CH:20][CH:19]=4)[C:13]=3[N:14]=2)[CH:5]=[N:4]1)[CH3:2].C(N(S(F)(F)[F:34])CC)C>ClCCl>[CH2:1]([N:3]1[CH:7]=[C:6]([NH:8][C:9]2[N:10]=[CH:11][C:12]3[N:17]=[N:16][N:15]([C:18]4[CH:23]=[CH:22][C:21]([C:24]([F:34])([CH3:26])[CH3:25])=[CH:20][CH:19]=4)[C:13]=3[N:14]=2)[CH:5]=[N:4]1)[CH3:2]
Reactant: CCN(CC)S(F)(F)F
Reactant: CCn1cc(Nc2ncc3nnn(-c4ccc(C(C)(C)O)cc4)c3n2)cn1
Solvent: ClCCl
Product: CCn1cc(Nc2ncc3nnn(-c4ccc(C(C)(C)F)cc4)c3n2)cn1
Temperature: -78 °C
Reaction time: 1 h

Procedure:
A suspension of 2-{4-[5-(1-ethyl-1H-pyrazol-4-ylamino)-[1,2,3]triazolo[4,5-d]pyrimidin-3-yl]-phenyl}-propan-2-ol (138 mg, 0.38 mmol) in dichloromethane (3 ml) is cooled to −78° C. Diethylaminosulfurtrifluoride (201 μl, 1.52 mmol) is added. The reaction mixture is allowed to reach room temperature over 1 hour. The reaction mixture is evaporated and the residue is treated with water and saturated sodium hydrogen carbonate solution. The solids are filtered off and chromatographed on a silica gel column with dichloromethane/methanol as eluent to afford (1-ethyl-1H-pyrazol-4-yl)-{3-[4-(1-fluoro-1-methyl-ethyl)-phenyl]-3H-[1,2,3]triazolo[4,5-d]pyrimidin-5-yl}-amine (“A128”) as yellow powder; HPLC/MS1.93 min (A), [M+H] 367;
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH:5]=O.ClC1C=CC(C[CH:16]2[C:21](=[O:22])[O:20][C:19]([CH3:24])([CH3:23])[O:18][C:17]2=[O:25])=CC=1.BrC1C=C2C(=CC=1)N=C(Cl)C(CC1C=CC(Cl)=CC=1)=C2Cl>>[Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH2:5][CH:16]1[C:21](=[O:22])[O:20][C:19]([CH3:24])([CH3:23])[O:18][C:17]1=[O:25]
Reactant: O=Cc1cccc(Cl)c1
Reactant: CC1(C)OC(=O)C(Cc2ccc(Cl)cc2)C(=O)O1
Agent: Clc1ccc(Cc2c(Cl)nc3ccc(Br)cc3c2Cl)cc1
Product: CC1(C)OC(=O)C(Cc2cccc(Cl)c2)C(=O)O1

Procedure:
The title compound was prepared using 3-chlorobenzaldehyde in place of 4-chlorobenzaldehyde using the procedure described for the preparation of 5-(4-chlorobenzyl)-2,2-dimethyl-1,3-dioxane-4,6-dione (Intermediate 3: step a).
Reaction SMILES: [CH3:1][Si:2]([CH3:16])([CH3:15])[CH:3]([CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[N+:12]([O-])=O)[CH3:4].C[Si](C)(C)C(CC1C=CC([N+]([O-])=O)=CC=1)C.[H][H]>[Pd]>[CH3:16][Si:2]([CH3:1])([CH3:15])[CH:3]([CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[NH2:12])[CH3:4]
Reactant: CC(Cc1ccccc1[N+](=O)[O-])[Si](C)(C)C
Reactant: [H][H]
Agent: [Pd]
Agent: CC(Cc1ccc([N+](=O)[O-])cc1)[Si](C)(C)C
Product: CC(Cc1ccccc1N)[Si](C)(C)C

