Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([CH2:7][C@H:8]([NH:14][C:15](=[O:21])[O:16][C:17]([CH3:20])([CH3:19])[CH3:18])[C:9](=[O:13])[C:10]([CH3:12])=[CH2:11])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[O-:22]Cl.[Na+]>CN(C=O)C.O.CCOC(C)=O>[CH:1]1([CH2:7][C@H:8]([NH:14][C:15](=[O:21])[O:16][C:17]([CH3:20])([CH3:19])[CH3:18])[C:9]([C@@:10]2([CH3:12])[CH2:11][O:22]2)=[O:13])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: [O-]Cl
Reactant: C=C(C)C(=O)[C@H](CC1CCCCC1)NC(=O)OC(C)(C)C
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N[C@@H](CC1CCCCC1)C(=O)[C@@]1(C)CO1
Reaction time: 2 h
Yield: 65 %

Procedure:
To (S)-tert-butyl (1-cyclohexyl-4-methyl-3-oxopent-4-en-2-yl)carbamate (5.36 g, 18.1 mmol) in DMF at −10° C. was added NaOCl (47.1 mL of a 9.5% w/w solution, 36.2 mmol). Addition of NaOCl was performed at a rate to maintain an internal temperature of ≦−10° C. After the addition was complete the reaction mixture was transferred to an ice bath and stirred for an additional 2 h at which time it was diluted with water and EtOAc, extracted with EtOAc (2×), washed with brine, dried with sodium sulfate, filtered, and concentrated. Purification by column chromatography (3:1 heptane/EtOAc) provided tert-butyl ((S)-3-cyclohexyl-1-((R)-2-methyloxiran-2-yl)-1-oxopropan-2-yl)carbamate (3.68 g, 65%) as a colorless amorphous solid. MS (EI) for C17H29NO4, found 310.2 (MH−).
Reaction SMILES: [NH2:1][CH2:2][C@H:3]1[CH2:6][C@H:5]([N:7]2[C:11]3[N:12]=[CH:13][N:14]=[C:15]([NH2:16])[C:10]=3[C:9]([C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([O:23][CH2:24][C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=4)[CH:18]=3)=[CH:8]2)[CH2:4]1.[CH2:31]([O:33][CH2:34][C:35](O)=[O:36])[CH3:32]>>[NH2:16][C:15]1[C:10]2[C:9]([C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([O:23][CH2:24][C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=4)[CH:18]=3)=[CH:8][N:7]([C@H:5]3[CH2:4][C@H:3]([CH2:2][NH:1][C:35](=[O:36])[CH2:34][O:33][CH2:31][CH3:32])[CH2:6]3)[C:11]=2[N:12]=[CH:13][N:14]=1
Reactant: NC[C@H]1C[C@H](n2cc(-c3cccc(OCc4ccccc4)c3)c3c(N)ncnc32)C1
Reactant: CCOCC(=O)O
Product: CCOCC(=O)NC[C@H]1C[C@H](n2cc(-c3cccc(OCc4ccccc4)c3)c3c(N)ncnc32)C1

