Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([C:3]1([CH3:17])[O:9][CH2:8][C:7]2[CH:10]=[CH:11][CH:12]=[CH:13][C:6]=2[N:5]2[CH:14]=[CH:15][CH:16]=[C:4]12)=O.Cl.[NH:19]1[CH2:24][CH2:23][CH:22]([N:25]2[CH2:29][CH2:28][NH:27][C:26]2=[O:30])[CH2:21][CH2:20]1.C([BH3-])#N.[Na+]>CO>[CH3:17][C:3]1([CH2:1][N:19]2[CH2:20][CH2:21][CH:22]([N:25]3[CH2:29][CH2:28][NH:27][C:26]3=[O:30])[CH2:23][CH2:24]2)[O:9][CH2:8][C:7]2[CH:10]=[CH:11][CH:12]=[CH:13][C:6]=2[N:5]2[CH:14]=[CH:15][CH:16]=[C:4]12
Reactant: CC1(C=O)OCc2ccccc2-n2cccc21
Reactant: O=C1NCCN1C1CCNCC1
Agent: Cl
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Product: CC1(CN2CCC(N3CCNC3=O)CC2)OCc2ccccc2-n2cccc21
Temperature: 25 °C
Reaction time: 192 h

Procedure:
To a solution of 4.5 g of 4-formyl-4-methyl-4H,6H-pyrrolo[1,2-a][4,1]benzoxazepine in 50 ml of methanol is added 3.6 ml of 5.5N methanolic HCl and 3.4 g of 1,3,4,5-tetrahydro-1-(4-piperidinyl)-2H-imidazol-2-one followed by 900 mg of sodium cyanoborohydride. The reaction mixture is allowed to stir at room temperature for 8 days. 2 ml of conc. HCl is added to the reaction mixture and the solvent is removed by evaporation under reduced pressure. The residue is dissolved in 150 ml water and washed with 150 ml of 1:1 ethyl acetate-ether mixture. The aqueous phase is separated, basified with dilute sodium hydroxide to pH 9 and extracted with 2×150 ml of ethyl acetate. The combined ethyl acetate extracts are dried over anhydrous MgSO4, filtered, and the solvent is removed by evaporation under reduced pressure to yield 1,3,4,5-tetrahydro-1-{1-[(4-methyl-4H,6H-pyrrolo[ 1,2-a][4,1]benzoxazepin-4-yl)-methyl]-4-piperidinyl}-2H-imidazol-2-one which is characterized as its maleate salt, m.p. 197°-199°.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([N:9]2[CH2:13][CH:12]([CH2:14]OS(C)(=O)=O)[O:11][C:10]2=[O:20])=[CH:5][CH:4]=1)#[N:2].[NH:21]1[CH2:26][CH2:25][CH:24]([C:27]([O:29][CH2:30][CH3:31])=[O:28])[CH2:23][CH2:22]1.C(=O)([O-])[O-].[K+].[K+].[I-].[K+]>C(#N)C>[C:1]([C:3]1[CH:4]=[CH:5][C:6]([N:9]2[CH2:13][CH:12]([CH2:14][N:21]3[CH2:26][CH2:25][CH:24]([C:27]([O:29][CH2:30][CH3:31])=[O:28])[CH2:23][CH2:22]3)[O:11][C:10]2=[O:20])=[CH:7][CH:8]=1)#[N:2]
Reactant: CS(=O)(=O)OCC1CN(c2ccc(C#N)cc2)C(=O)O1
Reactant: CCOC(=O)C1CCNCC1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CC#N
Product: CCOC(=O)C1CCN(CC2CN(c3ccc(C#N)cc3)C(=O)O2)CC1
Reaction time: 25 h