Procedure:
2-Trimethylsilyl-3-phenylpropene (2.5 g), prepared according to J. Org. Chem. 43, 147 (1978), was dissolved in THF and was then hydrogenated over Pd on charcoal under atmospheric pressure and at room temperature until the uptake of hydrogen ceased. Removal of the catalyst and the solvent yielded an oil (2.36 g) which was chromatographed on silica gel (eluent: hexane:ethylacetate 39:1) to give 2-trimethylsilyl-3-phenylpropane (2.3 g; 92.5% pure by NMR). This compound was dissolved in acetanhydride (4 ml), cooled to −35° C. and at this temperature a pre-cooled mixture of concentrated nitric acid (0.48 ml) and acetanhydride (2.4 ml) was added slowly. After warming to ambient temperature the reaction mixture was stirred for 3 hours and then poured into ice-cold diluted ammonia. After extraction with ethyl acetate and drying over sodium sulfate the solvent was removed and the residue was chromatographed on silica gel (eluent:hexane: THF:ethylacetate 39:4:1) added) to yield a yellow oil (1.4 g) which consisted of an approximate 1:1 mixture of 2-trimethylsilyl-3-(2′-nitrophenyl)-propane and 2-trimethylsilyl-3-(4′-nitrophenyl)-propane. This mixture was hydrogenated over Pd on charcoal under atmospheric pressure and at room temperature until the uptake of hydrogen ceased. Removal of the catalyst and the solvent and chromatography on silica gel (eluent: hexane:ethyl acetate, 4:1) yielded 2-trimethylsilyl-3-(2′-aminophenyl)-propane (0.75 g; pure according to NMR). 0.15 g of this compound was dissolved in dry THF, cooled with ice and 2-chloronicotinoylchloride (0.13 g) was added, followed by pyridine (0.01 ml). The reaction mixture was stirred at room temperature over night, poured on to water and extracted twice with ethylacetate. The organic phase was washed with water, dried with sodium sulfate and the solvent was removed. Recrystallisation of the resulting crystals from hexane yielded Compound Number 9.35 (0.16 g).
Reaction SMILES: CC(C)(S([NH:6][CH:7]([C:16]1[C:21]([F:22])=[CH:20][CH:19]=[CH:18][C:17]=1[O:23][CH2:24][CH3:25])[CH2:8][CH:9]([CH3:15])[C:10]([O:12][CH2:13][CH3:14])=[O:11])=O)C.Cl.O1CCOCC1>CCO>[NH2:6][CH:7]([C:16]1[C:21]([F:22])=[CH:20][CH:19]=[CH:18][C:17]=1[O:23][CH2:24][CH3:25])[CH2:8][CH:9]([CH3:15])[C:10]([O:12][CH2:13][CH3:14])=[O:11]
Reactant: CCOC(=O)C(C)CC(NS(=O)C(C)(C)C)c1c(F)cccc1OCC
Agent: Cl
Solvent: C1COCCO1
Solvent: CCO
Product: CCOC(=O)C(C)CC(N)c1c(F)cccc1OCC
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
A cooled (0° C.) solution of ethyl 4-(1,1-dimethylethylsulfinamido)-4-(2-ethoxy-6-fluorophenyl)-2-methylbutanoate (1.550 g; 4.00 mmol) in EtOH (20 ml) was treated dropwise with a solution of 4 M HCl in 1,4-dioxane (2.0 ml; 8.00 mmol). The resulting mixture was further stirred at 0° C., under nitrogen, for 10 min., and then at rt for 30 min. The reaction mixture was then concentrated to dryness under reduced pressure and the oily residue was further dried under HV to give the chlorhydrate salt of ethyl 4-amino-4-(2-ethoxy-6-fluorophenyl)-2-methylbutanoate. LC-MS (conditions A): tR=0.55 min. and [M+H]+: 284.07 g/mol; tR=0.57 min. and [M+H]+: 284.07 g/mol (mixture of diastereoisomers).
Reaction SMILES: [NH2:1][S:2][O:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([N:11]2[C:19]3[C:18]4[CH:20]=[C:21]([N+:24]([O-:26])=[O:25])[CH:22]=[CH:23][C:17]=4[CH2:16][CH2:15][C:14]=3[C:13]([C:27]([O:29]CC)=O)=[N:12]2)=[CH:7][CH:6]=1.[OH-].[NH4+:33]>CO>[NH2:1][S:2][O:3][O:4][C:5]1[CH:6]=[CH:7][C:8]([N:11]2[C:19]3[C:18]4[CH:20]=[C:21]([N+:24]([O-:26])=[O:25])[CH:22]=[CH:23][C:17]=4[CH2:16][CH2:15][C:14]=3[C:13]([C:27]([NH2:33])=[O:29])=[N:12]2)=[CH:9][CH:10]=1
Reactant: CCOC(=O)c1nn(-c2ccc(OOSN)cc2)c2c1CCc1ccc([N+](=O)[O-])cc1-2
Reactant: [NH4+]
Agent: [OH-]
Solvent: CO
Product: NSOOc1ccc(-n2nc(C(N)=O)c3c2-c2cc([N+](=O)[O-])ccc2CC3)cc1
Yield: 68 %