Procedure:
trans-N-{3-[4-Amino-5-(3-benzyloxy-phenyl)-pyrrolo[2,3-d]pyrimidin-7-yl]-cyclobutylmethyl}-2-ethoxy-acetamide is prepared starting from trans-7-(3-aminomethyl-cyclobutyl)-5-(3-benzyloxy-phenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-ylamine and ethoxy-acetic acid (Fluka, Buchs, Switzerland) according to a procedure known in the art (M. Bodanszky in Principles of Peptide Synthesis, Akad.-Verlag, 1984). Analytical HPLC: tR=7.07 min (Grad 2); ES-MS: m/eo=486.2.
Reaction SMILES: [CH3:1][C:2]([CH3:58])([CH2:10][C:11]([O:13][C@H:14]1[CH2:31][CH2:30][C@@:29]2([CH3:32])[C@@H:16]([CH2:17][CH2:18][C@:19]3([CH3:55])[C@@H:28]2[CH2:27][CH2:26][C@H:25]2[C@@:20]3([CH3:54])[CH2:21][CH2:22][C@@:23]3(/[CH:40]=[CH:41]/[C:42]([NH:44][C@H:45]([C:47]4[CH:52]=[CH:51][C:50]([Cl:53])=[CH:49][CH:48]=4)[CH3:46])=[O:43])[CH2:35][C:34](=[O:36])[C:33]([CH:37]([CH3:39])[CH3:38])=[C:24]32)[C:15]1([CH3:57])[CH3:56])=[O:12])[C:3]([O:5]C(C)(C)C)=[O:4].[C:59]([OH:65])([C:61]([F:64])([F:63])[F:62])=[O:60].CC#N>ClCCl>[C:59]([OH:65])([C:61]([F:64])([F:63])[F:62])=[O:60].[OH2:4].[Cl:53][C:50]1[CH:49]=[CH:48][C:47]([C@@H:45]([NH:44][C:42](=[O:43])/[CH:41]=[CH:40]/[C@:23]23[CH2:35][C:34](=[O:36])[C:33]([CH:37]([CH3:39])[CH3:38])=[C:24]2[C@@H:25]2[C@@:20]([CH3:54])([CH2:21][CH2:22]3)[C@@:19]3([CH3:55])[C@@H:28]([C@:29]4([CH3:32])[C@@H:16]([CH2:17][CH2:18]3)[C:15]([CH3:56])([CH3:57])[C@@H:14]([O:13][C:11](=[O:12])[CH2:10][C:2]([CH3:1])([CH3:58])[C:3]([OH:5])=[O:4])[CH2:31][CH2:30]4)[CH2:27][CH2:26]2)[CH3:46])=[CH:52][CH:51]=1
Reactant: CC(C)C1=C2[C@H]3CC[C@@H]4[C@@]5(C)CC[C@H](OC(=O)CC(C)(C)C(=O)OC(C)(C)C)C(C)(C)[C@@H]5CC[C@@]4(C)[C@]3(C)CC[C@@]2(/C=C/C(=O)N[C@@H](C)c2ccc(Cl)cc2)CC1=O
Solvent: CC#N
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(C)C1=C2[C@H]3CC[C@@H]4[C@@]5(C)CC[C@H](OC(=O)CC(C)(C)C(=O)O)C(C)(C)[C@@H]5CC[C@@]4(C)[C@]3(C)CC[C@@]2(/C=C/C(=O)N[C@@H](C)c2ccc(Cl)cc2)CC1=O
Product: O
Yield: 30.8 %

Procedure:
To a solution of 1-tert-butyl 4-((3aS,5aR,5bR,7aR,9S,11aR,11bR,13aS)-3a-((E)-3-(((S)-1-(4-chlorophenyl)ethyl)amino)-3-oxoprop-1-en-1-yl)-1-isopropyl-5a,5b,8,8,11a-pentamethyl-2-oxo-3,3a,4,5,5a,5b,6,7,7a,8,9,10,11,11a,11b,12,13,13a-octadecahydro-2H-cyclopenta[a]chrysen-9-yl) 2,2-dimethylsuccinate (420 mg, 0.513 mmol) in Dichloromethane (6 mL) was added TFA (3 mL, 0.513 mmol). The reaction mixture was stirred at r.t for 2 hs and evaporated in vacuo to afford crude product, which was purified by preparative-HPLC (Mobile Phase: A=0.05% TFA/H2O, B=MeCN) to give the product 4-(((3aS,5aR,5bR,7aR,9S,11aR,11bR,13aS)-3a-((E)-3-(((S)-1-(4-chlorophenyl)ethyl)amino)-3-oxoprop-1-en-1-yl)-1-isopropyl-5a,5b,8,8,11a-pentamethyl-2-oxo-3,3a,4,5,5a,5b,6,7,7a,8,9,10,11,11a,11b,12,13,13a-octadecahydro-2H-cyclopenta[a]chrysen-9-yl)oxy)-2,2-dimethyl-4-oxobutanoic acid (60 mg, 0.079 mmol, 15.34%) as a white solid. 1H NMR (400 MHz, CHLOROFORM-d) δ=7.44-7.18 (m, 4H), 6.97 (d, J=15.8 Hz, 1H), 5.80-5.58 (m, 2H), 5.25-5.09 (m, 1H), 4.50 (dd, J=5.3, 10.8 Hz, 1H), 3.27-3.13 (m, 1H), 2.79-2.52 (m, 2H), 2.36-2.01 (m, 3H), 2.00-0.65 (m, 47H); LC/MS: m/z calculated 761.4. Found 762.3 (M+1)+.
Reaction SMILES: ClC1N=C(C2SC(C(C)C)=NC=2C2C=C(NS(C3C(F)=CC=CC=3F)(=O)=O)C=CC=2)C=CN=1.[Cl:34][C:35]1[N:40]=[C:39]([C:41]2[S:45][C:44]([N:46]3[CH2:51][CH2:50][O:49][CH2:48][CH2:47]3)=[N:43][C:42]=2[C:52]2[C:53]([F:59])=[C:54]([CH:56]=[CH:57][CH:58]=2)[NH2:55])[CH:38]=[CH:37][N:36]=1.[O:60]1[CH:64]=[CH:63][CH:62]=[C:61]1[S:65](Cl)(=[O:67])=[O:66]>>[Cl:34][C:35]1[N:40]=[C:39]([C:41]2[S:45][C:44]([N:46]3[CH2:47][CH2:48][O:49][CH2:50][CH2:51]3)=[N:43][C:42]=2[C:52]2[C:53]([F:59])=[C:54]([NH:55][S:65]([C:61]3[O:60][CH:64]=[CH:63][CH:62]=3)(=[O:67])=[O:66])[CH:56]=[CH:57][CH:58]=2)[CH:38]=[CH:37][N:36]=1
Reactant: O=S(=O)(Cl)c1ccco1
Reactant: Nc1cccc(-c2nc(N3CCOCC3)sc2-c2ccnc(Cl)n2)c1F
Agent: CC(C)c1nc(-c2cccc(NS(=O)(=O)c3c(F)cccc3F)c2)c(-c2ccnc(Cl)n2)s1
Product: O=S(=O)(Nc1cccc(-c2nc(N3CCOCC3)sc2-c2ccnc(Cl)n2)c1F)c1ccco1
Yield: 63 %

