Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:5][C:6]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[C:14]1[CH:19]=[CH:18][C:17]([CH2:20][N:21]2[C:25]([C:26]([NH2:28])=[O:27])=[C:24]([CH:29]([OH:32])[CH2:30][CH3:31])[N:23]=[C:22]2[CH2:33][CH2:34][CH2:35][CH3:36])=[CH:16][CH:15]=1)=[O:7])(C)(C)C.Cl>O1CCOCC1>[CH2:33]([C:22]1[N:21]([CH2:20][C:17]2[CH:16]=[CH:15][C:14]([C:9]3[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=3[C:6]([OH:7])=[O:5])=[CH:19][CH:18]=2)[C:25]([C:26]([NH2:28])=[O:27])=[C:24]([CH:29]([OH:32])[CH2:30][CH3:31])[N:23]=1)[CH2:34][CH2:35][CH3:36]
Reactant: CCCCc1nc(C(O)CC)c(C(N)=O)n1Cc1ccc(-c2ccccc2C(=O)OC(C)(C)C)cc1
Agent: Cl
Solvent: C1COCCO1
Product: CCCCc1nc(C(O)CC)c(C(N)=O)n1Cc1ccc(-c2ccccc2C(=O)O)cc1

Procedure:
Following a procedure similar to that described in Example 45(d), but using 316 mg of 1-[(2'-t-butoxycarbonylbiphenyl4-yl)methyl]-2-butyl-4-(1-hydroxypropyl)imidazole-5-carboxamide [prepared as described in step (c) above] and 10 ml of a 4N solution of hydrogen chloride in dioxane, 148 mg of the hydrochloride of the title compound were obtained as an amorphous powder, melting at above 120° C. (with softening).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[CH2:10][O:9][CH2:8][N:7]([S:11]([C:14]3[CH:19]=[C:18]([Cl:20])[CH:17]=[CH:16][C:15]=3[O:21][CH3:22])(=[O:13])=[O:12])[C:6]=2[CH:23]=1.C(N(CC)CC)C.[C:31]([O:34][CH2:35]C)(=[O:33])C>CO>[CH3:35][O:34][C:31]([C:2]1[CH:3]=[CH:4][C:5]2[CH2:10][O:9][CH2:8][N:7]([S:11]([C:14]3[CH:19]=[C:18]([Cl:20])[CH:17]=[CH:16][C:15]=3[O:21][CH3:22])(=[O:13])=[O:12])[C:6]=2[CH:23]=1)=[O:33]
Reactant: CCOC(C)=O
Reactant: COc1ccc(Cl)cc1S(=O)(=O)N1COCc2ccc(Br)cc21
Solvent: CCN(CC)CC
Solvent: CO
Product: COC(=O)c1ccc2c(c1)N(S(=O)(=O)c1cc(Cl)ccc1OC)COC2
Yield: 43 %

Procedure:
A solution of 7-bromo-1-(5-chloro-2-methoxy-benzenesulfonyl)-1,4-dihydro-2H-benzo[d][1,3]oxazine (2.00 g, 4.78 mmol), triethylamine (1.21 g, 11.9 mmol), and dichloro[1,1′-bis(diphenylphosphino)ferrocene]palladium dichloromethane complex (200 mg, 0.239 mmol) in methanol (30 mL) and ethyl acetate (30 mL) was heated at 130° C. under a carbon monoxide atmosphere (100 bar) for 3 h. The reaction mixture was evaporated and the residue chromatographed (SiO2, heptane-ethyl acetate gradient) to produce 1-(5-chloro-2-methoxybenzenesulfonyl)-1,4-dihydro-2H-benzo[d][1,3]oxazine-7-carboxylic acid methyl ester (825 mg, 43%). Orange solid, MS (ISP)=398.1 (M+H)+.
Reaction SMILES: [CH:1]1([NH:4][C:5]([CH:7]2[O:11]C(C)=[N:9][CH:8]2[CH2:13][CH2:14][CH3:15])=[O:6])[CH2:3][CH2:2]1.[ClH:16]>CO>[ClH:16].[CH:1]1([NH:4][C:5](=[O:6])[C@@H:7]([OH:11])[C@@H:8]([NH2:9])[CH2:13][CH2:14][CH3:15])[CH2:3][CH2:2]1
Reactant: CCCC1N=C(C)OC1C(=O)NC1CC1
Agent: Cl
Solvent: CO
Product: CCC[C@H](N)[C@H](O)C(=O)NC1CC1
Temperature: 25 °C
Reaction time: 14 h
Yield: 26.9 %