Procedure:
The material of Step 2 (718 mg, 0.0016 mol), conc. ammonium hydroxide (30 mL), and methanol (15 mL) were stirred in a stoppered flask for 72 hours. Contents were filtered to give a light amber solid (606 mg). The solid was recrystallized from acetonitrile to give the product as a light amber solid, 450 mg (68% yield). FABHRMS m/z 414.0902 (M+H, C18H16N5O5S requires 414.0872). 1H NMR (DMSO-d6/300 MHz) 8.15–7.95 (m, 3H); 7.83 (d, 2H); 7.80–7.40 (m, 6H); 3.20–2.95 (m, 4H).
Reaction SMILES: [Cl:1][C:2]1[C:11]([O:12][CH:13]2[CH2:22][CH2:21][C:16]3(OCC[O:17]3)[CH2:15][CH2:14]2)=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][N:6]=[CH:7]2.C(O)(C(F)(F)F)=O>C1COCC1.O.ClCCl.O.C([O-])(O)=O.[Na+]>[Cl:1][C:2]1[C:11]([O:12][CH:13]2[CH2:14][CH2:15][C:16](=[O:17])[CH2:21][CH2:22]2)=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][N:6]=[CH:7]2
Reactant: Clc1c(OC2CCC3(CC2)OCCO3)ccc2cnccc12
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Solvent: O=C(O)C(F)(F)F
Product: O=C1CCC(Oc2ccc3cnccc3c2Cl)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
549 mg (1.72 mmol) 5-Chloro-6-(1,4-dioxa-spiro[4.5]dec-8-yloxy)-isoquinoline (78) were dissolved in 20 ml THF/H2O (3:1). 1 ml TFA was added and the mixture was stirred at room temperature. After 1 h, 2 ml TFA were added and the temperature was increased to 50° C. After 5 d at 50° C., 2 ml TFA were added. After one additional day, 2 ml TFA were added and the temperature was increased to 100° C. After 5 h, the reaction was allowed to cool down to room temperature and the mixture was diluted with dichloromethane and H2O, Solid NaHCO3 was added for neutralization. The phases were separated and the aqueous phase was extracted with dichloromethane. The combined organic layers were dried over MgSO4 and evaporated. After final purification by preparative HPLC, 533 mg of the title compound as trifluoroacetate were obtained. Rt=0.88 min (Method #4). Detected mass: 276.2/278.2 (M+H+).
Reaction SMILES: C([N:14]1[C:22]2[C:17](=[CH:18][C:19]([C:23]([C:29]([Cl:32])([F:31])[F:30])([C:25]([Cl:28])([F:27])[F:26])[OH:24])=[CH:20][CH:21]=2)[CH2:16][CH2:15]1)(C1C=CC=CC=1)C1C=CC=CC=1>Cl.[Pd]>[ClH:28].[Cl:32][C:29]([F:30])([F:31])[C:23]([C:25]([Cl:28])([F:26])[F:27])([C:19]1[CH:18]=[C:17]2[C:22](=[CH:21][CH:20]=1)[NH:14][CH2:15][CH2:16]2)[OH:24]
Reactant: OC(c1ccc2c(c1)CCN2C(c1ccccc1)c1ccccc1)(C(F)(F)Cl)C(F)(F)Cl
Agent: [Pd]
Agent: Cl
Product: OC(c1ccc2c(c1)CCN2)(C(F)(F)Cl)C(F)(F)Cl

