Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[C:7]([NH:12][C:13]([CH:15]3[CH2:17][CH2:16]3)=[O:14])[N:8]=[CH:9]2)=[CH:4][CH:3]=1.[CH3:18][N:19]1[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]1.CC(C1C=C(C(C)C)C(C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)=C(C(C)C)C=1)C.C(=O)([O-])[O-].[Cs+].[Cs+]>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.CN(C)C(=O)C>[CH3:18][N:19]1[CH2:24][CH2:23][N:22]([C:2]2[CH:11]=[C:10]3[C:5]([CH:6]=[C:7]([NH:12][C:13]([CH:15]4[CH2:17][CH2:16]4)=[O:14])[N:8]=[CH:9]3)=[CH:4][CH:3]=2)[CH2:21][CH2:20]1
Reactant: O=C(Nc1cc2ccc(Br)cc2cn1)C1CC1
Reactant: CN1CCNCC1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Solvent: CC(=O)N(C)C
Product: CN1CCN(c2ccc3cc(NC(=O)C4CC4)ncc3c2)CC1
Temperature: 120 °C
Reaction time: 18 h
Yield: 40.8 %

Procedure:
To a mixture of N-(7-bromoisoquinolin-3-yl)cyclopropanecarboxamide (131.4 mg, 0.4513 mmol), 1-methyl-piperazine (0.11 mL, 0.99 mmol), palladium (II) acetate (10.4 mg, 0.0463 mmol), XPhos (35.4 mg, 0.0742 mmol), and cesium carbonate (462 mg, 1.42 mmol) was added N,N-dimethylacetamide (4 mL). The reaction mixture was then stirred in a sealed vial at 120° C. for 18 hours. The reaction mixture was then cooled to room temperature and partitioned between ethyl acetate and half-saturated aqueous NaHCO3. The organic layer was dried over MgSO4, filtered, and evaporated in vacuo. The crude product was purified via flash chromatography on silica gel (12 g silica, solvent gradient: 10-30% methanol in dichloromethane) to yield 57.2 mg (41%) of N-(7-(4-methylpiperazin-1-yl)isoquinolin-3-yl)cyclopropanecarboxamide. LCMS (ESI): RT (min)=2.744, M+H=311.1, method=E; 1H NMR (400 MHz, CDCl3) δ 8.81 (s, 1H), 8.42 (s, 1H), 8.14 (s, 1H), 7.67 (d, J=9.1 Hz, 1H), 7.44 (dd, J=9.1, 2.5 Hz, 1H), 7.12 (d, J=2.4 Hz, 1H), 3.36-3.25 (m, 4H), 2.69-2.58 (m, 4H), 2.39 (s, 3H), 1.58 (m, 1H), 1.18-1.08 (m, 2H), 0.94-0.85 (m, 2H).
Reaction SMILES: [C:1]([O-:7])(=O)[CH2:2][C:3]([CH3:5])=[O:4].[Li+].C(N(CC)CC)C.[CH2:16]([NH:19][CH2:20][CH:21]1[CH2:23][CH2:22]1)[CH2:17][CH3:18].O=C1N(P(Cl)(N2CCOC2=O)=O)CCO1.Cl>ClC(Cl)C>[CH:21]1([CH2:20][N:19]([CH2:16][CH2:17][CH3:18])[C:1](=[O:7])[CH2:2][C:3](=[O:4])[CH3:5])[CH2:23][CH2:22]1
Reactant: CC(=O)CC(=O)[O-]
Reactant: CCCNCC1CC1
Agent: Cl
Agent: O=C1OCCN1P(=O)(Cl)N1CCOC1=O
Agent: [Li+]
Solvent: CCN(CC)CC
Solvent: CC(Cl)Cl
Product: CCCN(CC1CC1)C(=O)CC(C)=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 49.3 %