Procedure:
Following a procedure analogous to the procedure described in Intermediate 14 using 3-(5-(2-chloropyrimidin-4-yl)-2-morpholinothiazol-4-yl)-2-fluoroaniline (3.0 g, 7.6 mmol) and furan-2-sulfonyl chloride (1.4 g, 8.4 mmol) the title compound of Step A was obtained (2.5 g, 63% yield). 1H NMR (400 MHz, DMSO-d6) δ ppm 8.07 (d, J=5.5 Hz, 1H), 7.59-7.66 (m, 1H), 7.42-7.75 (br, 1H), 7.13-7.20 (m, 2H), 7.02 (d, J=5.5 Hz, 1H), 6.93-6.98 (m, 1H), 6.37-6.42 (m, 2H), 3.50-3.57 (m, 4H), 3.72-3.78 (m, 4H). MS (ES+): 522 [M+H]+.
Reaction SMILES: Cl.[NH2:2][C:3]1[N:32]=[C:6]2[N:7]([C:22]3[CH:27]=[CH:26][CH:25]=[C:24]([C:28]([F:31])([F:30])[F:29])[CH:23]=3)[C:8]([CH3:21])=[C:9]([C:19]#[N:20])[C@@H:10]([C:11]3[CH:16]=[CH:15][C:14]([C:17]#[N:18])=[CH:13][CH:12]=3)[N:5]2[N:4]=1.[CH3:33][O:34][CH2:35][CH2:36][O:37][CH2:38][CH2:39][O:40][CH2:41][C:42](Cl)=[O:43]>N1C=CC=CC=1>[C:19]([C:9]1[C@@H:10]([C:11]2[CH:16]=[CH:15][C:14]([C:17]#[N:18])=[CH:13][CH:12]=2)[N:5]2[N:4]=[C:3]([NH:2][C:42](=[O:43])[CH2:41][O:40][CH2:39][CH2:38][O:37][CH2:36][CH2:35][O:34][CH3:33])[N:32]=[C:6]2[N:7]([C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([C:28]([F:29])([F:31])[F:30])[CH:23]=2)[C:8]=1[CH3:21])#[N:20]
Reactant: CC1=C(C#N)[C@@H](c2ccc(C#N)cc2)n2nc(N)nc2N1c1cccc(C(F)(F)F)c1
Reactant: COCCOCCOCC(=O)Cl
Agent: Cl
Solvent: c1ccncc1
Product: COCCOCCOCC(=O)Nc1nc2n(n1)[C@H](c1ccc(C#N)cc1)C(C#N)=C(C)N2c1cccc(C(F)(F)F)c1
Reaction time: 12 h