Procedure:
The crude 1-benzhydryl-α,α-bis(chlorodifluoromethyl)-2,3-dihydro-1H-indole-5-methanol is dissolved in a mixture of 200 ml of alcohol and 20 ml of concentrated hydrochloric acid and is hydrogenated at an initial pressure of three atmospheres in the presence of 1.5 g of 10% palladium on charcoal in a Parr shaker apparatus until no further change of pressure is observed. The catalyst is filtered off, and the filtrate is evaporated. The residue is evaporated repeatedly with toluene to remove traces of water. Trituration of the residue with toluene gives crystals, which are filtered off to give 6.2 g of α,α-bis(chlorodifluoromethyl)-2,3-dihydro-1H-indole-5-methanol hydrochloride, m.p. 224°-228° (dec.). For analysis a portion is recrystallized from nitromethane to give crystals, m.p. 228°-229° (dec.). The structure is confirmed by nmr spectroscopy and elemental analysis:
Reaction SMILES: [NH2:1][CH2:2][C:3]([N:5]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[CH2:6][C:7]([N:9]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[CH2:10][C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])=[O:8])=[O:4].[CH3:30][C:31]1[CH:32]=[C:33]([N:37]=[C:38]=[O:39])[CH:34]=[CH:35][CH:36]=1>>[CH3:30][C:31]1[CH:32]=[C:33]([NH:37][C:38](=[O:39])[NH:1][CH2:2][C:3]([N:5]([CH2:6][C:7]([N:9]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH2:10][C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])=[O:8])[C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[O:4])[CH:34]=[CH:35][CH:36]=1
Reactant: CC(C)(C)OC(=O)CN(C(=O)CN(C(=O)CN)c1ccccc1)c1ccccc1
Reactant: Cc1cccc(N=C=O)c1
Product: Cc1cccc(NC(=O)NCC(=O)N(CC(=O)N(CC(=O)OC(C)(C)C)c2ccccc2)c2ccccc2)c1
Yield: 22.3 %

Procedure:
The procedure is analogous to that described in Example 1, but 1.4 g of tert-butyl N-{2-[(2-aminoacetyl)phenylamino]acetyl}-N-phenylglycinate and 0.45 g of 3-methylphenyl isocyanate are used as the starting material. The product obtained is purified by chromatography on 80 g of silica (0.04-0.063 mm) contained in a column 3 cm in diameter [eluent: methylene chloride/methanol (98-2 by volume)] using an excess pressure of 30 kPa of nitrogen and collecting 35 cm3 fractions. Fractions 19 to 21 are combined and concentrated to dryness under reduced pressure (2.7 kPa) at 40° C. After churning the residue obtained with 25 cm3 of heptane, 0.4 g of tert-butyl N-{2-{2-[3-(3-methylphenyl)ureido]-N-phenylacetamido}acetyl}-N-phenylglycinate melting at 76°-80° C. is obtained.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([CH2:7][CH2:8][NH2:9])=[CH:3][CH:2]=1.[Cl:10][C:11]1[CH:16]=[CH:15][N:14]=[C:13]2[CH:17]=[C:18]([C:20]([O-])=[O:21])[S:19][C:12]=12.[Li+]>>[N:1]1[CH:6]=[CH:5][C:4]([CH2:7][CH2:8][NH:9][C:20]([C:18]2[S:19][C:12]3[C:13](=[N:14][CH:15]=[CH:16][C:11]=3[Cl:10])[CH:17]=2)=[O:21])=[CH:3][CH:2]=1
Reactant: NCCc1ccncc1
Reactant: O=C([O-])c1cc2nccc(Cl)c2s1
Agent: [Li+]
Product: O=C(NCCc1ccncc1)c1cc2nccc(Cl)c2s1

Procedure:
The title compound was prepared from 2-pyridin-4-yl-ethyl amine and lithium 7-chloro-thieno[3,2-b]pyridine-2-carboxylate by a procedure analogous to Example 1B. MS: 318/320 (MH+); HPLC Rf: 4.08 min.; HPLC purity 99%.
Reaction SMILES: [ClH:1].Cl.[C:3]1([CH:9]([CH2:12][NH2:13])[CH2:10][NH2:11])[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[OH-].[Na+].Cl.[C:17](N)(=N)[CH3:18].N>>[ClH:1].[CH3:17][C:18]1[NH:13][CH2:12][CH:9]([C:3]2[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=2)[CH2:10][N:11]=1
Reactant: NCC(CN)c1ccccc1
Reactant: CC(=N)N
Agent: Cl
Agent: N
Agent: [Na+]
Product: CC1=NCC(c2ccccc2)CN1
Yield: 32 %