Procedure:
N-Cyclopropyl-2-methyl-4-propyl-4,5-dihydro-1,3-oxazole-5-carboxamide (0.10 g, 0.5 mmol), methanol (4 ml) and concentrated hydrochloric acid (0.5 ml, 5.5 mmol) were mixed, and the mixture was stirred at room temperature for 14 hours. The solvent was evaporated away under reduced pressure. Isopropanol (4 ml) was added to the obtained solid, and the mixture was stirred at room temperature for 10 minutes. The crystal was collected by filtration, and was dried under reduced pressure to obtain the title compound as a white solid (0.03 g, yield: 28%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([NH2:8])[C:3]=1[I:9].[N+:10]([O-])([O-:12])=[O:11].[K+]>OS(O)(=O)=O>[Cl:1][C:2]1[C:7]([N+:10]([O-:12])=[O:11])=[CH:6][N:5]=[C:4]([NH2:8])[C:3]=1[I:9]
Reactant: Nc1nccc(Cl)c1I
Reactant: O=[N+]([O-])[O-]
Agent: O=S(=O)(O)O
Agent: [K+]
Product: Nc1ncc([N+](=O)[O-])c(Cl)c1I
Temperature: 0 °C
Reaction time: 1 h
Yield: 46.8 %

Procedure:
A solution of 4-chloro-3-iodopyridin-2-amine (4.00 g, 15.7 mmol, Adesis) in concd H2SO4 (45 mL) was cooled to about 0° C. in an ice bath. Potassium nitrate (3.50 g, 34.6 mmol) was added in four portions over about 10 min. The resulting solution was stirred at about 0° C. for about 1 h, then at ambient temperature for about 4 h. The reaction mixture was slowly poured over crushed ice (total volume 1 L) resulting in formation of a solid that was collected by vacuum filtration and dried under vacuum to give 4-chloro-3-iodo-5-nitropyridin-2-amine (2.2 g, 47%) as a yellow solid: LC/MS (Table 1, Method c) Rt=1.48 min; MS m/z 298 (M−H)−.
Reaction SMILES: [N+:1]([O-:4])(O)=[O:2].[NH:5]1[C:9]([C:10]([OH:12])=[O:11])=[CH:8][C:7]([C:13]([OH:15])=[O:14])=[N:6]1.[OH-].[K+]>S(=O)(=O)(O)O>[N+:1]([C:8]1[C:7]([C:13]([OH:15])=[O:14])=[N:6][NH:5][C:9]=1[C:10]([OH:12])=[O:11])([O-:4])=[O:2]
Reactant: O=[N+]([O-])O
Reactant: O=C(O)c1cc(C(=O)O)[nH]n1
Agent: O=S(=O)(O)O
Agent: [K+]
Agent: [OH-]
Product: O=C(O)c1n[nH]c(C(=O)O)c1[N+](=O)[O-]
Temperature: 40 °C
Reaction time: 18 h
Yield: 76 %

Procedure:
Fuming sulphuric acid (105 ml) was added dropwise over 45 minutes to ice-cooled finning nitric acid (88 ml), so as to maintain the internal temperature below 20° C. Once addition was complete the mixture was warmed to 40° C., pyrazole-3,5-dicarboxylic acid (125 g, 0.80 mol) added portionwise over 75 minutes, so as to maintain the reaction temperature below 50° C., and the reaction then stirred at 60° C. for 18 hours. The cooled mixture was poured onto ice (1 kg), and flaked potassium hydroxide carefully added with stirring, until the solution pH was 2. The resulting precipitate was filtered, and triturated with boiling water (500 ml), to afford the title compound (123 g, 76%) as a white solid. m.p. 325-327° C.
Reaction SMILES: [Cl:1][C:2]1[CH:12]=[C:11]([NH:13][CH3:14])[C:5]([C:6](OCC)=[O:7])=[CH:4][N:3]=1.[H-].[H-].[H-].[H-].[Li+].[Al+3].O.[OH-].[Na+]>C1COCC1>[Cl:1][C:2]1[N:3]=[CH:4][C:5]([CH2:6][OH:7])=[C:11]([NH:13][CH3:14])[CH:12]=1
Reactant: CCOC(=O)c1cnc(Cl)cc1NC
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: CNc1cc(Cl)ncc1CO
Reaction time: 0.33 h
Yield: 89.8 %