Procedure:
A stirred mixture of lithium acetoacetate (scheme 2: (G)) (1.00 g, 9.26 mmoles), triethylamine (2.58 mL, 18.5 mmoles), and n-propylcyclopropylmethyl amine (scheme 2: (E)) (1.32 mL, 9.26 mmoles) in dry dichloroethane (60 mL) was treated with bis(2-oxo-3-oxazolidinyl)phosphinic chloride (BOPCl) (2.36g, 9.26 mmoles). The mixture was stirred overnight at room temperature, and then acidified (pH˜1) with 1M hydrochloric acid. The mixture was extracted with ethyl acetate, washed with saturated sodium bicarbonate, brine, and dried over MgSO4. Concentration in vacuo and purification by silica gel chromatography (30% ethyl acetate/hexane) gave 900 mg of a yellow oil.
Reaction SMILES: [I:1][C:2]1[C:3]([O:22][CH3:23])=[CH:4][C:5]([CH:19]([CH3:21])[CH3:20])=[C:6]([O:8]S(C2C=CC(C)=CC=2)(=O)=O)[CH:7]=1.[OH-].[K+].Cl.CCCCCC>C(O)(C)(C)C.O>[I:1][C:2]1[C:3]([O:22][CH3:23])=[CH:4][C:5]([CH:19]([CH3:21])[CH3:20])=[C:6]([OH:8])[CH:7]=1
Reactant: COc1cc(C(C)C)c(OS(=O)(=O)c2ccc(C)cc2)cc1I
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCCCCC
Solvent: CC(C)(C)O
Product: COc1cc(C(C)C)c(O)cc1I
Temperature: 25 °C
Reaction time: 8 h
Yield: 84 %

Procedure:
To a mixture of 292 grams of toluene-4-sulfonic acid 5-iodo-2-isopropyl-4-methoxy-phenyl ester (0.66 Moles) in 600 mL tert-butyl alcohol was gradually added a solution of 90 g KOH in 400 mL water, and the resultant mixture was stirred overnight at 82 degrees C. The reaction mixture was neutralized with conc. HCl to a pH of 5-6, and then partitioned between 600 mL ethyl acetate and 400 mL water. The organic phase was dried over sodium sulfate, filtered and stripped under vacuum at 65 degrees C. to give a resinous liquid. Hexane (700 mL) was then added and the mixture heated to reflux. The liquid phase was decanted into another flask and stirred overnight at room temperature, during which time a white solid precipitated. The solid was isolated by filtration and vacuum dried to give 162 g of 5-iodo-2-isopropyl-4-methoxy-phenol, representing a yield of 82%: MS (M+H)=293.
Reaction SMILES: [O:1]=[O+][O-].[CH3:4][S:5]([O:8][CH2:9][C@:10]1([CH2:43][CH:44]=C)[CH2:15][C@H:14]([C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([Cl:22])[CH:17]=2)[C@@H:13]([C:23]2[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][CH:24]=2)[N:12]([C@@H:30]([CH2:40][CH3:41])[CH2:31][N:32]([CH3:39])[S:33]([CH:36]2[CH2:38][CH2:37]2)(=[O:35])=[O:34])[C:11]1=[O:42])(=[O:7])=[O:6].CSC>CO.C(Cl)Cl>[CH3:4][S:5]([O:8][CH2:9][C@:10]1([CH2:43][CH:44]=[O:1])[CH2:15][C@H:14]([C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([Cl:22])[CH:17]=2)[C@@H:13]([C:23]2[CH:24]=[CH:25][C:26]([Cl:29])=[CH:27][CH:28]=2)[N:12]([C@@H:30]([CH2:40][CH3:41])[CH2:31][N:32]([CH3:39])[S:33]([CH:36]2[CH2:37][CH2:38]2)(=[O:35])=[O:34])[C:11]1=[O:42])(=[O:7])=[O:6]
Reactant: C=CC[C@@]1(COS(C)(=O)=O)C[C@H](c2cccc(Cl)c2)[C@@H](c2ccc(Cl)cc2)N([C@@H](CC)CN(C)S(=O)(=O)C2CC2)C1=O
Reactant: O=[O+][O-]
Solvent: CSC
Solvent: ClCCl
Solvent: CO
Product: CC[C@@H](CN(C)S(=O)(=O)C1CC1)N1C(=O)[C@](CC=O)(COS(C)(=O)=O)C[C@H](c2cccc(Cl)c2)[C@H]1c1ccc(Cl)cc1
Temperature: 25 °C