Procedure:
A mixture consisting of 20 g (0.0897 mol) of 2-phenylpropane-1,3-diamine dihydrochloride, 10.76 g (0.269 mol) of sodium hydroxide pellets and 8.48 g (0.0897 mol) of acetamidine hydrochloride is heated under reflux until the evolution of NH3 has ended. The reaction medium is cooled, the insoluble material is filtered off and discarded, the filtrate is acidified with ethanol containing HCl and evaporated to half the volume, and the insoluble material formed is filtered off. The filtrate is diluted with an equal volume of ether, the insoluble material formed is filtered off and the resulting filtrate is evaporated to dryness. Recrystallization of the evaporation residue from an acetone/ethanol mixture (1:1 v/v) gives 6 g (yield: 32%) of CRL 41 352. M.p. (inst.)=220° C.
Reaction SMILES: FC(F)(F)S([O-])(=O)=O.[Mg+2].FC(F)(F)S([O-])(=O)=O.[O:18]1[CH2:20][C@H:19]1[C:21]([O:23][CH3:24])=[O:22].[Si:25]([O:42][CH2:43][CH2:44][OH:45])([C:38]([CH3:41])([CH3:40])[CH3:39])([C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>>[Si:25]([O:42][CH2:43][CH2:44][O:45][CH2:20][C@H:19]([OH:18])[C:21]([O:23][CH3:24])=[O:22])([C:38]([CH3:40])([CH3:41])[CH3:39])([C:32]1[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=1)[C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1
Reactant: CC(C)(C)[Si](OCCO)(c1ccccc1)c1ccccc1
Reactant: COC(=O)[C@@H]1CO1
Agent: O=S(=O)([O-])C(F)(F)F
Agent: [Mg+2]
Product: COC(=O)[C@@H](O)COCCO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C
Temperature: 10 °C
Reaction time: 0.17 h
Yield: 43.1 %

Procedure:
Magnesium trifluoromethanesulfonate (3.95 g, 12.24 mmol) was added in one portion to (S)-methyl oxirane-2-carboxylate (5 g, 48.98 mmol) and 2-(tert-butyldiphenylsilyloxy)ethanol (14.72 g, 48.98 mmol) at 10° C. The resulting suspension was stirred at 10° C. for 10 minutes and then warmed to 45° C. and stirred for 3 days. The crude product was purified by flash silica chromatography, eluting with 0 to 30% ethyl acetate in isohexane to afford the product (8.50 g, 43.1%). 1H NMR (400 MHz, CDCl3) δ 1.05 (9H, s), 3.10 (1H, d), 3.62 (2H, t), 3.74-3.87 (7H, m), 4.26-4.34 (1H, m), 7.35-7.46 (6H, m), 7.63-7.71 (4H, m); m/z (ESI+) (M+Na)+=425.37; HPLC tR=3.15 min.
Reaction SMILES: ON1C2C=CC=CC=2N=N1.[Cl:11][C:12]1[S:41][C:15]2[NH:16][C:17]([C:19]([NH:21][CH:22]3[CH2:31][C:30]4[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=4)[N:24]([CH2:32][C@H:33]4COC(C)(C)O4)[C:23]3=[O:40])=[O:20])=[CH:18][C:14]=2[CH:13]=1.ClC1S[C:46]2[NH:47][C:48](C(NC3CC4C(=CC=CC=4)N(CC(O)CO)C3=O)=O)=CC=2C=1.CCN=C=NCCCN(C)C>CN(C=O)C.CCOC(C)=O.C([O-])(O)=O.[Na+]>[Cl:11][C:12]1[S:41][C:15]2[NH:16][C:17]([C:19]([NH:21][CH:22]3[CH2:31][C:30]4[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=4)[N:24]([CH2:32][CH2:33][N:47]([CH3:48])[CH3:46])[C:23]3=[O:40])=[O:20])=[CH:18][C:14]=2[CH:13]=1
Reactant: O=C(NC1Cc2ccccc2N(CC(O)CO)C1=O)c1cc2cc(Cl)sc2[nH]1
Reactant: CC1(C)OC[C@H](CN2C(=O)C(NC(=O)c3cc4cc(Cl)sc4[nH]3)Cc3ccccc32)O1
Agent: CCN=C=NCCCN(C)C
Agent: O=C([O-])O
Agent: On1nnc2ccccc21
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CN(C)CCN1C(=O)C(NC(=O)c2cc3cc(Cl)sc3[nH]2)Cc2ccccc21
Yield: 40 %