Procedure:
A mixture of 2.96 g of 3-(4-cyanophenyl)-5-methanesulfonyloxymethyl-2-oxazolidinone (m.p. 162°-163°; obtainable by reacting 4-aminobenzonitrile with 2,3-epoxypropanol to give 4-(2,3-dihydroxypropylamino)benzonitrile (oily), reacting with diethyl carbonate/potassium tert-butylate at 110° to give 3-(4-cyanophenyl)-5-hydroxymemthyl-2-oxazolidinone (m.p. 130°-131°) and esterifying with methanesulfonyl chloride), 1.69 g of ethyl piperidine-4-carboxylate, 70 ml of acetonitrile, 1.38 g of potassium carbonate and 1.65 g of potassium iodide is boiled for 25 h. After customary working up, ethyl 1-(3-(4-cyanophenyl)-2-oxo-5-oxazolidinylmethyl)piperidine-4-carboxylate ("IA") is obtained, FAB 358.
Reaction SMILES: Cl.[NH2:2][N:3]=[CH:4][C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:12](=[O:18])[CH2:13][CH2:14][C:15]([OH:17])=O)=[CH:7][CH:6]=1.CN1CCOCC1.ClC(OCC(C)C)=O.[CH2:34]([O:36][C:37](=[O:48])[CH2:38][CH:39]([NH2:47])[CH2:40][CH2:41][C:42]([O:44][CH2:45][CH3:46])=[O:43])[CH3:35].CN(C1C=CC=CN=1)C>CN(C=O)C>[CH2:34]([O:36][C:37](=[O:48])[CH2:38][CH:39]([NH:47][C:15](=[O:17])[CH2:14][CH2:13][C:12]([NH:11][C:8]1[CH:7]=[CH:6][C:5]([CH:4]=[N:3][NH2:2])=[CH:10][CH:9]=1)=[O:18])[CH2:40][CH2:41][C:42]([O:44][CH2:45][CH3:46])=[O:43])[CH3:35]
Reactant: CCOC(=O)CCC(N)CC(=O)OCC
Reactant: NN=Cc1ccc(NC(=O)CCC(=O)O)cc1
Agent: CC(C)COC(=O)Cl
Agent: CN(C)c1ccccn1
Agent: Cl
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Product: CCOC(=O)CCC(CC(=O)OCC)NC(=O)CCC(=O)Nc1ccc(C=NN)cc1
Reaction time: 0.08 h
Yield: 37.5 %

Procedure:
4-[[4-(Aminoiminomethyl)phenyl]-amino]-4-oxobutanoic acid hydrochloride prepared in Example 1, Step 1 (5.0 g, 18.5 mmol) was added to dry DMF (250 ml) followed by N-methylmorpholine (1.8 g, 18.5 mmol) and isobutyl chloroformate (2.7 g, 17 mmol) at 25° C. The mixture was stirred for 5 min. Diethyl-3-aminoadipate (4.0 g, 18.5 retool) was added followed by dimethylaminopyridine. After 1 hour, the solvent was removed under reduced pressure and the product purified by reverse phase chromatography (0.05% TFA water/acetonitrile) to result in 3.0 g of a white solid: 1HNMR (d6 -DMSO) δ1.14 (t, 6H, J=7 Hz), 1.55 (m, 1H), 1.7 (m, 1H), 2.3 (m, 2H), 2.57 (m, 2H), 2.67 (m, 2H), 4.02 (q, 4H, J=7 Hz), 4.03 (m, 1H), 7.79 (s, 4H), 7.99 (d, 1, J=8.1 Hz), 9.06 (bs, 2H), 9.15 (bs, 2H), 10.22 (s, 1H); MS (FAB) m/z 435.2 (MH+).
Reaction SMILES: [CH2:1]([NH:8][C:9]1[C:17]([S:18](=[O:21])(=[O:20])[NH2:19])=[CH:16][C:12]([C:13]([OH:15])=[O:14])=[CH:11][C:10]=1[N+:22]([O-])=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.N(C1C(S(=O)(=O)N)=CC(C(O)=O)=CC=1[N+]([O-])=O)C1C=CC=CC=1>>[NH2:22][C:10]1[CH:11]=[C:12]([CH:16]=[C:17]([S:18](=[O:21])(=[O:20])[NH2:19])[C:9]=1[NH:8][CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[C:13]([OH:15])=[O:14]
Reactant: NS(=O)(=O)c1cc(C(=O)O)cc([N+](=O)[O-])c1NCc1ccccc1
Agent: NS(=O)(=O)c1cc(C(=O)O)cc([N+](=O)[O-])c1Nc1ccccc1
Product: Nc1cc(C(=O)O)cc(S(N)(=O)=O)c1NCc1ccccc1