Procedure:
A 0° C. solution of ethyl 6-chloro-4-(methylamino)nicotinate (4 g, 18.7 mmol) in THF (40 mL), under a N2 atmosphere, was treated portion-wise with LiAlH4 (1.4 g, 37.4 mmol), stirred for 20 min, then carefully treated with water followed by 2 N NaOH. The suspension was filtered and the filtrate was concentrated to afford (6-chloro-4-(methylamino)pyridin-3-yl)methanol (2.9 g, 91% yield), which was used in next step without purification. 1H NMR (400 MHz, DMSO-d6): δ 7.96 (s, 1H), 6.63 (s, 1H), 6.46 (s, 1H), 5.04 (s, 1H), 4.39 (m, 2H), 2.81-2.68 (m, 3H).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([CH2:18][C:19](O)=[O:20])=[C:9]([C:11]3[CH:16]=[CH:15][C:14]([CH3:17])=[CH:13][CH:12]=3)[N:10]=2)[CH:7]=1>C1COCC1>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([CH2:18][CH2:19][OH:20])=[C:9]([C:11]3[CH:16]=[CH:15][C:14]([CH3:17])=[CH:13][CH:12]=3)[N:10]=2)[CH:7]=1
Reactant: Cc1ccc(-c2nc3ccc(C)cn3c2CC(=O)O)cc1
Solvent: C1CCOC1
Product: Cc1ccc(-c2nc3ccc(C)cn3c2CCO)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 92.3 %

Procedure:
To a mechanically stirred suspension of (6-methyl-2-p-tolyl-imidazo[1,2-a]pyridin-3-yl)-acetic acid 1a (5.0 g, 17.9 mmol) in THF (50 ml) at 0° C. under nitrogen atmosphere was added dropwise a 1.0 M solution of borane-tetrahydrofuran complex (56 ml, 56 mmol). The mixture was slowly warmed to ambient temperature and stirred for 2 h (nearly homogeneous at this point, slightly hazy). The reaction was quenched with 1.0 N HCl at 0° C., and stirred at ambient temperature for 0.5 h. The solution was concentrated in vacuo in order to remove the volatiles. The resulting solution was basified at 0° C. with 10% NaOH and extracted with dichloromethane (2×250 ml). The organic layers were combined, dried (Na2SO4), and concentrated to afford 4.4 g (93%) of product as a white solid. 1H NMR (400 MHz, CDCl3) δ 1.80 (broad s, 1H), 2.29 (s, 3H), 2.37 (s, 3H), 3.21 (t J=6.2 Hz, 2H), 4.00 (t, J=6.2 Hz, 2H), 6.82 (dd, J=1.5, 8.8 Hz, 1H), 7.14 (d, J=8.0 Hz, 2H), 7.29 (d, J=9.1 Hz, 1H), 7.58 (d, J=8.0 Hz, 2H), 7.84 (s, 1H).
Reaction SMILES: [C:1]1([C:7]2[NH:8][C:9]3[CH:10]=[CH:11][CH:12]=[C:13]4[C:18](=O)[CH2:17][CH2:16][C:15]=2[C:14]=34)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH2:20][CH2:21][CH2:22][OH:23].CO.C([BH3-])#N.[Na+]>C(Cl)Cl>[OH:23][CH2:22][CH2:21][NH:20][CH:18]1[C:13]2[C:14]3[C:15](=[C:7]([C:1]4[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=4)[NH:8][C:9]=3[CH:10]=[CH:11][CH:12]=2)[CH2:16][CH2:17]1
Reactant: O=C1CCc2c(-c3ccccc3)[nH]c3cccc1c23
Reactant: NCCO
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: ClCCl
Product: OCCNC1CCc2c(-c3ccccc3)[nH]c3cccc1c23
Temperature: 25 °C
Reaction time: 13 h
Yield: 32 %

Procedure:
A portion (0.20 g) of the compound obtained in Example 41 and 2-aminoethanol (0.49 ml) were suspended in a mixed solvent of methanol (3 ml) and methylene chloride (2 ml) and to the suspension was added sodium cyanoborohydride (61 mg). The mixture was stirred for 13 hours at room temperature and heated to reflux for further 8 hours. The reaction mixture was concentrated under reduced pressure. Water was added to the residue, followed by extraction with three portions of methylene chloride. The organic layers were combined, washed with saturated aqueous solution of sodium chloride and dried over anhydrous sodium sulfate. Then, the solvent was distilled off under reduced pressure and the residue was purified by silica gel column chromatography (methylene chloride/methanol=19:1) and further crystallized from ether to yield 75 mg (32%) of the titled compound as yellowish brown crystals.
Reaction SMILES: [CH3:1][C:2]1[N:3]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[CH3:23])[C:4]([C:7](=[N:15]O)[CH2:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[N:5][N:6]=1>C(O)(=O)C.[Zn]>[CH3:1][C:2]1[N:3]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[CH3:23])[C:4]([CH:7]([NH2:15])[CH2:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[N:5][N:6]=1
Reactant: Cc1ccccc1-n1c(C)nnc1C(Cc1ccccc1)=NO
Agent: [Zn]
Solvent: CC(=O)O
Product: Cc1ccccc1-n1c(C)nnc1C(N)Cc1ccccc1