Procedure:
Under an atmosphere of argon protective gas, (7R)-2-amino-7-(4-cyanophenyl)-5-methyl-4-[3-(trifluoromethyl)phenyl]-4,7-dihydro[1,2,4]triazolo[1,5-a]pyrimidine-6-carbonitrile hydrochloride (14 mg, 31 μmol) was dissolved in abs. pyridine (0.7 ml). At room temperature, 2-[2-(2-methoxy-ethoxy)ethoxy]acetyl chloride (12 mg, 61 μmol, 2 eq.) was added. After 12 h, analysis of the reaction by HPLC showed substantial conversion. The reaction mixture was concentrated under reduced pressure and purified by preparative HPLC (Gromsil C18 column, 30×250 mm; mobile phase: acetonitrile-water-0.1% TFA). After lyophilization, the product was obtained as a solid (12.4 mg, 70% of theory).
Reaction SMILES: [CH2:1]([N:4]1[CH2:9][CH2:8][CH2:7][CH2:6][CH2:5]1)[C:2]#[CH:3].[CH3:10][O:11][C:12](=[O:42])[CH2:13][O:14][C:15]1[CH:20]=[CH:19][C:18]([O:21][CH2:22][C:23]#[C:24][C:25]2[CH:30]=[C:29]([C:31]#[C:32][CH2:33][N:34]3[CH2:39][CH2:38][CH2:37][CH2:36][CH2:35]3)[CH:28]=[C:27](Br)[CH:26]=2)=[CH:17][C:16]=1[CH3:41]>CN(C=O)C.C(N(CC)CC)C.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.[Cu]I>[CH3:10][O:11][C:12](=[O:42])[CH2:13][O:14][C:15]1[CH:20]=[CH:19][C:18]([O:21][CH2:22][C:23]#[C:24][C:25]2[CH:26]=[C:27]([C:3]#[C:2][CH2:1][N:4]3[CH2:9][CH2:8][CH2:7][CH2:6][CH2:5]3)[CH:28]=[C:29]([C:31]#[C:32][CH2:33][N:34]3[CH2:39][CH2:38][CH2:37][CH2:36][CH2:35]3)[CH:30]=2)=[CH:17][C:16]=1[CH3:41]
Reactant: C#CCN1CCCCC1
Reactant: COC(=O)COc1ccc(OCC#Cc2cc(Br)cc(C#CCN3CCCCC3)c2)cc1C
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COC(=O)COc1ccc(OCC#Cc2cc(C#CCN3CCCCC3)cc(C#CCN3CCCCC3)c2)cc1C
Temperature: 60 °C

Procedure:
A mixture of 1-prop-2-ynyl-piperidine (322 mg, 2.62 mmol), (4-{3-[3-bromo-5-(3-piperidin-1-yl-prop-1-ynyl)-phenyl]-prop-2-ynyloxy}-2-methyl-phenoxy)-acetic acid methyl ester (204 mg, 0.4 mmol, example 3), Pd(PPh3)4 (50 mg, 0.044 mmol), CuI (23 mg, 0.122 mmol) in dry DMF (2 ml) and triethylamine (2 ml) was heated in a microwave own for 30 min at 60° C. in a sealed tube. The reaction mixture was filtered through Decalite and the filtrate was evaporated. The residue was purified on column chromatography using ethyl acetate/methanol mixtures to give (4-{3-[3,5-bis-(3-piperidin-1-yl-prop-1-ynyl)-phenyl]-prop-2-ynyloxy}-2-methyl-phenoxy)-acetic acid methyl ester in 138 mg (57%) yield.
Reaction SMILES: [NH2:1][S:2]([C:5]1[C:6]([Cl:21])=[CH:7][C:8]([NH:14][CH2:15][C:16]2[O:17][CH:18]=[CH:19][CH:20]=2)=[C:9]([CH:13]=1)[C:10](Cl)=[O:11])(=[O:4])=[O:3].C=[O:23].Cl[CH2:25][Cl:26]>>[NH2:1][S:2]([C:5]1[C:6]([Cl:21])=[CH:7][C:8]([NH:14][CH2:15][C:16]2[O:17][CH:18]=[CH:19][CH:20]=2)=[C:9]([CH:13]=1)[C:10]([O:23][CH2:25][Cl:26])=[O:11])(=[O:4])=[O:3]
Reactant: C=O
Reactant: ClCCl
Reactant: NS(=O)(=O)c1cc(C(=O)Cl)c(NCc2ccco2)cc1Cl
Product: NS(=O)(=O)c1cc(C(=O)OCCl)c(NCc2ccco2)cc1Cl
Temperature: 90 °C