Procedure:
By substituting 4-benzylamino-3-nitro-5-sulphamyl-benzoic acid for the 4-anilino-3-nitro-5-sulphamyl-benzoic acid of Example 9 B, the above compound was obtained with a melting point of 218°-219° C after recrystallization from aqueous methanol.
Reaction SMILES: [OH-:1].[Li+].[C:3]([O:7][C:8]([NH:10][C@H:11]([CH:32]1[CH2:36][C@@H:35]([CH3:37])[C:34](=[O:38])[O:33]1)[CH2:12][C@@H:13]([CH:29]([CH3:31])[CH3:30])[CH2:14][C:15]1[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[C:17]([O:23][CH2:24][CH2:25][CH2:26][O:27][CH3:28])[CH:16]=1)=[O:9])([CH3:6])([CH3:5])[CH3:4]>COCCOC.O>[C:3]([O:7][C:8]([NH:10][C@@H:11]([CH2:12][C@@H:13]([CH:29]([CH3:31])[CH3:30])[CH2:14][C:15]1[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[C:17]([O:23][CH2:24][CH2:25][CH2:26][O:27][CH3:28])[CH:16]=1)[C@@H:32]([OH:1])[CH2:36][C@@H:35]([CH3:37])[C:34]([OH:33])=[O:38])=[O:9])([CH3:5])([CH3:6])[CH3:4]
Reactant: COCCCOc1cc(C[C@@H](C[C@H](NC(=O)OC(C)(C)C)C2C[C@@H](C)C(=O)O2)C(C)C)ccc1OC
Reactant: [OH-]
Agent: [Li+]
Solvent: COCCOC
Solvent: O
Product: COCCCOc1cc(C[C@@H](C[C@H](NC(=O)OC(C)(C)C)[C@@H](O)C[C@@H](C)C(=O)O)C(C)C)ccc1OC
Temperature: 25 °C
Reaction time: 1 h

Procedure:
28.5 ml of 1N lithium hydroxide solution are added to 3.6 g of 2-{1(S)-tert-butoxycarbonylamino-3(S)-isopropyl-4-[4-methoxy-3-(3-methoxy-propyloxy)-phenyl]-butyl}-4(R)-methyl-tetrahydrofuran-5-one in 210 ml of 1,2-dimethoxyethane/water (2:1) at room temperature. The reaction mixture is stirred at room temperature for a further 1 hour and then concentrated by evaporation. Ice and 10% aqueous citric acid solution are added to the residue. Repeated extraction with chloroform yields the crude title compound: Rf (ethyl acetate/hexane=1:1)=0.05; HPLC Rt =16.41 minutes.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([OH:11])=O)=[C:4]([CH3:12])[CH:3]=1.[K+].[CH3:14][O:15][C:16](=[O:21])[CH2:17]C([O-])=O>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9](=[O:11])[CH2:17][C:16]([O:15][CH3:14])=[O:21])=[C:4]([CH3:12])[CH:3]=1
Reactant: COC(=O)CC(=O)[O-]
Reactant: Cc1cc(F)ccc1CC(=O)O
Agent: [K+]
Product: COC(=O)CC(=O)Cc1ccc(F)cc1C
Yield: 78 %

Procedure:
The title compound was prepared in 78% yield from 2-(4-fluoro-2-methylphenyl)acetic acid and 3-methoxy-3-oxopropanoic acid potassium salt according to the procedure for the preparation of Example 170, part A. 1H NMR (300 MHz, CDCl3): δ 2.24 (3H, s), 3.47 (2H, s), 3.74 (3H, s), 3.83 (2H, s), 6.88-6.94 (2H, m), 7.07-7.12 (1H, m).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]2[C:8]([CH:11]3[CH2:16][CH2:15][N:14]([CH3:17])[CH2:13][CH2:12]3)=[CH:9][NH:10][C:5]2=[CH:4][CH:3]=1.[F:18][C:19]1[CH:27]=[CH:26][CH:25]=[CH:24][C:20]=1[C:21](Cl)=[O:22]>>[F:18][C:19]1[CH:27]=[CH:26][CH:25]=[CH:24][C:20]=1[C:21]([NH:1][C:2]1[N:7]=[C:6]2[C:8]([CH:11]3[CH2:16][CH2:15][N:14]([CH3:17])[CH2:13][CH2:12]3)=[CH:9][NH:10][C:5]2=[CH:4][CH:3]=1)=[O:22]
Reactant: CN1CCC(c2c[nH]c3ccc(N)nc23)CC1
Reactant: O=C(Cl)c1ccccc1F
Product: CN1CCC(c2c[nH]c3ccc(NC(=O)c4ccccc4F)nc23)CC1
Yield: 81.5 %