Procedure:
The suspension of 10E (120 mg, 0.4 mmol) and zinc powder (256 mg, 4 mmol) in 2 mL of acetic acid was heated to reflux for 30 minutes. The reaction was filtered and purified on prep reverse phase HPLC using 20-80% B over 20 min. (A=0.1% TFA/H2O; B=0.1% TFA/Acetonitrile). Combined pure fractions as determined by LC/MS and lyophilized to provide the desired product. MS (m/z) 293 [M+H]+.
Reaction SMILES: [Br:1][C:2]1[C:7]([S:8]([C:11]2[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=2)(=[O:10])=[O:9])=[CH:6][CH:5]=[C:4]([CH3:18])[N:3]=1.C([O-])([O-])=O.[K+].[K+].[CH3:25][O:26][C:27]1[CH:34]=[CH:33][CH:32]=[CH:31][C:28]=1[CH2:29]Cl.CO>CC#N.CCOC(C)=O>[Br:1][C:2]1[C:7]([S:8]([C:11]2[CH:16]=[CH:15][C:14]([O:17][CH2:29][C:28]3[CH:31]=[CH:32][CH:33]=[CH:34][C:27]=3[O:26][CH3:25])=[CH:13][CH:12]=2)(=[O:9])=[O:10])=[CH:6][CH:5]=[C:4]([CH3:18])[N:3]=1
Reactant: Cc1ccc(S(=O)(=O)c2ccc(O)cc2)c(Br)n1
Reactant: COc1ccccc1CCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: CCOC(C)=O
Solvent: CC#N
Product: COc1ccccc1COc1ccc(S(=O)(=O)c2ccc(C)nc2Br)cc1
Temperature: 25 °C
Yield: 78 %

Procedure:
4-(2-Bromo-6-methylpyridine-3-sulfonyl)-phenol from part E (3.22 g, 9.81 mmol), KI (1.95 g, 11.77 mmol), K2CO3 (1.63 g, 11.77 mmol), and 2-methoxybenzyl chloride (1.64 mL, 11.77 mmol) were suspended in MeCN (10 mL) and heated at reflux overnight. The mixture was cooled to rt, diluted with EtOAc, and filtered through a pad of Celite. The filtrate was concentrated and purified by column chromatography on silica gel (20% ethyl acetate in hexanes). Tritration with methanol afforded the desired product (3.44 g, 78% yield) as a colorless solid: mp 76–78° C.; 1H NMR (300 MHz, CDCl3) δ 8.43 (d, J=7.6 Hz, 1H), 7.82 (d, J=7.0 Hz, 2H), 7.31 (d, J=7.0 Hz, 1H), 7.25 (d, J=8.0 Hz, 2H), 7.01 (d, J=7.0, Hz, 2H), 6.92 (d, J=6.6 Hz, 1H), 6.85 (d, J=8.0 Hz, 1H), 5.10 (s, 2H), 3.80 (s, 3H), 2.53 (s, 3H); LRMS (APCI) m/z 448.0 [(M+H)+, calcd for C20H19NO4BrS, 448.0].
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5]([CH3:16])[C:6]=1[C:7](=O)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[F:14].[C:17](=O)([O:19]CC)[NH2:18]>[Cl-].[Zn+2].[Cl-]>[F:14][C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=1[C:7]1[C:6]2[C:5]([CH3:16])=[CH:4][S:3][C:2]=2[NH:1][C:17](=[O:19])[N:18]=1
Reactant: CCOC(N)=O
Reactant: Cc1csc(N)c1C(=O)c1ccccc1F
Agent: [Cl-]
Agent: [Zn+2]
Product: Cc1csc2[nH]c(=O)nc(-c3ccccc3F)c12
Temperature: 200 °C