Procedure:
A mixture of 5-(aminosulfonyl)-4-chloro-2-[(2-furanylmethyl)amino]benzoyl chloride (13) (0.040 mole) and paraformaldehyde (0.040 mole) is heated in a sealed vessel at 90° C. for 3 hours. The reaction is cooled, and the solids is dissolved in dichloromethane. The solution is washed with 5% aqueous sodium bicarbonate, with water, and then with a saturated sodium chloride solution. The organic layer is dried over sodium sulfate, filtered and concentrated in vacuo to give crude product, which may be purified by column chromatography on silica gel with hexanes/ethyl acetate as eluent. The fractions that contain pure product may be combined and spin evaporated in vacuo to give chloromethyl 5-(aminosulfonyl)-4-chloro-2-[(2-furanylmethyl)amino]benzoate (15). See Bodor, et al., J. Med. Chem., 23, 469 (1980), and Ulich, et al., J. Am. Chem. Soc., (1921) 43: 660.
Reaction SMILES: [N:1]1([NH2:6])[CH:5]=[CH:4][CH:3]=[CH:2]1.C(N(CC)CC)C.Cl[S:15]([C:18]1[CH2:23][CH2:22][CH2:21][CH2:20][C:19]=1[C:24]([O:26][CH2:27][CH3:28])=[O:25])(=[O:17])=[O:16].O>C(OCC)(=O)C>[N:1]1([NH:6][S:15]([CH:18]2[C:19]([C:24]([O:26][CH2:27][CH3:28])=[O:25])=[CH:20][CH2:21][CH2:22][CH2:23]2)(=[O:17])=[O:16])[CH:5]=[CH:4][CH:3]=[CH:2]1
Reactant: Nn1cccc1
Reactant: CCOC(=O)C1=C(S(=O)(=O)Cl)CCCC1
Solvent: O
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: CCOC(=O)C1=CCCCC1S(=O)(=O)Nn1cccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 52.3 %

Procedure:
To a solution of 1.0 g (12.18 mmol) of 1H-pyrrol-1-ylamine and 1.8 ml (13.40 mmol) of triethylamine in 60 ml of ethyl acetate was added dropwise a solution of 3.6 g (12.18 mmol) of ethyl 2-chlorosulfonyl-1-cyclohexene-1-carboxylate (compound disclosed in the specification of Japanese Patent Application (Kokai) No. 2000-178246) in 12 ml of ethyl acetate with stirring under ice-cooling, followed by stirring overnight at room temperature. Water was added to the reaction solution and the mixture was extracted with ethyl acetate. The organic layer was washed with water and dried over anhydrous magnesium sulfate, followed by concentration under reduced pressure. The residue was subjected to silica gel column chromatography (solvent; hexane:ethyl acetate=3:1) and the resulting solid was further washed with isopropyl ether to give 1.9 g of the title compound as a white powder (yield: 52%).
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([NH:11][C:12]2[CH:13]=[C:14]([CH:18]=[CH:19][CH:20]=2)[C:15]([OH:17])=O)[C:5]2[S:10][CH2:9][CH2:8][C:6]=2[N:7]=1.CN(C(ON1N=[N:36][C:31]2C=[CH:33][CH:34]=[N:35][C:30]1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH:45](N(C(C)C)CC)(C)C.ClC1N=C(CCCN)C2S(=O)(=O)CCC=2N=1>CS(C)=O>[CH3:45][N:35]1[CH2:30][CH2:31][N:36]([C:15]([C:14]2[CH:18]=[CH:19][CH:20]=[C:12]([NH:11][C:4]3[C:5]4[S:10][CH2:9][CH2:8][C:6]=4[N:7]=[C:2]([Cl:1])[N:3]=3)[CH:13]=2)=[O:17])[CH2:33][CH2:34]1
Reactant: CCN(C(C)C)C(C)C
Reactant: O=C(O)c1cccc(Nc2nc(Cl)nc3c2SCC3)c1
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: NCCCc1nc(Cl)nc2c1S(=O)(=O)CC2
Solvent: CS(C)=O
Product: CN1CCN(C(=O)c2cccc(Nc3nc(Cl)nc4c3SCC4)c2)CC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 32.9 %