Procedure:
1-Hydroxybenzotriazole (0.69 g, 0.51 mmol) was added to a solution of 3-amino-1-[2-(dimethylamino)ethyl]-3,4-dihydroquinolin-2(1H)-one (Method 10, 100 mg, 0.427 mmol) in DMF (3 mL) followed by 2-chloro-6H-thieno[2,3-b]pyrrole-5-carboxylic acid (Method 9, 86 mg, 0.42 mmol) and EDCI (0.98 g, 0.51 mmol). The reaction was diluted with EtOAc (40 mL) and sat. aqueous NaHCO3 (20 mL) and the separated organic layer was dried (MgSO4), filtered and evaporated to dryness. Purification by column chromatography (MeOH:DCM 1:9) afforded the title compound (70 mg, 56%) as a yellow solid.
Reaction SMILES: CO[C:3]1[CH:8]=[CH:7][C:6]([Cl:9])=[CH:5][C:4]=1[C:10]1([CH2:17][C:18]([O:20]CC)=[O:19])[C:14](=[O:15])[NH:13][C:12](=[O:16])[NH:11]1.I>O>[Cl:9][C:6]1[CH:5]=[C:4]2[C:10]3([C:14](=[O:15])[NH:13][C:12](=[O:16])[NH:11]3)[CH2:17][C:18](=[O:19])[O:20][C:3]2=[CH:8][CH:7]=1
Reactant: CCOC(=O)CC1(c2cc(Cl)ccc2OC)NC(=O)NC1=O
Agent: I
Solvent: O
Product: O=C1NC(=O)C2(CC(=O)Oc3ccc(Cl)cc32)N1

Procedure:
A solution of 4.0 g. (0.0122 mole) of 4-(2'-methoxy-5'-chlorophenyl)-4-(carboethoxymethyl)imidazolidine 2,5-dione in 40 ml. of 58% hydriodic acid was heated to 115° C. for 4 hours. The reaction mixture was cooled, poured into water and extracted with ethyl acetate. The combined extracts were washed with a sodium bisulfite solution, water and brine, dried over magnesium sulfate and concentrated in vacuo to dryness. The residue was chromatographed using ethyl acetatehexane as the eluent (1:1; V:V) to give 106 mg. of product as the less polar material, m.p. 289°-290° C. (dec.).
Reaction SMILES: [CH2:1]([O:3][C:4]1[C:9]([CH:10]=[O:11])=[C:8]([C:12]([F:15])([F:14])[F:13])[N:7]=[CH:6][N:5]=1)[CH3:2].[BH4-].[Na+].O>CO>[CH2:1]([O:3][C:4]1[C:9]([CH2:10][OH:11])=[C:8]([C:12]([F:14])([F:15])[F:13])[N:7]=[CH:6][N:5]=1)[CH3:2]
Reactant: CCOc1ncnc(C(F)(F)F)c1C=O
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: CCOc1ncnc(C(F)(F)F)c1CO
Temperature: 0 °C
Reaction time: 1 h
Yield: 98.7 %

Procedure:
A solution of 3.82 g (17.2 mmoles) of 4-ethoxy-6-trifluoromethylpyrimidine-5-carboaldehyde dissolved in 50 ml of methanol was added, with ice-cooling, to a solution of 1.7 g (45.7 mmoles) of sodium borohydride dissolved in 50 ml of methanol. The mixture was stirred at 0° C. for 1 hour to give rise to a reaction. After the completion of the reaction, the reaction mixture was poured into water, followed by extraction with ethyl acetate. The resulting organic layer was washed with an aqueous sodium chloride solution and then dried over anhydrous magnesium sulfate. The resulting solution was subjected to vacuum distillation to remove the solvent contained therein, to obtain 3.77 g (yield: 97.8%) of (4-ethoxy-6-trifluoromethylpyrimidin-5-yl)-methanol
Reaction SMILES: [Br:1][CH2:2][CH2:3][CH2:4][C:5](Cl)=[O:6].[F:8][CH:9]([F:36])[C:10]([NH:12][C@H:13]([CH2:34][F:35])[C@H:14]([OH:33])[C:15]1[CH:20]=[CH:19][C:18]([C:21]2[CH:22]=[N:23][C:24]([CH2:27][NH:28][S:29]([CH3:32])(=[O:31])=[O:30])=[CH:25][CH:26]=2)=[CH:17][CH:16]=1)=[O:11].C(N(CC)C(C)C)(C)C>CN(C)C1C=CN=CC=1.CN(C)C=O>[Br:1][CH2:2][CH2:3][CH2:4][C:5]([O:33][C@H:14]([C:15]1[CH:16]=[CH:17][C:18]([C:21]2[CH:22]=[N:23][C:24]([CH2:27][NH:28][S:29]([CH3:32])(=[O:30])=[O:31])=[CH:25][CH:26]=2)=[CH:19][CH:20]=1)[C@H:13]([NH:12][C:10](=[O:11])[CH:9]([F:8])[F:36])[CH2:34][F:35])=[O:6]
Reactant: O=C(Cl)CCCBr
Reactant: CS(=O)(=O)NCc1ccc(-c2ccc([C@@H](O)[C@@H](CF)NC(=O)C(F)F)cc2)cn1
Agent: CN(C)c1ccncc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CS(=O)(=O)NCc1ccc(-c2ccc([C@@H](OC(=O)CCCBr)[C@@H](CF)NC(=O)C(F)F)cc2)cn1
Reaction time: 1 h
Yield: 59.4 %