Procedure:
Ozone was bubbled through a solution of ((3S,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-(N-methylcyclopropanesulfonamido)butan-2-yl)-2-oxopiperidin-3-yl)methyl methanesulfonate (Example 414, Step E, 1.12 g, 1.703 mmol) in 10% MeOH-DCM at −78° C. until a blue color developed. The reaction was purged with nitrogen gas followed by addition of dimethyl sulfide (1.251 ml, 17.03 mmol). The reaction was warmed to room temperature. The crude material was purified by chromatography on a RediSep® pre-packed silica gel column (Teledyne Isco, Lincoln, Nebr.) (12 g), eluting with a gradient of 0% to 80% EtOAc in hexane, to provide the title compound as an oil.
Reaction SMILES: [C:1]([C:4]1[CH:9]=[C:8]([O:10][C:11]2[CH:16]=[CH:15][C:14]([NH:17][C:18]3[C:23]([C:24]([NH:26][C:27]4[CH:32]=[CH:31][C:30]([F:33])=[CH:29][C:28]=4[F:34])=[O:25])=[CH:22][N:21]=[C:20](S(C)(=O)=O)[N:19]=3)=[CH:13][C:12]=2[F:39])[CH:7]=[CH:6][N:5]=1)(=[O:3])[NH2:2].[C-:40]#[N:41].[K+]>CN(C=O)C>[C:1]([C:4]1[CH:9]=[C:8]([O:10][C:11]2[CH:16]=[CH:15][C:14]([NH:17][C:18]3[C:23]([C:24]([NH:26][C:27]4[CH:32]=[CH:31][C:30]([F:33])=[CH:29][C:28]=4[F:34])=[O:25])=[CH:22][N:21]=[C:20]([C:40]#[N:41])[N:19]=3)=[CH:13][C:12]=2[F:39])[CH:7]=[CH:6][N:5]=1)(=[O:3])[NH2:2]
Reactant: CS(=O)(=O)c1ncc(C(=O)Nc2ccc(F)cc2F)c(Nc2ccc(Oc3ccnc(C(N)=O)c3)c(F)c2)n1
Reactant: [C-]#N
Agent: [K+]
Solvent: CN(C)C=O
Product: N#Cc1ncc(C(=O)Nc2ccc(F)cc2F)c(Nc2ccc(Oc3ccnc(C(N)=O)c3)c(F)c2)n1
Temperature: 80 °C
Reaction time: 5 h
Yield: 94 %

Procedure:
To a solution of 4-(4-(2-carbamoylpyridin-4-yloxy)-3-fluorophenylamino)-N-(2,4-difluorophenyl)-2-(methylsulfonyl)pyrimidine-5-carboxamide (200 mg, 0.36 mmol) in DMF (4 mL) was added potassium cyanide (94 mg, 1.44 mmol) and the mixture was heated to 80° C. After 5 h. The mixture was cooled to rt and the solvent was removed in vacuo. The residue was diluted with brine and extracted with EtOAc. The combined organic layers were washed with brine, dried over anhydrous MgSO4, and concentrated in vacuo to give the nitrile (171 mg, 94%) as a solid. MS(ESI+) m/z 506 (M+H)+.
Reaction SMILES: C[O:2][C:3](=[O:36])[C:4]([N:7]1[CH2:12][CH2:11][CH:10]([S:13][C:14]2[CH:15]=[CH:16][C:17]3[O:26][CH2:25][CH2:24][N:23]4[C:19](=[N:20][C:21]([C:27]5[N:28]([CH:32]([CH3:34])[CH3:33])[N:29]=[CH:30][N:31]=5)=[CH:22]4)[C:18]=3[CH:35]=2)[CH2:9][CH2:8]1)([CH3:6])[CH3:5].[Li+].[OH-]>C1COCC1.O>[CH:32]([N:28]1[C:27]([C:21]2[N:20]=[C:19]3[N:23]([CH2:24][CH2:25][O:26][C:17]4[CH:16]=[CH:15][C:14]([S:13][CH:10]5[CH2:11][CH2:12][N:7]([C:4]([CH3:6])([CH3:5])[C:3]([OH:36])=[O:2])[CH2:8][CH2:9]5)=[CH:35][C:18]=43)[CH:22]=2)=[N:31][CH:30]=[N:29]1)([CH3:34])[CH3:33]
Reactant: COC(=O)C(C)(C)N1CCC(Sc2ccc3c(c2)-c2nc(-c4ncnn4C(C)C)cn2CCO3)CC1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)n1ncnc1-c1cn2c(n1)-c1cc(SC3CCN(C(C)(C)C(=O)O)CC3)ccc1OCC2
Temperature: 25 °C
Reaction time: 6 h