Procedure:
Beginning with 0.085 gm (0.369 mMol) 5-amino-3-(1-methylpiperidin-4-yl)pyrrolo[3,2-b]pyridine and 0.093 mL (0.776 mMol) 2-fluorobenzoyl chloride, 0.106 gm (82%) of the title compound was recovered as a crystalline solid by the procedure described in Example 16.
Reaction SMILES: C1COC2C=CC(NC3C(F)=CN=C(NC4C=CC=C(O)C=4)N=3)=CC=2O1.[S:27]1[C:31]2[CH:32]=[CH:33][CH:34]=[CH:35][C:30]=2[C:29]([CH2:36][NH2:37])=[CH:28]1.[Cl:38][C:39]1[N:44]=[C:43](Cl)[C:42]([F:46])=[CH:41][N:40]=1>>[S:27]1[C:31]2[CH:32]=[CH:33][CH:34]=[CH:35][C:30]=2[C:29]([CH2:36][NH:37][C:41]2[C:42]([F:46])=[CH:43][N:44]=[C:39]([Cl:38])[N:40]=2)=[CH:28]1
Reactant: Fc1cnc(Cl)nc1Cl
Reactant: NCc1csc2ccccc12
Agent: Oc1cccc(Nc2ncc(F)c(Nc3ccc4c(c3)OCCO4)n2)c1
Product: Fc1cnc(Cl)nc1NCc1csc2ccccc12

Procedure:
In a manner analogous to the preparation of N4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine, the reaction of benzothiophen-3-ylmethylamine (244 mg, 1.5 mmol) and 2,4-dichloro-5-fluoropyrimidine (50 mg, 0.3 mmol) gave N4-(benzothiophen-3-ylmethyl)-2-chloro-5-fluoro-4-pyrimidineamine. The reaction of N4-(benzothiophen-3-ylmethyl)-2-chloro-5-fluoro-4-pyrimidineamine and 3-aminophenol (200 mg, 1.83 mmol) gave N4-(benzothiophen-3-ylmethyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine. (40 mg, 36%). 1H NMR (CDCl3): δ 4.45 (br, 1H), 4.95 (dd, J=1.2 and 5.4 Hz, 2H), 5.33 (br, 1H), 6.40 (ddd, J=1.2, 2.4 and 8.1 Hz, 1H), 6.85 (ddd, J=0.9, 2.1 and 8.1 Hz, 1H), 6.91 (br, 1H), 7.05 (t, J=8.1 Hz, 1H), 7.26 (m, 1H), 7.39-7.47 (m, 3H), 7.81 (dd, J=1.2 and 5.1 Hz, 1H), 7.84 (d, J=3.3 Hz, 1H), 7.92 (m, 1H); 19F NMR (282 MHz, CDCl3): δ−168.89; LCMS: ret. time: 21.91 min.; purity: 99.34%; MS (m/e): 366.96 (MH+).
Reaction SMILES: C(OC(=O)[NH:7][CH:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15]2[C:24]3[C:19](=[CH:20][CH:21]=[C:22]([C:25]4[CH:30]=[C:29]([Cl:31])[C:28]([OH:32])=[C:27]([Cl:33])[CH:26]=4)[N:23]=3)[N:18]=[CH:17][C:16]=2[C:34](=[O:36])[CH3:35])[CH2:10][CH2:9]1)(C)(C)C.C(O)(C(F)(F)F)=O.C1(N)C(F)=C(F)C(F)=C(N)C=1F.[ClH:57].Cl>>[ClH:31].[ClH:57].[NH2:7][C@H:8]1[CH2:13][CH2:12][C@H:11]([NH:14][C:15]2[C:24]3[C:19](=[CH:20][CH:21]=[C:22]([C:25]4[CH:26]=[C:27]([Cl:33])[C:28]([OH:32])=[C:29]([Cl:31])[CH:30]=4)[N:23]=3)[N:18]=[CH:17][C:16]=2[C:34](=[O:36])[CH3:35])[CH2:10][CH2:9]1
Reactant: CC(=O)c1cnc2ccc(-c3cc(Cl)c(O)c(Cl)c3)nc2c1NC1CCC(NC(=O)OC(C)(C)C)CC1
Agent: Cl
Agent: Nc1c(F)c(N)c(F)c(F)c1F
Solvent: O=C(O)C(F)(F)F
Product: CC(=O)c1cnc2ccc(-c3cc(Cl)c(O)c(Cl)c3)nc2c1N[C@H]1CC[C@H](N)CC1