Procedure:
A mixture of 18.5 g of 2-amino-3-(o-fluorobenzoyl)-4-methylthiophene, 26.6 g of ethyl carbamate and 1.61 g of zinc chloride is heated at 200°C for 30 minutes. After cooling, the reaction mixture is washed with chloroform, then with water, and filtered to give crude crystals of 4-(o-fluorophenyl)-5-methyl-1,2-dihydrothieno[2,3-d]pyrimidin-2-one having a melting point of 258° - 261°C.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:13]([NH:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[CH3:21])=[C:12]([F:22])[C:8]2[NH:9][CH:10]=[N:11][C:7]=2[CH:6]=1)=[O:4].[Cl:23]N1C(=O)CCC1=O>>[CH3:1][O:2][C:3]([C:5]1[C:13]([NH:14][C:15]2[CH:20]=[CH:19][C:18]([Cl:23])=[CH:17][C:16]=2[CH3:21])=[C:12]([F:22])[C:8]2[N:9]=[CH:10][NH:11][C:7]=2[CH:6]=1)=[O:4]
Reactant: O=C1CCC(=O)N1Cl
Reactant: COC(=O)c1cc2nc[nH]c2c(F)c1Nc1ccccc1C
Product: COC(=O)c1cc2[nH]cnc2c(F)c1Nc1ccc(Cl)cc1C

Procedure:
7-Fluoro-6-o-tolylamino-3H-benzoimidazole-5-carboxylic acid methyl ester 7a is converted by the procedure already described for bromination, except N-chlorosuccinimide is used instead of N-bromosuccinimide, to yield the desired product. MS ESI (+) m/z 334, 336 (M+, Cl pattern) detected.
Reaction SMILES: O=[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([C:11]3[CH:12]=[C:13]([CH:16]=[CH:17][CH:18]=3)[C:14]#[N:15])[CH:9]=2)[CH2:4][C:3]21[CH2:24][CH2:23][CH2:22][C:21]1[CH:25]=[CH:26][CH:27]=[CH:28][C:20]=1[CH2:19]2.C[Si]([N:33]=[C:34]=[N:35][Si](C)(C)C)(C)C>C(Cl)Cl.Cl[Ti](Cl)(Cl)Cl>[C:14]([C:13]1[CH:12]=[C:11]([C:8]2[CH:7]=[C:6]3[C:5](=[CH:10][CH:9]=2)[CH2:4][C:3]2([CH2:19][CH2:20][CH2:28][C:27]4[CH:23]=[CH:22][CH:21]=[CH:25][C:26]=4[CH2:2]2)[C:24]3=[N:35][C:34]#[N:33])[CH:18]=[CH:17][CH:16]=1)#[N:15]
Reactant: C[Si](C)(C)N=C=N[Si](C)(C)C
Reactant: N#Cc1cccc(-c2ccc3c(c2)C(=O)C2(CCCc4ccccc4C2)C3)c1
Agent: Cl[Ti](Cl)(Cl)Cl
Solvent: ClCCl
Product: N#CN=C1c2cc(-c3cccc(C#N)c3)ccc2CC12CCCc1ccccc1C2
Temperature: 50 °C
Reaction time: 0.08 h
Yield: 150 %

Procedure:
To a solution of 3-(1′-oxo-1′,3′,5,7,8,9-hexahydrospiro[benzo[7]annulene-6,2′-indene]-6′-yl)benzonitrile (31 mg, 0.086 mmol) in CH2Cl2 (2 mL) was added TiCl4 (66 mg). It was stirred in microwave at 50° C. for 5 minutes. Then bis-trimethylsilylcarbodiimide (112 mg, 0.6 mmol) was added. The resulting mixture was stirred in microwave at 60° C. for 10 minutes. The reaction mixture was poured into ice-water, extracted with DCM. The combined organic phases were dried over anhydrous Na2SO4, and filtered. The filtrate was concentrated to give N-(5′-(3-cyanophenyl)-5,7,8,9-tetrahydrospiro[benzo[7]annulene-6,2′-indene]-3′(1′H)-ylidene)cyanamide (50 mg, crude).
Reaction SMILES: [C:1]1([CH:7]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[N:8]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[C:10](O)([C:17]3[C:26]([OH:27])=[CH:25][C:20]4[O:21][CH2:22][CH2:23][O:24][C:19]=4[CH:18]=3)[C:9]2=[O:29])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.ClC1C=CC=C2C=1C(O)(C1C(O)=CC3OCCC=3C=1)C(=O)N2C(C1C=CC=CC=1)C1C=CC=CC=1>>[C:30]1([CH:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[N:8]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[CH:10]([C:17]3[C:26]([OH:27])=[CH:25][C:20]4[O:21][CH2:22][CH2:23][O:24][C:19]=4[CH:18]=3)[C:9]2=[O:29])[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=1
Reactant: O=C1N(C(c2ccccc2)c2ccccc2)c2ccccc2C1(O)c1cc2c(cc1O)OCCO2
Agent: O=C1N(C(c2ccccc2)c2ccccc2)c2cccc(Cl)c2C1(O)c1cc2c(cc1O)OCC2
Product: O=C1C(c2cc3c(cc2O)OCCO3)c2ccccc2N1C(c1ccccc1)c1ccccc1