Procedure:
To a solution of 2-{4-[2-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-1,3a-diazabenzo[e]azulen-9-ylsulfanyl]piperidin-1-yl}-2-methylpropionic acid methyl ester (50 mg, 0.0979 mmol) in THF (4 mL) was added 1.0M LiOH in water (0.5 mL). The reaction mixture was first stirred at RT for 6 h, then left at RT for 7 days, and then heated at 120° C. for 1 h using microwave irradiation. Volatiles were removed under reduced pressure and the resulting residue was purified by column chromatography (C18, gradient 2-80% MeOH in H2O) and then loaded onto an Isolute® SCX-2 cartridge. The cartridge was washed with MeOH and the product eluted with 2M NH3/MeOH affording the title compound as a white solid (20 mg, 42%). LCMS: RT 2.45 min [M−H]+ 495.0.
Reaction SMILES: Cl.Cl.[CH2:3]([O:5][C:6](=[O:12])[CH2:7][NH:8][CH2:9][CH2:10][NH2:11])[CH3:4].[Cl:13][C:14]1[CH:19]=[C:18]([Cl:20])[CH:17]=[CH:16][C:15]=1[C:21]1[S:25][C:24]([S:26](Cl)(=[O:28])=[O:27])=[N:23][N:22]=1>>[CH2:3]([O:5][C:6](=[O:12])[CH2:7][NH:8][CH2:9][CH2:10][NH:11][S:26]([C:24]1[S:25][C:21]([C:15]2[CH:16]=[CH:17][C:18]([Cl:20])=[CH:19][C:14]=2[Cl:13])=[N:22][N:23]=1)(=[O:28])=[O:27])[CH3:4]
Reactant: CCOC(=O)CNCCN
Reactant: O=S(=O)(Cl)c1nnc(-c2ccc(Cl)cc2Cl)s1
Agent: Cl
Product: CCOC(=O)CNCCNS(=O)(=O)c1nnc(-c2ccc(Cl)cc2Cl)s1

Procedure:
The title compound was synthesized by the reaction of N-(2-aminoethyl)-glycine ethyl ester 2HCl with 5-(2,4-dichloro-phenyl)-1,3,4-thiadiazole-2-sulfonyl chloride as per the procedure of example 1. 1H NMR (400 MHz; DMSO-d6) δ 8.29 (d, 1H), 7.98 (d, 1H), 7.70 (dd, 1H), 5.65 (brs, 1H), 4.05 (q, 2H), 3.28 (s, 2H), 3.19 (t, 2H), 2.67 (t, 2H), 1.17 (t, 3H).
Reaction SMILES: C([O:8][C:9]1[CH:37]=[CH:36][CH:35]=[CH:34][C:10]=1[O:11][C:12]1[CH:13]=[C:14]([N:18]([CH2:27][C:28]2[CH:29]=[N:30][CH:31]=[CH:32][CH:33]=2)[S:19]([CH2:22][C:23]([F:26])([F:25])[F:24])(=[O:21])=[O:20])[CH:15]=[CH:16][CH:17]=1)C1C=CC=CC=1>CO.[Ni]>[OH:8][C:9]1[CH:37]=[CH:36][CH:35]=[CH:34][C:10]=1[O:11][C:12]1[CH:13]=[C:14]([N:18]([CH2:27][C:28]2[CH:29]=[N:30][CH:31]=[CH:32][CH:33]=2)[S:19]([CH2:22][C:23]([F:25])([F:24])[F:26])(=[O:21])=[O:20])[CH:15]=[CH:16][CH:17]=1
Reactant: O=S(=O)(CC(F)(F)F)N(Cc1cccnc1)c1cccc(Oc2ccccc2OCc2ccccc2)c1
Agent: [Ni]
Solvent: CO
Product: O=S(=O)(CC(F)(F)F)N(Cc1cccnc1)c1cccc(Oc2ccccc2O)c1
Reaction time: 3 h
Yield: 89.9 %