Procedure:
Following general procedure IV-2, tert-butyl(4-{[3-acetyl-6-(3,5-dichloro-4-hydroxyphenyl)-1,5-naphthyridin-4-yl]amino}cyclohexyl)carbamate (0.23 mmol) was reacted with TFA (2 mL) followed by formation of the dihydrochloride salt to afford the desired product (32 mg, 27% over two steps) as a gray solid: 1H NMR (300 MHz, D2O) δ 8.96 (s, 1H), 8.18-8.00 (m, 2H), 7.53 (s, 2H), 3.28-3.23 (m, 1H), 2.68 (s, 3H), 2.28-2.24 (m, 2H), 2.16-2.13 (m, 2H), 1.76-1.64 (m, 2H), 1.57-1.45 (m, 2H); ESI MS m/z 445 [M+H]+; HPLC 98.4% (AUC), tR=9.34 min.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]2[S:14][C@@H:13]([CH2:15][C:16](OCC)=[O:17])[C@@H:12]([CH3:21])[NH:11][C:10]3[N:22]([CH3:26])[N:23]=[C:24]([CH3:25])[C:9]2=3)=[C:4]([CH3:27])[CH:3]=1.CC(C[AlH]CC(C)C)C.[C@H](O)(C([O-])=O)[C@@H](O)C([O-])=O.[Na+].[K+].[H-].[H-].[H-].[H-].[Li+].[Al+3]>C1COCC1.CCOC(C)=O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]2[S:14][C@@H:13]([CH2:15][CH2:16][OH:17])[C@@H:12]([CH3:21])[NH:11][C:10]3[N:22]([CH3:26])[N:23]=[C:24]([CH3:25])[C:9]2=3)=[C:4]([CH3:27])[CH:3]=1
Reactant: CCOC(=O)C[C@@H]1S[C@@H](c2ccc(Cl)cc2C)c2c(C)nn(C)c2N[C@@H]1C
Agent: CC(C)C[AlH]CC(C)C
Agent: O=C([O-])[C@H](O)[C@@H](O)C(=O)[O-]
Agent: [Al+3]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: Cc1cc(Cl)ccc1[C@@H]1S[C@@H](CCO)[C@@H](C)Nc2c1c(C)nn2C
Temperature: 25 °C
Reaction time: 4 h
Yield: 24.7 %