Procedure:
4-Bromobutanoyl chloride (29.6 μL, 0.255 mmol) is added dropwise to a stirred solution of 2,2-difluoro-N-{(1S,2R)-1-(fluoromethyl)-2-hydroxy-2-[4-(6-{[(methylsulfonyl)amino]methyl}pyridin-3-yl)phenyl]ethyl}acetamide (100.0 mg, 0.232 mmol), N,N-diisopropylethylamine (48.4 μL, 0.278 mmol), and 4-dimethylaminopyridine (11.3 mg, 0.093 mmol) in N,N-dimethylformamide (1.00 mL) at rt. The reaction mixture is stirred for 1 hour before being concentrated. The residue was purified by CombiFlash (4 g column) eluting with 0-100% ethyl acetate to yield the title compound (80.0 mg, 59%) as a yellow foam. MS (ESI+) m/z 581.7 [M+H].
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5](B2OC(C)(C)C(C)(C)O2)=[C:6]2[C:10]=1[C@H:9]([O:11][C:12]1[CH:25]=[CH:24][C:15]3[C@H:16]([CH2:19][C:20]([O:22][CH3:23])=[O:21])[CH2:17][O:18][C:14]=3[CH:13]=1)[CH2:8][CH2:7]2.Br[C:36]1[C:47]([CH3:48])=[CH:46][C:39]([O:40][C@@H:41]2[CH2:45][CH2:44][O:43][CH2:42]2)=[CH:38][C:37]=1[CH3:49]>>[CH3:49][C:37]1[CH:38]=[C:39]([O:40][C@@H:41]2[CH2:45][CH2:44][O:43][CH2:42]2)[CH:46]=[C:47]([CH3:48])[C:36]=1[C:5]1[CH:4]=[CH:3][C:2]([F:1])=[C:10]2[C:6]=1[CH2:7][CH2:8][C@H:9]2[O:11][C:12]1[CH:25]=[CH:24][C:15]2[C@H:16]([CH2:19][C:20]([O:22][CH3:23])=[O:21])[CH2:17][O:18][C:14]=2[CH:13]=1
Reactant: Cc1cc(O[C@@H]2CCOC2)cc(C)c1Br
Reactant: COC(=O)C[C@@H]1COc2cc(O[C@@H]3CCc4c(B5OC(C)(C)C(C)(C)O5)ccc(F)c43)ccc21
Product: COC(=O)C[C@@H]1COc2cc(O[C@@H]3CCc4c(-c5c(C)cc(O[C@@H]6CCOC6)cc5C)ccc(F)c43)ccc21

Procedure:
The title compound is prepared from methyl 2-((S)-6-((R)-7-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,3-dihydro-1H-inden-1-yloxy)-2,3-dihydrobenzofuran-3-yl)acetate and (R)-3-(4-bromo-3,5-dimethylphenoxy)tetrahydrofuran following a procedure analogous to that described in Step 5 of Intermediate 1. LC (method 4): tR=1.89 min; Mass spectrum (ESI+): m/z=555 [M+Na]+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([S:8]([N:11]2[C:19]3[C:14](=[CH:15][CH:16]=[C:17]([C:20](O)=[O:21])[CH:18]=3)[CH2:13][CH2:12]2)(=[O:10])=[O:9])[CH:5]=[CH:6][CH:7]=1.[CH2:23]([O:25][C:26](=[O:34])[CH2:27][C:28]1[N:29]=[C:30]([NH2:33])[S:31][CH:32]=1)[CH3:24]>>[CH2:23]([O:25][C:26](=[O:34])[CH2:27][C:28]1[N:29]=[C:30]([NH:33][C:20]([C:17]2[CH:18]=[C:19]3[C:14]([CH2:13][CH2:12][N:11]3[S:8]([C:4]3[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=3)(=[O:10])=[O:9])=[CH:15][CH:16]=2)=[O:21])[S:31][CH:32]=1)[CH3:24]
Reactant: CCOC(=O)Cc1csc(N)n1
Reactant: O=C(O)c1ccc2c(c1)N(S(=O)(=O)c1cccc(Cl)c1)CC2
Product: CCOC(=O)Cc1csc(NC(=O)c2ccc3c(c2)N(S(=O)(=O)c2cccc(Cl)c2)CC3)n1

