Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[C:15](=[O:20])[NH:16][CH:17]=[CH:18][N:19]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CC([O-])(C)C.[K+].[F:27][C:28]1[CH:42]=[C:41]([F:43])[C:40]([F:44])=[CH:39][C:29]=1[O:30][CH2:31][CH2:32][CH2:33]OS(C)(=O)=O.O>C1COCC1>[F:27][C:28]1[CH:42]=[C:41]([F:43])[C:40]([F:44])=[CH:39][C:29]=1[O:30][CH2:31][CH2:32][CH2:33][N:16]1[CH:17]=[CH:18][N:19]=[C:14]([N:11]2[CH2:10][CH2:9][N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])[CH2:13][CH2:12]2)[C:15]1=[O:20]
Reactant: CC(C)(C)OC(=O)N1CCN(c2ncc[nH]c2=O)CC1
Reactant: CS(=O)(=O)OCCCOc1cc(F)c(F)cc1F
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCN(c2nccn(CCCOc3cc(F)c(F)cc3F)c2=O)CC1
Reaction time: 0.17 h

Procedure:
A mixture of 3-(4-tert-butoxycarbonyl-1-piperazinyl)-2(1H)-pyrazinone (0.83 g, 3.0 mmol; from Example 48, Step 1) and t-BuOK (497 mg, 4.4 mmol) in THF (5 mL) was stirred for 10 min, and then added to methanesulfonic acid 3-(2,4,5-trifluoro-phenoxy)-propyl ester (0.80 g, 3.0 mmol; from Step 2) in THF (50 mL). After being stirred at room temperature for 1 day, HPLC showed about 20% conversion. After 6 days, the reaction was worked up: water was added, THF was evaporated and the aqueous mixture was extracted twice with EtOAc, dried and concentrated to yield 1.33 g of the crude product as a yellow oil. HPLC analysis showed a 1/1 ratio between the title product and the isomeric O-alkylated product. Purification by chromatography on silica gel using EtOAc/hexane (1/3 to 1/1.7) as eluent gave 427 mg (30%) of the title product as a colorless oil. HPLC purity: 96%. MS m/z 469 (M+H)+.
Reaction SMILES: Cl.Cl.[NH2:3][CH2:4][C:5]1[C:14]([O:15][C@@H:16]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH2:17][N:18]2[CH:22]=[CH:21][N:20]=[CH:19]2)=[CH:13][CH:12]=[C:11]2[C:6]=1[CH2:7][CH2:8][CH2:9][C:10]2=[O:29].[C:30]1([S:36](Cl)(=[O:38])=[O:37])[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1>N1C=CC=CC=1.CN(C1C=CN=CC=1)C>[N:18]1([CH2:17][C@H:16]([C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)[O:15][C:14]2[CH:13]=[CH:12][C:11]3[C:10](=[O:29])[CH2:9][CH2:8][CH2:7][C:6]=3[C:5]=2[CH2:4][NH:3][S:36]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)(=[O:38])=[O:37])[CH:22]=[CH:21][N:20]=[CH:19]1
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: NCc1c(O[C@H](Cn2ccnc2)c2ccccc2)ccc2c1CCCC2=O
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: c1ccncc1
Product: O=C1CCCc2c1ccc(O[C@H](Cn1ccnc1)c1ccccc1)c2CNS(=O)(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 66.7 %