Procedure:
A solution of N-(3-(2-benzyloxyphenoxy)phenyl)-N-(2,2,2-trifluoroethylsulfonyl)pyrid-3-ylmethylamine (529 mg, 1.00 mmol) in methanol (50 mL) was carefully treated with Raney® nickel (one tsp.), placed on a Parr® apparatus, and hydrogenated at 45-50 psi pressure for 3 h. The mixture was carefully filtered through celite® under nitrogen without allowing the filter cake to dry, and the filtrate was concentrated in vacuo. The residual solid was triturated from petroleum ethers (30°-60°) to afford the title compound (394 mg, 90%) as a white solid; mp 57.5-60.0° C. The title compound was converted to the hydrochloride salt by treatment in methanol with ethereal HCl. 1H NMR: 8.50 (br s,1H), 8.25 (br s,1H), 7.68 (d,1H, J=8 Hz), 7.25-7.30 (m,2H); 6.95-7.10 (m,2H), 6.90-6.95 (m,2H), 6.70-6.85 (m,3H), 6.05 (br s,1H), 4.82 (s,2H), 3.75-3.85 (m,2H).MS calcd. 438.4; MS(M+1) 439.3
Reaction SMILES: [NH2-].[Na+].[Cl:3][C:4]1[C:9]2[C:10](=[O:22])[N:11]3[CH2:21][CH2:20][C@H:12]3[C:13]3[N:14]([CH:15]=[N:16][C:17]=3[CH:18]=O)[C:8]=2[CH:7]=[CH:6][CH:5]=1.O1CCC[CH2:24]1>[Br-].C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[Cl:3][C:4]1[C:9]2[C:10](=[O:22])[N:11]3[CH2:21][CH2:20][C@H:12]3[C:13]3[N:14]([CH:15]=[N:16][C:17]=3[CH:18]=[CH2:24])[C:8]=2[CH:7]=[CH:6][CH:5]=1
Reactant: O=Cc1ncn2c1[C@@H]1CCN1C(=O)c1c(Cl)cccc1-2
Reactant: C1CCOC1
Agent: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Agent: [NH2-]
Product: C=Cc1ncn2c1[C@@H]1CCN1C(=O)c1c(Cl)cccc1-2
Reaction time: 1 h

Procedure:
8.70 g of an equimolar mixture of methyltriphenylphosphonium bromide and sodium amide were stirred for 20 minutes in 60 ml of tetrahydrofuran. 6 g (20 mmol) of (S)-8-chloro-12,12a-dihydro-9-oxo-9H,11H-azeto[2,1-c]imidazo[1,5-a][1,4]benzodiazepine-1-carboxaldehyde was then added portionwise thereto and the mixture was stirred for a further 1 hour. The mixture was subsequently filtered and the filtrate was evaporated. After chromatography of the residue on silica gel while eluting with cyclohexane/ether/isopropanol (3:3:1) and subsequent recrystallization from ethyl acetate there was obtained (S)-8-chloro-12,12a-dihydro-1-vinyl-9H,11H-azeto[2,1-c]imidazo[1,5-a][1,4]benzodiazepin-9-one of melting point 171°-172°.
Reaction SMILES: [NH:1](C(OCC1C=CC=CC=1)=O)[C@H:2]([C:7]([O:9]N1C(=O)CCC1=O)=[O:8])[CH2:3][CH:4]([CH3:6])[CH3:5].C(O)(C(F)(F)F)=O.CO.II>CN(C=O)C.CCN(CC)CC>[NH2:1][C@H:2]([C:7]([OH:9])=[O:8])[CH2:3][CH:4]([CH3:6])[CH3:5]
Reactant: CC(C)C[C@H](NC(=O)OCc1ccccc1)C(=O)ON1C(=O)CCC1=O
Agent: II
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: O=C(O)C(F)(F)F
Product: CC(C)C[C@H](N)C(=O)O

Procedure:
Z-Leu-OSu (LXIII) (10.8 gm), and the above TFA salt (LXIV) (17.8 gm) in DMF (200 mg) and Et3N (8.4 ml), were stirred at room temperature for 24 hours. The reaction mixture was evaporated in vacuo and the resulting peptide was partitioned between H2O and CHCl3. The dried (Na2SO4) organic layer was evaporated and crystallized from acetone-MeOH to afford 17.7 gm (80%) of pure LXV: m.p. 138°-140°C; [α]D22 -35.4 (c, 1.16, MeOH); Rf1 0.86 and Rf3 0.68, single spot with I2 reagent. Amino acid analysis gave Leu 1.1; Arg 0.9; Pro 1.0; Gly 1.0; NH3 0.9.
Reaction SMILES: C1C(=O)N([Br:8])C(=O)C1.[CH3:9][C:10]1[S:14][C:13]([C:15]([O:17]C)=[O:16])=[CH:12][C:11]=1[C:19]1[N:23]([CH3:24])[N:22]=[CH:21][CH:20]=1.[OH-].[Na+]>O1CCCC1>[Br:8][C:20]1[CH:21]=[N:22][N:23]([CH3:24])[C:19]=1[C:11]1[CH:12]=[C:13]([C:15]([OH:17])=[O:16])[S:14][C:10]=1[CH3:9]
Reactant: O=C1CCC(=O)N1Br
Reactant: COC(=O)c1cc(-c2ccnn2C)c(C)s1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: Cc1sc(C(=O)O)cc1-c1c(Br)cnn1C
Temperature: 70 °C
Reaction time: 2 h
Yield: 105.2 %