Procedure:
0.600 g (1.95 mmol) of 3-(2-chloro-6,7-dihydrothieno[3,2-d]pyrimidin-4-ylamino)benzoic acid (I), 0.741 g (1.95 mmol) of O-(7-azabenzotriazol-1-yl-)—N,N,N′,N′-tetramethyluronium hexafluorophosphate (HATU), and 0.680 mL (3.90 mmol) of diisopropylethylamine are placed in 10 mL of dimethylsulfoxide, then stirred for 0.5 hours at ambient temperature. 0.220 mL (1.95 mmol) of methylpiperazine (II) is added, then the mixture is stirred for 3 hours at ambient temperature. Then the reaction mixture is concentrated by evaporation and the residue is combined with water. Any precipitate formed is suction filtered and dried. The crude product is purified by chromatography through a 50 g silica cartridge with ethyl acetate/methanol 8:2. 0.250 g of product III (33%) is obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl-].[Al+3].[Cl-].[Cl-].[CH3:12][S:13](Cl)(=[O:15])=[O:14]>CO>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:13]([CH3:12])(=[O:15])=[O:14])=[CH:4][CH:3]=1
Reactant: CS(=O)(=O)Cl
Reactant: Clc1ccccc1
Agent: [Al+3]
Agent: [Cl-]
Solvent: CO
Product: CS(=O)(=O)c1ccc(Cl)cc1
Temperature: 15 °C

Procedure:
To 600 ml of chlorobenzene were added 272 g of anhydrous aluminum chloride and 229 g of methanesulfonyl chloride and the mixture was heated on a steam bath for 6 hours with stirring. The solution thus formed was poured into ice-water, and then the produce was extracted with 400 ml of methylene chloride. Methylene chloride was distilled off from the extract under reduced pressure. To the residue thus formed was added 300 ml of methanol, the mixture was cooled to 15° C., and crystals thus deposited were collected by filtration to provide 212 g 1-chloro-4-methylsulfonyl benzene having a melting point of 92° to 94° C.
Reaction SMILES: Br[CH2:2][CH2:3][C:4]1([CH3:24])[CH2:8][C:7]2[C:9]([CH3:23])=[C:10]([NH:15][C:16](=[O:22])[O:17][C:18]([CH3:21])([CH3:20])[CH3:19])[C:11]([CH3:14])=[C:12]([CH3:13])[C:6]=2[O:5]1.[C:25]1([CH:31]([C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=2)[O:32][CH2:33][CH2:34][CH:35]2[CH2:40][CH2:39][NH:38][CH2:37][CH2:36]2)[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>>[C:25]1([CH:31]([C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=2)[O:32][CH2:33][CH2:34][CH:35]2[CH2:40][CH2:39][N:38]([CH2:2][CH2:3][C:4]3([CH3:24])[CH2:8][C:7]4[C:9]([CH3:23])=[C:10]([NH:15][C:16](=[O:22])[O:17][C:18]([CH3:21])([CH3:20])[CH3:19])[C:11]([CH3:14])=[C:12]([CH3:13])[C:6]=4[O:5]3)[CH2:37][CH2:36]2)[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1
Reactant: c1ccc(C(OCCC2CCNCC2)c2ccccc2)cc1
Reactant: Cc1c(C)c2c(c(C)c1NC(=O)OC(C)(C)C)CC(C)(CCBr)O2
Product: Cc1c(C)c2c(c(C)c1NC(=O)OC(C)(C)C)CC(C)(CCN1CCC(CCOC(c3ccccc3)c3ccccc3)CC1)O2
Yield: 83 %