Procedure:
To a solution of rac-ethyl 2-((4S,6S,7R)-4-(4-chloro-2-methylphenyl)-1,3,7-trimethyl-4,6,7,8-tetrahydro-1H-pyrazolo[3,4-e][1,4]thiazepin-6-yl)acetate (0.39 g, 0.97 mmol) in THF (9 mL) at about 0° C. was added DIBAL-H (2.6 mL, 2.6 mmol). After about 30 min the reaction mixture was warmed to ambient temperature and stirred for about 4 h. To the reaction mixture was added EtOAc (10 mL) and 10% aqueous Rochelle's salt (15 mL) and stirred for about 16 h. The layers were separated and the aqueous layer was back extracted with EtOAc (2×10 mL). The combined organic layers were dried over MgSO4, filtered and concentrated under reduced pressure. The residue was dissolved in THF (9 mL) and cooled to about 0° C. and LAH (1 M solution in Et2O, 1.3 mL, 1.3 mmol) was added dropwise. The ice bath was removed and the reaction was stirred for about 30 min. The reaction was cooled to 0° C. and aqueous NH4Cl (10 mL) was added to the reaction mixture. Ethyl acetate (20 mL) was added and the mixture was stirred at rt for about 1 h. The layers were separated and the aqueous layer was back extracted with EtOAc (10 mL). The combined organic layers were washed with brine (10 mL), dried over MgSO4, filtered and concentrated under reduced pressure. The crude material was purified by column chromatography (SiO2, DCM/MeOH 100:0 to 95:5) to afford rac-2-((4S,6S,7R)-4-(4-chloro-2-methylphenyl)-1,3,7-trimethyl-4,6,7,8-tetrahydro-1H-pyrazolo[3,4-e][1,4]thiazepin-6-yl)ethanol (0.09 g, 0.24 mmol, 18%). LC-MS (Table 1, Method g) Rt=1.98, m/z 366 (M+H)+. 1H-NMR (DMSO-d6, Bruker 400 MHz) δ 7.24 (s, 1H), 7.13-7.08 (m, 2H), 5.55-5.50 (m, 1H), 4.86 (s, 1H), 4.334-4.26 (m, 1H), 3.54 (s, 3H), 3.50-3.42 (m, 1H), 3.42-3.34 (m, 1H), 3.22-3.08 (m, 2H), 2.45 (s, 3H), 1.81 (s, 3H), 1.54-1.42 (m, 1H), 1.38-1.28 (m, 1H), 1.01 (d, J=6.4 Hz, 3H).
Reaction SMILES: C(OC(=O)[NH:7][C@@H:8]([C:42]1([CH3:48])[CH2:47][CH2:46][O:45][CH2:44][CH2:43]1)[C:9]([N:11]1[C@H:22]([C:23](=[O:41])[NH:24][C@:25]2([C:30]([NH:32][S:33]([N:36]3[CH2:40][CH2:39][CH2:38][CH2:37]3)(=[O:35])=[O:34])=[O:31])[CH2:27][C@H:26]2[CH:28]=[CH2:29])[CH2:21][C@:13]2([C:18]([CH3:20])([CH3:19])[C:14]32[CH2:17][CH2:16][CH2:15]3)[CH2:12]1)=[O:10])(C)(C)C.Cl>O1CCOCC1>[N:36]1([S:33]([NH:32][C:30]([C@@:25]2([NH:24][C:23]([C@@H:22]3[CH2:21][C@:13]4([C:18]([CH3:20])([CH3:19])[C:14]54[CH2:15][CH2:16][CH2:17]5)[CH2:12][N:11]3[C:9](=[O:10])[C@@H:8]([NH2:7])[C:42]3([CH3:48])[CH2:43][CH2:44][O:45][CH2:46][CH2:47]3)=[O:41])[CH2:27][C@H:26]2[CH:28]=[CH2:29])=[O:31])(=[O:34])=[O:35])[CH2:40][CH2:39][CH2:38][CH2:37]1
Reactant: C=C[C@@H]1C[C@]1(NC(=O)[C@@H]1C[C@@]2(CN1C(=O)[C@@H](NC(=O)OC(C)(C)C)C1(C)CCOCC1)C(C)(C)C21CCC1)C(=O)NS(=O)(=O)N1CCCC1
Agent: Cl
Solvent: C1COCCO1
Product: C=C[C@@H]1C[C@]1(NC(=O)[C@@H]1C[C@@]2(CN1C(=O)[C@@H](N)C1(C)CCOCC1)C(C)(C)C21CCC1)C(=O)NS(=O)(=O)N1CCCC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of [(S)-2-{(5R,8S)-10,10-Dimethyl-8-[(1R,2S)-1-(pyrrolidine-1-sulfonylaminocarbonyl)-2-vinyl-cyclopropyl-carbamoyl]-7-aza-dispiro[3.0.4.1]dec-7-yl}-1-(4-methyl-tetrahydro-pyran-4-yl)-2-oxo-ethyl]-carbamic acid tert-butyl ester (0.415 g; 0.588 mmol) and 13.0 mL HCl (4 M in dioxane) in 10 mL dioxane was stirred overnight at ambient temperature. The mixture was concentrated under reduced pressure to yield the title compound which was used in the next step without further purification. LC-MS (method E): Rt=1.45 min; M/z=606 [M+]; HPLC (method A3): Rt=4.01 min
Reaction SMILES: [S:1](Cl)(=[O:4])(=[O:3])[NH2:2].C1(C)C=CC=CC=1.[OH:13][C:14]1[CH:19]=[CH:18][C:17]([S:20][CH2:21][CH2:22][CH2:23][N:24]([N:33]2[CH:37]=[N:36][N:35]=[CH:34]2)[C:25]2[CH:32]=[CH:31][C:28]([C:29]#[N:30])=[CH:27][CH:26]=2)=[CH:16][CH:15]=1>O.C(OCC)(=O)C.CN(C)C(=O)C>[C:29]([C:28]1[CH:31]=[CH:32][C:25]([N:24]([N:33]2[CH:37]=[N:36][N:35]=[CH:34]2)[CH2:23][CH2:22][CH2:21][S:20][C:17]2[CH:18]=[CH:19][C:14]([O:13][S:1](=[O:4])(=[O:3])[NH2:2])=[CH:15][CH:16]=2)=[CH:26][CH:27]=1)#[N:30]
Reactant: NS(=O)(=O)Cl
Reactant: N#Cc1ccc(N(CCCSc2ccc(O)cc2)n2cnnc2)cc1
Solvent: CC(=O)N(C)C
Solvent: Cc1ccccc1
Solvent: O
Product: N#Cc1ccc(N(CCCSc2ccc(OS(N)(=O)=O)cc2)n2cnnc2)cc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
Sulphamoyl chloride solution in toluene (3 mL, 0.7 M, 2.1 mmol) was concentrated under reduced pressure (30° C. water bath temperature) to ca. 0.5 mL volume. The residue was cooled to 0° C. (ice bath) and N,N-dimethylacetamide (5 mL) was added. 4-{[3-(4-hydroxy-phenylsulfanyl)-propyl]-[1,2,4]triazol-4-yl-amino}-benzonitrile (CAB02182, 140 mg, 0.40 mmol) was added to the colourless solution and the mixture was stirred for 18 hours at room temperature. Ethyl acetate (50 mL) and water (50 mL) were added to the solution, the organic layer was separated, washed with water (2×30 mL) and brine (20 mL), dried over sodium sulphate and concentrated under reduced pressure. The residue was dissolved in a small amount of acetone and precipitated by addition of hexane. The precipitate was filtered off and dried under high vacuum. Yield: 139 mg (81%) light yellow powder. 1H-NMR (400 MHz, d6-DMSO)=1.74 (tt, J=7.0, 7.0 Hz, 2H), 3.97 (t, J=7.0 Hz, 2H), 6.62 (d, J=9.0 Hz, 2H), 7.22 (d, J=8.6 Hz, 2H), 7.43 (d, J=8.6 Hz, 2H), 7.74 (d, J=9.0 Hz, 2H), 8.03 (s, 2H, —NH2), 9.00 (s, 2H). LRMS (FAB+): 431.1 (100, [M+H]+).
Reaction SMILES: [C:1]1(/[CH:7]=[CH:8]/[C:9]2[C:17]3[C:12](=[CH:13][CH:14]=[C:15]([C:18]#[N:19])[CH:16]=3)[N:11]([CH:20]3[CH2:25][CH2:24][CH2:23][CH2:22][O:21]3)[N:10]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1>C(OCC)(=O)C>[O:21]1[CH2:22][CH2:23][CH2:24][CH2:25][CH:20]1[N:11]1[C:12]2[C:17](=[CH:16][C:15]([C:18]#[N:19])=[CH:14][CH:13]=2)[C:9]([CH2:8][CH2:7][C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)=[N:10]1
Reactant: N#Cc1ccc2c(c1)c(/C=C/c1ccccc1)nn2C1CCCCO1
Solvent: CCOC(C)=O
Product: N#Cc1ccc2c(c1)c(CCc1ccccc1)nn2C1CCCCO1
Reaction time: 5 h
Yield: 42.5 %