Procedure:
NBS (1.84 g, 10.33 mmol) was added in portions to a 150 mL sealed tube reactor containing methyl 5-methyl-4-(1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxylate (2 g, 8.46 mmol) [prepared according to the procedure of Preparation 10] in Tetrahydrofuran (THF) (40 ml) at room temperature. The mixture was heated to 70° C. for 1 h. 6N NaOH (28 ml, 168 mmol) was then added and the mixture stirred at 70° C. for 2 h. The mixture was partitioned between CHCl3 and H2O and the aqueous layer was made acidic with 6N HCl. The aqueous phase was washed several times with CHCl3 and the organic fractions were combined, dried over Na2SO4 and concentrated affording the title compound (2.68 g, 8.9 mmol, quant.): LC-MS (ES) m/z=302 (M+H)+.
Reaction SMILES: C([N:8]([C@@H:17]([CH3:27])[C@H:18]([CH3:26])[C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[C@@H](C)C1C=CC=CC=1)C1C=CC=CC=1>CCO.[OH-].[OH-].[Pd+2]>[C:22]([O:21][C:19](=[O:20])[C@@H:18]([CH3:26])[C@@H:17]([NH2:8])[CH3:27])([CH3:24])([CH3:23])[CH3:25]
Reactant: C[C@H](C(=O)OC(C)(C)C)[C@H](C)N(Cc1ccccc1)[C@@H](C)c1ccccc1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CCO
Product: C[C@H](N)[C@H](C)C(=O)OC(C)(C)C
Reaction time: 48 h
Yield: 74.3 %

Procedure:
A mixture of tert-butyl (2S,3S,αS)-3-(N-benzyl-N-α-methylbenzylamino)-2-methyl-butyrate (245 mg, 0.668 mmol) and 20% Pd(OH)2 on carbon (100 mg) in EtOH (10 mL) was stirred under H2 atmosphere (1 atm) for 48 h, then filtered through a pad of Celite. The filtrate was concentrated to give 86 mg of the title compound, which was used in the next step without purification. 1H NMR (CDCl3, 200 MHz): δ=5.5 (broad), 3.45-3.65 (m, 1H), 2.60-2.75 (m, 1H), 1.46 (s, 9H), 1.36 (d, 3H, J=6.6 Hz), 1.26 (d, 3H, J=7.0 Hz).
Reaction SMILES: [N:1]1([S:5]([NH2:8])(=[O:7])=[O:6])[CH2:4][CH2:3][CH2:2]1.Cl[C:10]1[CH:15]=[C:14]([S:16][CH:17]2[CH2:22][O:21][CH:20]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[O:19][CH2:18]2)[N:13]=[C:12]([S:29][CH2:30][C:31]2[CH:36]=[CH:35][CH:34]=[C:33]([F:37])[C:32]=2[F:38])[N:11]=1>>[F:38][C:32]1[C:33]([F:37])=[CH:34][CH:35]=[CH:36][C:31]=1[CH2:30][S:29][C:12]1[N:11]=[C:10]([NH:8][S:5]([N:1]2[CH2:4][CH2:3][CH2:2]2)(=[O:7])=[O:6])[CH:15]=[C:14]([S:16][CH:17]2[CH2:18][O:19][CH:20]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[O:21][CH2:22]2)[N:13]=1
Reactant: NS(=O)(=O)N1CCC1
Reactant: Fc1cccc(CSc2nc(Cl)cc(SC3COC(c4ccccc4)OC3)n2)c1F
Product: O=S(=O)(Nc1cc(SC2COC(c3ccccc3)OC2)nc(SCc2cccc(F)c2F)n1)N1CCC1