Procedure:
Using tert-butyl [2-(2-bromoethyl)-2,3-dihydro-2,4,6,7-tetramethylbenzofuran-5-yl]carbamate and 4-(2-(diphenylmethoxy)ethyl]piperidine, the procedure of Reference Example 58 was otherwise repeated to provide the title compound. Yield 83%.
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[CH:9][C:5]([CH2:6][NH:7][NH2:8])=[CH:4][C:3]=1[C:11]([F:14])([F:13])[F:12].C([O:17][C:18](=O)[CH:19]=[C:20]([NH2:24])OCC)C.C1(C)C=CC(S(O)(=O)=O)=CC=1>C(O)C>[NH2:24][C:20]1[NH:8][N:7]([CH2:6][C:5]2[CH:9]=[CH:10][C:2]([CH3:1])=[C:3]([C:11]([F:12])([F:13])[F:14])[CH:4]=2)[C:18](=[O:17])[CH:19]=1
Reactant: Cc1ccc(CNN)cc1C(F)(F)F
Reactant: CCOC(=O)C=C(N)OCC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCO
Product: Cc1ccc(Cn2[nH]c(N)cc2=O)cc1C(F)(F)F
Reaction time: 8 h

Procedure:
34 g of 4-methyl-3-trifluoromethylbenzylhydrazine were added dropwise, under nitrogen, to a solution of 26.5 g of β-amino-β-ethoxyacrylic acid ethyl ester and a pinch of p-toluenesulphonic acid in 100 ml of ethanol. After stirring overnight, the compound identified above, which had precipitated, was filtered off and recrystallised from ethanol. Melting point: 103°, 20 g (44%).
Reaction SMILES: [N+:1]([CH2:4][CH3:5])([O-:3])=[O:2].P([O-])([O-])([O-])=O.[K+].[K+].[K+].[Cl:14][C:15]1[CH:22]=[C:21]([Cl:23])[CH:20]=[CH:19][C:16]=1[CH:17]=[O:18].O>C(#N)C>[Cl:14][C:15]1[CH:22]=[C:21]([Cl:23])[CH:20]=[CH:19][C:16]=1[CH:17]([OH:18])[CH:4]([N+:1]([O-:3])=[O:2])[CH3:5]
Reactant: CC[N+](=O)[O-]
Reactant: O=Cc1ccc(Cl)cc1Cl
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC#N
Product: CC(C(O)c1ccc(Cl)cc1Cl)[N+](=O)[O-]
Reaction time: 4 h

Procedure:
To a stirred solution of nitroethane (8.3 g, 0.11 mol) in acetonitrile (150 ml) was added anhydrous potassium phosphate (1.0 g, 4.6 mmol) followed by 2,4-dichloro-benzaldehyde (17.5 g, 0.10 mol). The reaction mixture was stirred for 4 hours. Water (300 ml) was added and the reaction mixture was extracted with diethyl ether (200 ml). The organic extract was washed with water and dried over anhydrous Na2SO4, the solvent was removed and the resulting residue was purified by flash chromatography over silicagel (eluent:cyclohexane/ethylacetate 9:1). 20.7 g (82.5% of theory) of a threo/erythro-mixture of 1-(2,4-dichlorophenyl)-2-nitro-propan-1-ol was obtained. Crystallisation from cyclohexane yielded pure erythro 1-(2,4-dichlorophenyl)-2-nitro-propan-1-ol.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([F:21])=[C:6]([C@:8]2([CH:18]([F:20])[F:19])[CH2:14][CH2:13][S:12](=[O:16])(=[O:15])[CH2:11][C:10]([NH2:17])=[N:9]2)[CH:7]=1.C(N(CC)CC)C.[CH3:29][O:30][C:31]1[CH:52]=[CH:51][C:34]([C:35](Cl)([C:44]2[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=2)[C:36]2[CH:41]=[CH:40][C:39]([O:42][CH3:43])=[CH:38][CH:37]=2)=[CH:33][CH:32]=1>ClCCl>[CH3:43][O:42][C:39]1[CH:38]=[CH:37][C:36]([C:35]([NH:17][C:10]2[CH2:11][S:12](=[O:16])(=[O:15])[CH2:13][CH2:14][C@:8]([C:6]3[CH:7]=[C:2]([Br:1])[CH:3]=[CH:4][C:5]=3[F:21])([CH:18]([F:19])[F:20])[N:9]=2)([C:34]2[CH:33]=[CH:32][C:31]([O:30][CH3:29])=[CH:52][CH:51]=2)[C:44]2[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=2)=[CH:41][CH:40]=1
Reactant: NC1=N[C@@](c2cc(Br)ccc2F)(C(F)F)CCS(=O)(=O)C1
Reactant: COc1ccc(C(Cl)(c2ccccc2)c2ccc(OC)cc2)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1ccc(C(NC2=N[C@@](c3cc(Br)ccc3F)(C(F)F)CCS(=O)(=O)C2)(c2ccccc2)c2ccc(OC)cc2)cc1
Temperature: 25 °C
Reaction time: 6 h
Yield: 64.3 %