Procedure:
The title compound was prepared as for example 8, steps 1 to 4. Step 1 was performed using 3-chlorobenzensulfonyl chloride and yielded 1-(3-chloro-benzenesulfonyl)-2,3-dihydro-1H-indole-6-carboxylic acid methyl ester) which was hydrolyzed to 1-(3-chloro-benzenesulfonyl)-2,3-dihydro-1H-indole-6-carboxylic acid in step 2 and coupled to (2-amino-thiazol-4-yl)-acetic acid ethyl ester in step 3 to yield (2-{[1-(3-chloro-benzenesulfonyl)-2,3-dihydro-1H-indole-6-carbonyl]-amino}-thiazol-4-yl)-acetic acid ethyl ester. This was hydrolyzed to (2-{[1-(3-chloro-benzenesulfonyl)-2,3-dihydro-1H-indole-6-carbonyl]-amino}-thiazol-4-yl)-acetic acid in step 4: white solid, 0.08 g (96%), MS (ISP): m/e=476.0 (M−H).
Reaction SMILES: Cl.[CH:2]1([NH:5][C:6]2[C:9](=[O:10])[C:8](=[O:11])[C:7]=2[NH:12][C:13]2[CH:14]=[C:15]([C:19]3[CH:24]=[CH:23][C:22]([O:25][CH2:26][C@@H:27]([C:29]([O:31][CH3:32])=[O:30])[NH2:28])=[CH:21][CH:20]=3)[CH:16]=[CH:17][CH:18]=2)[CH2:4][CH2:3]1.Cl[C:34]([O:36][CH2:37][CH3:38])=[O:35].C(N(C(C)C)C(C)C)C.[NH4+].[Cl-]>C1COCC1.C(OCC)(=O)C>[CH:2]1([NH:5][C:6]2[C:9](=[O:10])[C:8](=[O:11])[C:7]=2[NH:12][C:13]2[CH:14]=[C:15]([C:19]3[CH:24]=[CH:23][C:22]([O:25][CH2:26][C@@H:27]([C:29]([O:31][CH3:32])=[O:30])[NH:28][C:34]([O:36][CH2:37][CH3:38])=[O:35])=[CH:21][CH:20]=3)[CH:16]=[CH:17][CH:18]=2)[CH2:4][CH2:3]1
Reactant: CCOC(=O)Cl
Reactant: COC(=O)[C@@H](N)COc1ccc(-c2cccc(Nc3c(NC4CC4)c(=O)c3=O)c2)cc1
Agent: Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CCOC(=O)N[C@@H](COc1ccc(-c2cccc(Nc3c(NC4CC4)c(=O)c3=O)c2)cc1)C(=O)OC
Temperature: 0 °C
Reaction time: 1 h

Procedure:
The compound of Example 15 (97.0 mg, 0.2 mmol, 1 equiv) and ethyl chloroformate (29.8 mg, 0.3 mmol, 1.3 equiv) were suspended in THF (2 mL) and cooled to 0° C. Ethyldiisopropyl amine (82.1 mg, 0.6 mmol, 3 equiv) was added dropwise and the reaction mixture was allowed to reach rt. It was stirred for 1 hour at ambient temperature. Ethyl acetate and saturated aqueous NH4Cl solution were added and the phases were separated. The aqueous layer was extracted three times with ethyl acetate and the combined organic extracts were dried over Na2SO4. After removal of the solvents under reduced pressure the crude product was purified by chromatography (SiO2, gradient CH/EtOAc 6:4 to EtOAc 100%). Yield 39.0 mg, 37.3%. 1H NMR (CDCl3, 400 MHz) δ 7.61-7.55 (m, 1H); 7.52-7.49 (m, 2H); 7.31-7.18 (m, 2H); 7.09-6.96 (m, 1H); 6.82 (d, 2H); 5.71 (d, 1H); 4.79-4.64 (m, 1H); 4.34-4.29 (m, 1H); 4.19-4.02 (m, 4H); 3.75 (s, 3H); 3.19-3.06 (m, 1H); 1.23 (t, 3H); 0.89-0.75 (m, 2 H); 0.76-0.68 (m, 2H). MS (EI) 494 (M+H).