Procedure:
The subtitle compound was prepared from azetidine-1-sulfonamide (prepared according to patent WO 2004/011443, 0.11 g) and 4-Chloro-2-[[(2,3-difluorophenyl)methyl]thio]-6-[(2-phenyl-1,3-dioxan-5-yl)thio]pyrimidine (the product of step i) (0.17 g) according to the procedure outlined in Example 1, step iv). The residue was purified by flash chromatography on silica gel, eluting with EtOAc/iso-hexane (2:8) to give the subtitle compound as a colourless oil. Yield: 0.11 g
Reaction SMILES: C([S:4][CH2:5][C@@H:6]1[CH2:10][C@@H:9]([O:11][Si:12]([C:15]([CH3:18])([CH3:17])[CH3:16])([CH3:14])[CH3:13])[CH2:8][N:7]1[C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])(=O)C.[OH-].[Na+].Cl>CO>[C:22]([O:21][C:19]([N:7]1[CH2:8][C@H:9]([O:11][Si:12]([C:15]([CH3:18])([CH3:17])[CH3:16])([CH3:14])[CH3:13])[CH2:10][C@H:6]1[CH2:5][SH:4])=[O:20])([CH3:25])([CH3:24])[CH3:23]
Reactant: CC(=O)SC[C@@H]1C[C@@H](O[Si](C)(C)C(C)(C)C)CN1C(=O)OC(C)(C)C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CC(C)(C)OC(=O)N1C[C@H](O[Si](C)(C)C(C)(C)C)C[C@H]1CS
Reaction time: 0.5 h

Procedure:
To a solution of (2S,4R)-2-acetylthiomethyl-N-t-butoxycarbonyl-4-t-butyldimethylsiloxypyrrolidine (3.9 g, 10 mmol) in methanol (50 ml), 1N aqueous NaOH (11.0 ml, 11 mmol) was added in nitrogen stream under cooling with ice. The resulting solution was stirred for 30 minutes, then brought together with 1N aqueous HCl (12.0 ml, 12 mmol), and concentrated in vacuo. The resulting residue was poured into a liquid mixture of ethyl acetate with water. The organic layer was washed with saturated aqueous sodium chloride, and dried over anhydrous magnesium sulfate, and concentrated in vacuo to give a crude product of (2S,4R)-N-t-butoxycarbonyl-4-t-butyldimethylsiloxy-2-mercaptomethylpyrrolidine.
Reaction SMILES: [CH2:1]([C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][C:11]=1[CH2:12][CH3:13])[CH2:8][C:7]([NH:15][C:16](=O)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)([CH3:14])[CH2:6]2)[CH3:2].C(NC1CC2C(=CC(CC)=C(CC)C=2)C1)C1C=CC=CC=1>>[CH2:16]([NH:15][C:7]1([CH3:14])[CH2:8][C:9]2[C:5](=[CH:4][C:3]([CH2:1][CH3:2])=[C:11]([CH2:12][CH3:13])[CH:10]=2)[CH2:6]1)[C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: CCc1cc2c(cc1CC)CC(C)(NC(=O)c1ccccc1)C2
Agent: CCc1cc2c(cc1CC)CC(NCc1ccccc1)C2
Product: CCc1cc2c(cc1CC)CC(C)(NCc1ccccc1)C2