Procedure:
3-((1E)-2-Phenylvinyl)-1-perhydro-2H-pyran-2-yl-1H-indazole-5-carbonitrile (0.275 g, 0.83 mmol) was dissolved in ethyl acetate (20 mL). The flask was purged with nitrogen, then hydrogen. To this solution was added palladium on carbon (10 weight %, 14 mg). The mixture was stirred under an atmosphere of hydrogen for 5 hours. The catalyst was filtered and washed with small portions of ethyl acetate (5 mL). The filtrate was concentrated under reduced pressure resulting in the title compound (oil solidified under vacuum) (0.117 g, 84% yield): ES-MS (m/z) 332 [M+1]+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:21]=[CH:20][C:19]([NH:22][C:23]([C:25]2[CH:30]=[CH:29][C:28]([N+:31]([O-])=O)=[CH:27][CH:26]=2)=[O:24])=[CH:18][CH:17]=1>CN(C)C=O.C(OCC)(=O)C.[C].[Pd]>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:17]=[CH:18][C:19]([NH:22][C:23]([C:25]2[CH:30]=[CH:29][C:28]([NH2:31])=[CH:27][CH:26]=2)=[O:24])=[CH:20][CH:21]=1
Reactant: COc1cc2nccc(Oc3ccc(NC(=O)c4ccc([N+](=O)[O-])cc4)cc3)c2cc1OC
Agent: [Pd]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COc1cc2nccc(Oc3ccc(NC(=O)c4ccc(N)cc4)cc3)c2cc1OC
Temperature: 25 °C
Reaction time: 22 h
Yield: 91.1 %