Procedure:
A solution of (S)-5-(5-bromo-2-fluoro-phenyl)-5-difluoromethyl-1,1-dioxo-2,5,6,7-tetrahydro-1H-1λ6-[1,4]thiazepin-3-ylamine (318 mg, 826 μmol) and triethylamine (167 mg, 1.65 mmol) in dichloromethane (15 ml) was treated at 0° C. with 4,4′-dimethoxytritylchloride (336 mg, 991 μmol). The green reaction mixture was stirred at room temperature for 6 hours. Thereafter, the reaction mixture was evaporated, and the crude product was purified by chromatography on silica gel using a gradient of heptane and ethyl acetate 100:0 to 50:50 as the eluent. The [bis-(4-methoxy-phenyl)-phenyl-methyl]-[(S)-5-(5-bromo-2-fluoro-phenyl)-5-difluoromethyl-1,1-dioxo-2,5,6,7-tetrahydro-1H-1λ6-[1,4]thiazepin-3-yl]-amine (365 mg, 63% yield) was obtained as a grey foam. MS (ISP): m/z=687.0 [M+H]+and 689.3 [M+2+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]2[NH:8][C:9](=[O:35])[C:10]3([CH:15]([C:16]4[CH:21]=[CH:20][CH:19]=[C:18]([Cl:22])[CH:17]=4)[CH2:14][C:13](=[O:23])[NH:12][CH:11]3[C:24]3[CH:29]=[C:28](I)[CH:27]=[CH:26][C:25]=3[O:31][CH2:32][CH2:33][OH:34])[C:5]2=[CH:4][CH:3]=1.[CH3:36][Si:37]([C:40]#[CH:41])([CH3:39])[CH3:38].CCN(CC)CC>CN(C=O)C.[Cu]I>[Cl:1][C:2]1[CH:7]=[C:6]2[NH:8][C:9](=[O:35])[C:10]3([CH:15]([C:16]4[CH:21]=[CH:20][CH:19]=[C:18]([Cl:22])[CH:17]=4)[CH2:14][C:13](=[O:23])[NH:12][CH:11]3[C:24]3[CH:29]=[C:28]([C:41]#[C:40][Si:37]([CH3:39])([CH3:38])[CH3:36])[CH:27]=[CH:26][C:25]=3[O:31][CH2:32][CH2:33][OH:34])[C:5]2=[CH:4][CH:3]=1
Reactant: O=C1CC(c2cccc(Cl)c2)C2(C(=O)Nc3cc(Cl)ccc32)C(c2cc(I)ccc2OCCO)N1
Reactant: C#C[Si](C)(C)C
Agent: [Cu]I
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: C[Si](C)(C)C#Cc1ccc(OCCO)c(C2NC(=O)CC(c3cccc(Cl)c3)C23C(=O)Nc2cc(Cl)ccc23)c1
Temperature: 76 °C

Procedure:
To a solution of racemic (2′R,3R,4′S)-6-chloro-4′-(3-chlorophenyl)-2′-[5-iodo-2-(2-hydroxy-ethoxy)-phenyl]spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione (6.05 g, 9.71 mmol) prepared in example 190c in DMF (80 mL) were added trimethylsilylacetylene (10 mL), CuI (40 mg), Et3N (50 mL), PdCl2(Ph3P)2 (Aldrich, 205 mg, 0.29 mmol) were added. The mixture was purged with nitrogen and heated at 76° C. for 1.5 h, then cooled to room temperature. The mixture was poured into water, extracted with EtOAc several times. The extracts were combined and dried with sodium sulfate and dried to give a foam. The foam was purified by chromatography to give the title compound as a light yellow solid. Yield 3.28 g, 57%.