Procedure:
Benzyl-(5,6-diethyl-2-methyl-indan-2-yl)-amine is prepared from N-(5,6-diethyl-2-methyl-indan-2-yl)-benzamide by an analogous procedure to that used to prepare benzyl-(5,6-diethyl-indan-2-yl)-amine in Intermediate 18. ES+ MS m/e 294 (MH+).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([C:8]([F:20])([C:16]([F:19])([F:18])[F:17])[C:9]([F:15])([F:14])[C:10]([F:13])([F:12])[F:11])[CH:5]=[C:4]([Cl:21])[C:3]=1[NH2:22].C(N(CC)CC)C.[C:30]([C:32]1[CH:40]=[CH:39][C:35]([C:36](O)=[O:37])=[CH:34][C:33]=1[N+:41]([O-:43])=[O:42])#[N:31].O=C1N([ClH]P([ClH]N2CCOC2=O)=O)CCO1>ClCCCl>[Br:1][C:2]1[CH:7]=[C:6]([C:8]([F:20])([C:16]([F:17])([F:18])[F:19])[C:9]([F:14])([F:15])[C:10]([F:11])([F:13])[F:12])[CH:5]=[C:4]([Cl:21])[C:3]=1[NH:22][C:36](=[O:37])[C:35]1[CH:39]=[CH:40][C:32]([C:30]#[N:31])=[C:33]([N+:41]([O-:43])=[O:42])[CH:34]=1
Reactant: N#Cc1ccc(C(=O)O)cc1[N+](=O)[O-]
Reactant: Nc1c(Cl)cc(C(F)(C(F)(F)F)C(F)(F)C(F)(F)F)cc1Br
Solvent: CCN(CC)CC
Solvent: ClCCCl
Product: N#Cc1ccc(C(=O)Nc2c(Cl)cc(C(F)(C(F)(F)F)C(F)(F)C(F)(F)F)cc2Br)cc1[N+](=O)[O-]
Temperature: 90 °C
Reaction time: 6 h
Yield: 90.1 %

Procedure:
To a suspension of 2-bromo-6-chloro-4-(1,2,2,3,3,3-hexafluoro-1-trifluoromethyl-propyl)phenylamine (Example 3.3) (70 g, 165 mmol) in 1,2-dichloroethane (660 ml) was added triethylamine (50.09 g, 495 mmol), followed by 4-cyano-3-nitrobenzoic acid (made as in WO 2008/074427) (63.4 g, 330 mmol) and bis(2-oxo-3-oxazolidinyl)phosphonic chloride (“BOP-Cl”) (84 g, 330 mmol). The reaction mixture was stirred at 90° C. for 6 hours. The reaction was quenched by addition of aqueous hydrochloric acid (1M) (500 ml) and the phases were separated. The organic phase was washed with saturated aqueous sodium hydrogen carbonate and brine. The aqueous phase was extracted twice with 1,2-dichloroethane. The combined organic extracts were dried over sodium sulfate and concentrated. The residue was purified by column chromatography on silica gel (eluent: cyclohexane/ethyl acetate 7:3) to give N-[2-bromo-6-chloro-4-(1,2,2,3,3,3-hexafluoro-1-trifluoromethylpropyl)phenyl]-4-cyano-3-nitrobenzamide (89 g, 90% yield). 1H NMR (400 MHz, CDCl3): 8.89 (s, 1H), 8.40 (d, 1H), 8.12 (d, 1H), 7.88 (m, 2H), 7.72 (s, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([CH3:18])[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[C:10](=O)O2)=[CH:4][CH:3]=1.C1(C)C=CC(S(O)(=O)=O)=CC=1.[CH2:30]([NH2:33])[CH2:31][NH2:32].Cl>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[C:10]3=[N:33][CH2:30][CH2:31][N:32]3[CH2:18]2)=[CH:4][CH:3]=1
Reactant: NCCN
Reactant: CC1(c2ccc(Cl)cc2)OC(=O)c2ccccc21
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: Cl
Product: Clc1ccc(C2CN3CCN=C3c3ccccc32)cc1
Temperature: 200 °C
Yield: 70.1 %

Procedure:
A mixture of 60 g of 3-(4chlorophenyl)-3-methyl-1(3H)-isobenzofuranone and 257 g of ethylenediamine p-toluenesulfonate (166 ml ethylenediamine treated with 470 g p-toluenesulfonic acid and crystallised from 2-propanol) was heated to 200° C. and kept at this temperature overnight. The reaction mixture was allowed to cool and 850 ml of an aqueous 1N hydrochloride solution were added. The resulting mixture was extracted with 600 ml of chloroform. The organic layer was washed with 700 ml of an aqueous 1N potassium hydroxide solution, dried and evaporated in vacuo. The residue was crystallised from a 1:3 mixture of diethyl ether and hexane at -20° C. to give 46 g of (rac)-6-(4-chlorophenyl)-2,3,5,6-tetrahydroimidazo[2,1-a]isoquinoline as a yellow solid. The hydrochloride salt was prepared by the addition of a solution of hydrochloric acid in methanol resulting in (rac)6-(4-chlorophenyl)-2,3,5,6-tetrahydroimidazo[2,1-a]isoquinoline hydrochloride, melting point 230° C.