Procedure:
{4-[(6,7-Dimethoxy-4-quinolinyl)oxy]phenyl}-(4-nitrophenyl)carboxamide (100 mg) was dissolved in N,N-dimethylformamide/ethyl acetate (9 ml/5 ml), 10% palladium-carbon (69 mg) was added, and the admixture was stirred at room temperature under hydrogen for 22 hours. The reaction mixture was filtered using Celite. The filtrate was then distilled under reduced pressure to remove the solvents, and the resultant residue was purified by column chromatography on silica gel eluting chloroform/acetone to obtain 85 mg of the title compound (yield: 91%).
Reaction SMILES: [CH2:1]([C:5]1[N:9]([CH2:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[C:23]3[NH:27][N:26]=[N:25][N:24]=3)=[CH:13][CH:12]=2)[C:8]2[C:28]([C:33]([O:35]CC)=[O:34])=[C:29]([CH3:32])[CH:30]=[CH:31][C:7]=2[N:6]=1)[CH2:2][CH2:3][CH3:4]>[OH-].[Na+].C(O)C>[CH2:1]([C:5]1[N:9]([CH2:10][C:11]2[CH:12]=[CH:13][C:14]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[C:23]3[NH:27][N:26]=[N:25][N:24]=3)=[CH:15][CH:16]=2)[C:8]2[C:28]([C:33]([OH:35])=[O:34])=[C:29]([CH3:32])[CH:30]=[CH:31][C:7]=2[N:6]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1nc2ccc(C)c(C(=O)OCC)c2n1Cc1ccc(-c2ccccc2-c2nnn[nH]2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CCCCc1nc2ccc(C)c(C(=O)O)c2n1Cc1ccc(-c2ccccc2-c2nnn[nH]2)cc1
Yield: 42.4 %

Procedure:
A mixture of ethyl 2-butyl-6-methyl-1-[[2'-(1H-tetrazol-5-yl)biphenyl-4-yl]methyl]benzimidazole-7-carboxylate (0.55 g) in 5N aqueous sodium hydroxide (5 ml) and ethanol (10 ml) was heated for 100 hours under reflux. The reaction mixture was concentrated to dryness and then was dissolved in water, and the solution was made acidic with conc. HCl. Precipitates separated out were collected by filtration and washed with a mixture of dichloromethane and methanol. The precipitates were dissolved in saturated aqueous sodium bicarbonate. After removal of insoluble materials by filtration, the filtrate was made acidic with conc. HCl. Precipitates then separated out were collected by filtration and crystallized from dimethylformamide --H2O to afford colorless crystals (0.22 g, 42%), m.p. 298-299° C.
Reaction SMILES: [CH2:1]1[CH:3]([C:4]([NH2:6])=[NH:5])[CH2:2]1.Cl.[CH2:8]([O:10][C:11](=[O:19])[C:12](=O)/[CH:13]=[CH:14]/OCC)[CH3:9].[O-]CC.[Na+]>C(O)C>[CH2:8]([O:10][C:11]([C:12]1[CH:13]=[CH:14][N:6]=[C:4]([CH:3]2[CH2:2][CH2:1]2)[N:5]=1)=[O:19])[CH3:9]
Reactant: N=C(N)C1CC1
Reactant: CCO/C=C/C(=O)C(=O)OCC
Agent: CC[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: CCOC(=O)c1ccnc(C2CC2)n1
Yield: 45.9 %

Procedure:
Reference: Riley, T. A.; Hennen, W. J.; Dalley, N. K.; Wilson, B. E.; J. Heterocyclic Chem., 1987, 24, 955-964. Heat a mixture of cyclopropylcarbamidine hydrochloride (2.05 g, 17 mmol), (E)-4-ethoxy-2-oxo-but-3-enoic acid ethyl ester (4.39 g, 25.5 mmol), ethanol (12 mL), and sodium ethoxide (1.16 g, 17 mmol) in a microwave at 140° C. for 20 min. Concentrate the reaction mixture under reduced pressure and partition the residue between ethyl acetate and brine. Separate the organic layer and concentrate under reduced pressure. Purify the residue by silica gel chromatography (10-30% ethyl acetate/hexane) to give 2-cyclopropyl-pyrimidine-4-carboxylic acid ethyl ester (1.5 g, 46%) as light yellow oil. MS (m/z): 193.0 (M+H)+.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH:7]([OH:9])[CH3:8].[H-].[Na+].[CH3:12]I>CS(C)=O>[CH3:12][O:9][CH:7]([C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=1)[CH3:8]
Reactant: CI
Reactant: CC(O)c1ccccn1
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Product: COC(C)c1ccccn1
Temperature: 20 °C
Reaction time: 2 h

Procedure:
To a stirred solution of 223 g. of 1-(2-pyridyl)-ethanol in 1500 ml. of dry dimethylsulfoxide is added 2.3 moles of sodium hydride in portions, under nitrogen, maintaining the temperature of 20° C. After two hours, 331 g. of methyl iodide is added at 20° C. After stirring for another three hours, the mixture is poured onto ice-water and extracted three times with ether. The organic phase is washed with water, dried over magnesium sulfate, concentrated in vacuo, and the residue is distilled to give 2-(1-methoxyethyl)pyridine.