Procedure:
Following the procedure as described in PREPARATION 4C, and making non-critical variations using 1-(diphenylmethyl)-3-hydroxy-3-(7-hydroxy-2,3-dihydro-1,4-benzodioxin-6-yl)-1,3-dihydro-2H-indol-2-one to replace 4-chloro-1-(diphenylmethyl)-3-hydroxy-3-(6-hydroxy-2,3-dihydro-1-benzofuran-5-yl)-1,3-dihydro-2H-indol-2-one, 1-(diphenylmethyl)-3-(7-hydroxy-2,3-dihydro-1,4-benzodioxin-6-yl)-1,3-dihydro-2H-indol-2-one was obtained (quantitative) as a pale pink solid: mp 157-160° C. (diethyl ether/hexanes); 1H NMR (300 MHz, DMSO-d6) δ9.19 (br s, 1H), 7.42-7.27 (m, 10H), 6.98-6.91 (m, 3H), 6.88-6.82 (m, 1H), 6.69-6.63 (m, 1H), 6.37 (d, J=7.8 Hz, 1H), 6.30 (s, 1H), 4.81 (s, 1H), 4.21-4.11 (m, 4H); 13C NMR (75 MHz, DMSO-d6) δ176.2, 149.2, 142.8, 142.6, 138.2, 137.8, 135.8, 130.1, 128.6, 128.4, 128.3, 128.2, 127.7, 1275, 126.8, 123.6, 121.7, 118.9, 117.0, 110.6, 103.8, 64.3, 63.8, 57.4, 47.4; MS (ES+) m/z 450.3 (M+1).
Reaction SMILES: [CH3:1][C:2]([CH3:13])([CH3:12])[C@@H:3]([C:5]([O:7][C:8]([CH3:11])([CH3:10])[CH3:9])=[O:6])[NH2:4].C(N(CC)CC)C.[CH3:21][S:22](Cl)(=[O:24])=[O:23]>ClCCl.CN(C)C1C=CN=CC=1>[CH3:1][C:2]([CH3:13])([CH3:12])[C@@H:3]([C:5]([O:7][C:8]([CH3:11])([CH3:10])[CH3:9])=[O:6])[NH:4][S:22]([CH3:21])(=[O:24])=[O:23]
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)(C)OC(=O)[C@@H](N)C(C)(C)C
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)[C@@H](NS(C)(=O)=O)C(C)(C)C
Temperature: 25 °C
Yield: 99.7 %

Procedure:
A solution of tert-butyl 3-methyl-L-valinate (50 mg, 0.223 mmol) in dichloromethane (1 mL) at 0° C. was treated with 4-(dimethylamino)pyridine (5.4 mg, 0.045 mmol), triethylamine (93.4 μL, 0.67 mmol), and methanesulfonyl chloride (34.5 L, 0.45 mmol), and the mixture was warmed to 25° C. for 1 h. The mixture was washed with 5% potassium bisulfate, saturated sodium bicarbonate, brine, and dried over MgSO4, filtered, and the solvents were evaporated to give the crude title compound (59 mg, 100%).
Reaction SMILES: C([N:4]1[CH2:9][CH2:8][N:7]([C:10]2[CH:15]=[CH:14][C:13]([NH:16][S:17]([CH3:20])(=[O:19])=[O:18])=[C:12]([CH3:21])[CH:11]=2)[CH2:6][CH2:5]1)(=O)C.Cl>>[CH3:20][S:17]([NH:16][C:13]1[CH:14]=[CH:15][C:10]([N:7]2[CH2:8][CH2:9][NH:4][CH2:5][CH2:6]2)=[CH:11][C:12]=1[CH3:21])(=[O:18])=[O:19]
Reactant: CC(=O)N1CCN(c2ccc(NS(C)(=O)=O)c(C)c2)CC1
Agent: Cl
Product: Cc1cc(N2CCNCC2)ccc1NS(C)(=O)=O
Yield: 93.2 %

Procedure:
1-Acetyl-4-(4-methanesulphonamido-3-methylphenyl)piperazine (5.93 g) and 2N aqueous hydrochloric acid (85 ml) were refluxed for 2 hours, cooled, evaporated to low bulk, basified with sodium carbonate to pH 9-10 and extracted with 5×100 ml 5% methanol in dichloromethane. The organic layers were combined and evaporated to give the title compound as a brown foam, (4.78 g), m.p. 79°-81°.
Reaction SMILES: Cl.[NH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[N:9]1[CH2:14][CH2:13][O:12][CH2:11][CH2:10]1.[C:15](#[N:19])[CH:16]([CH3:18])[CH3:17]>>[O:12]1[CH2:13][CH2:14][N:9]([C:4]2[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=2[NH:2][C:15](=[NH:19])[CH:16]([CH3:18])[CH3:17])[CH2:10][CH2:11]1
Reactant: Nc1ccccc1N1CCOCC1
Reactant: CC(C)C#N
Agent: Cl
Product: CC(C)C(=N)Nc1ccccc1N1CCOCC1
Temperature: 165 °C

Procedure:
A mixture of 4-(2-aminophenyl)morpholine hydrochloride (10 g) and isobutyronitrile (60 ml) was heated at 165° C. for 26 hours in a sealed stainless steel pressure vessel to yield N-(2-morpholinophenyl)isobutyramidine (m.p. 140°-141° C.) which was recrystallised from hexane.
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]1[CH2:11][CH2:10][CH:9]([CH2:12][CH2:13][C:14]([OH:16])=O)[CH2:8][CH2:7]1)=[O:5])[CH3:2].S(Cl)([Cl:19])=O>ClC(Cl)Cl>[Cl:19][C:14](=[O:16])[CH2:13][CH2:12][CH:9]1[CH2:10][CH2:11][N:6]([C:4]([O:3][CH2:1][CH3:2])=[O:5])[CH2:7][CH2:8]1
Reactant: CCOC(=O)N1CCC(CCC(=O)O)CC1
Reactant: O=S(Cl)Cl
Solvent: ClC(Cl)Cl
Product: CCOC(=O)N1CCC(CCC(=O)Cl)CC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 47 %

Procedure:
To a stirred mixture of 200 parts of 1-(ethoxycarbonyl)-4-piperidinepropanoic acid and 750 parts of trichloromethane were added 320 parts of thionyl chloride. The whole was stirred for 18 hours at room temperature. The reaction mixture was evaporated with methylbenzene. The residue was distilled, yielding 102.6 parts (47%) of ethyl 4-(3-chloro-3-oxopropyl) -1-piperdinecarboxylate; bp. 165-170 at 399 Pa (int. 45).
Reaction SMILES: [C:1]([NH:8][C@H:9]([C:18]([OH:20])=O)[CH2:10][C:11]1[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][CH:12]=1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].Cl.[CH3:22][O:23][C:24](=[O:31])[C@@H:25]([C:27]([SH:30])([CH3:29])[CH3:28])[NH2:26]>>[Cl:17][C:14]1[CH:13]=[CH:12][C:11]([CH2:10][C@@H:9]([C:18]([NH:26][C@@H:25]([C:24]([O:23][CH3:22])=[O:31])[C:27]([SH:30])([CH3:29])[CH3:28])=[O:20])[NH:8][C:1]([O:3][C:4]([CH3:5])([CH3:6])[CH3:7])=[O:2])=[CH:16][CH:15]=1
Reactant: COC(=O)[C@H](N)C(C)(C)S
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccc(Cl)cc1)C(=O)O
Agent: Cl
Product: COC(=O)[C@H](NC(=O)[C@H](Cc1ccc(Cl)cc1)NC(=O)OC(C)(C)C)C(C)(C)S

Procedure:
The title compound was synthesized by coupling Nα -Boc-(p-chloro) phenylalanine (4.96 g, 16.5 mmol) to 3.6 g (18.2 mmol) of D-penicillamine methylester hydrochloride using the procedure described above in Example 19. The title compound was obtained as a white solid (6.2 g, 84.5%).
Reaction SMILES: OC[CH2:3][S:4]([CH2:7][CH2:8][NH:9][C@:10]12[CH2:44][CH2:43][C@@H:42]([C:45]([CH3:47])=[CH2:46])[C@@H:11]1[C@@H:12]1[C@@:25]([CH3:28])([CH2:26][CH2:27]2)[C@@:24]2([CH3:29])[C@@H:15]([C@:16]3([CH3:41])[C@@H:21]([CH2:22][CH2:23]2)[C:20]([CH3:31])([CH3:30])[C:19]([C:32]2[CH:40]=[CH:39][C:35]([C:36]([OH:38])=[O:37])=[CH:34][CH:33]=2)=[CH:18][CH2:17]3)[CH2:14][CH2:13]1)(=[O:6])=[O:5].CS(C=C)(=O)=O>>[CH3:28][C@:25]12[C@@:24]3([CH3:29])[C@@H:15]([C@:16]4([CH3:41])[C@@H:21]([CH2:22][CH2:23]3)[C:20]([CH3:30])([CH3:31])[C:19]([C:32]3[CH:33]=[CH:34][C:35]([C:36]([OH:38])=[O:37])=[CH:39][CH:40]=3)=[CH:18][CH2:17]4)[CH2:14][CH2:13][C@@H:12]1[C@H:11]1[C@H:42]([C:45]([CH3:47])=[CH2:46])[CH2:43][CH2:44][C@:10]1([NH:9][CH2:8][CH2:7][S:4]([CH3:3])(=[O:6])=[O:5])[CH2:27][CH2:26]2
Reactant: C=C(C)[C@@H]1CC[C@]2(NCCS(=O)(=O)CCO)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(c6ccc(C(=O)O)cc6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Agent: C=CS(C)(=O)=O
Product: C=C(C)[C@@H]1CC[C@]2(NCCS(C)(=O)=O)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(c6ccc(C(=O)O)cc6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12

Procedure:
The title compound was prepared following the method described above for the synthesis of 4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-(2-(2-hydroxyethylsulfonyl)ethylamino)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoic acid using methylsulfonylethene instead of vinylsulfonylethene in Step 1. The product was isolated as a white solid (6 mg, 39%). LCMS: m/e 636.37 (M+H)+, 2.53 min (method 10). 1H NMR (500 MHz, Acetic acid d4) δ ppm 8.04 (d, J=8.24 Hz, 2H), 7.30 (d, J=8.24 Hz, 2H), 5.44-5.33 (m, 1H), 4.88 (s, 1H), 4.76 (s, 1H), 4.17-4.00 (m, 1H), 3.93-3.69 (m, 3H), 3.22 (s, 3H), 3.00-2.85 (m, 1H), 2.40-1.26 (m, 22H), 1.77 (s, 3H), 1.23 (s, 3H), 1.14 (s, 3H), 1.10 (s, 3H), 1.02 (s, 3H), 1.00 (s, 3H).
Reaction SMILES: [CH:1]1([N:6]2[C:10]3[N:11]=[C:12]([NH:15][C:16]4[CH:24]=[CH:23][C:19]([C:20]([OH:22])=O)=[CH:18][N:17]=4)[N:13]=[CH:14][C:9]=3[CH:8]=[C:7]2[C:25](=[O:29])[N:26]([CH3:28])[CH3:27])[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH2:30]1[CH:34]2[CH2:35][NH:36][CH2:37][CH:33]2[CH2:32][N:31]1[C:38]([O:40][C:41]([CH3:44])([CH3:43])[CH3:42])=[O:39]>>[CH:1]1([N:6]2[C:10]3[N:11]=[C:12]([NH:15][C:16]4[CH:24]=[CH:23][C:19]([C:20]([N:36]5[CH2:35][CH:34]6[CH2:30][N:31]([C:38]([O:40][C:41]([CH3:44])([CH3:43])[CH3:42])=[O:39])[CH2:32][CH:33]6[CH2:37]5)=[O:22])=[CH:18][N:17]=4)[N:13]=[CH:14][C:9]=3[CH:8]=[C:7]2[C:25](=[O:29])[N:26]([CH3:27])[CH3:28])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CN(C)C(=O)c1cc2cnc(Nc3ccc(C(=O)O)cn3)nc2n1C1CCCC1
Reactant: CC(C)(C)OC(=O)N1CC2CNCC2C1
Product: CN(C)C(=O)c1cc2cnc(Nc3ccc(C(=O)N4CC5CN(C(=O)OC(C)(C)C)CC5C4)cn3)nc2n1C1CCCC1
Yield: 63 %

Procedure:
The 6-(7-cyclopentyl-6-(dimethylcarbamoyl)-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino)nicotinic acid was combined with tert-butyl hexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate following amide formation method 3 which gave tert-butyl 5-(6-(7-cyclopentyl-6-(dimethylcarbamoyl)-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino)nicotinoyl)hexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate (45 mg) in 63% yield. HR-MS (m/z MH+) 589.33 RT 4.31 min