Procedure:
5-Aminomethyl-6-((S)-2-imidazol-1-yl-1-phenyl-ethoxy)-3,4-dihydro-2H-naphthalen-1-one bis-hydrochloride (74 mg, 0.171 mmol) was dissolved in pyridine (1 mL) and catalytic DMAP (2 mg) was added followed by benzenesulfonyl chloride (26 μL, 0.205 mmol, 1.2 equiv). The reaction was stirred overnight at RT. The mixture was concentrated and the residue was dissolved in CH2Cl2. The organics were washed with H2O and brine, dried over MgSO4 and concentrated to give a tan foam. Purification by chromatography (5% MeOH/EtOAc with 1% NH4OH) afforded the title compound as a white foam (57 mg, 0.114 mmol, 67%). The structure was confirmed by NMR and mass spectrometry. MS m/z 502 (M++H).
Reaction SMILES: [NH:1]([C:13]([O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[O:14])[C@H:2]([C:10]([OH:12])=O)[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[NH:23]([CH3:48])[C@H:24]([C:28]([N:30]([CH3:47])[C@H:31]([C:44]([NH2:46])=[O:45])[CH2:32][C:33]1[CH:38]=[CH:37][C:36]([OH:39])=[C:35]([C:40]([CH3:43])([CH3:42])[CH3:41])[CH:34]=1)=[O:29])[CH:25]([CH3:27])[CH3:26].O.C(OCC)(=O)C>C1COCC1.ClC(OCC(C)C)=O.CN1CCOCC1>[NH:1]([C:13]([O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[O:14])[C@H:2]([C:10]([N:23]([CH3:48])[C@H:24]([C:28]([N:30]([CH3:47])[C@H:31]([C:44]([NH2:46])=[O:45])[CH2:32][C:33]1[CH:38]=[CH:37][C:36]([OH:39])=[C:35]([C:40]([CH3:43])([CH3:41])[CH3:42])[CH:34]=1)=[O:29])[CH:25]([CH3:27])[CH3:26])=[O:12])[CH2:3][C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: CN[C@H](C(=O)N(C)[C@@H](Cc1ccc(O)c(C(C)(C)C)c1)C(N)=O)C(C)C
Reactant: O=C(N[C@@H](Cc1ccccc1)C(=O)O)OCc1ccccc1
Agent: CC(C)COC(=O)Cl
Solvent: O
Solvent: CN1CCOCC1
Solvent: CCOC(C)=O
Product: CC(C)[C@@H](C(=O)N(C)[C@@H](Cc1ccc(O)c(C(C)(C)C)c1)C(N)=O)N(C)C(=O)[C@H](Cc1ccccc1)NC(=O)OCc1ccccc1
Reaction time: 0.25 h

Procedure:
To a solution of Z-Phe-OH (742 mg) in THF (3 ml), isobutyl chloroformate (0.32 ml) and NMM (0.27 ml) were added under cooling with ice and the mixture was stirred for 15 minutes. Subsequently, a solution of N-Me-Val-N-Me-Tyr(3-tBu)-NH2 (600 mg) in THF (3 ml) was added and the mixture was stirred at room temperature for 10 hours. Water was added to the reaction mixture and extraction was effected with ethyl acetate. The extract was washed with saturated brine, dried with sodium sulfate, and concentrated under reduced pressure. The resulting residue was subjected to silica gel column chromatography (eluting solvent; n-hexane:acetone=3:2) to give Z-Phe-N-Me-Val-N-Me-Tyr(3-tBu)-NH2 in the amount of 611 mg (58%).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]2[N:9]=[C:10]([NH2:12])[S:11][C:7]=2[C:6]([O:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[CH:5][CH:4]=1.[F:20][C:21]1[CH:29]=[CH:28][C:24]([C:25](Cl)=[O:26])=[CH:23][CH:22]=1>>[F:20][C:21]1[CH:29]=[CH:28][C:24]([C:25]([NH:12][C:10]2[S:11][C:7]3[C:6]([O:13][C:14]4[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=4)=[CH:5][CH:4]=[C:3]([O:2][CH3:1])[C:8]=3[N:9]=2)=[O:26])=[CH:23][CH:22]=1
Reactant: COc1ccc(Oc2ccccc2)c2sc(N)nc12
Reactant: O=C(Cl)c1ccc(F)cc1
Product: COc1ccc(Oc2ccccc2)c2sc(NC(=O)c3ccc(F)cc3)nc12

Procedure:
Using 4-methoxy-7-phenoxy-benzothiazol-2-ylamine and 4-fluoro-benzoyl chloride the title compound was obtained crude, which was chromatographed over SiO2 (Merck 230-400 mesh) eluting with CH2Cl2/EtOAc (1:1), to afford the pure title compound as a white solid (75% yield), MS: m/e=394.1 (M+).
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[CH:4][C:3]=1[O:12][CH3:13].C([Li])(C)(C)C.[CH2:19]([O:26][CH2:27][C@H:28]1[CH2:37][CH2:36][C@:30]2([O:34][CH2:33][C:32](=[O:35])[CH2:31]2)[C@@H:29]1[C:38]1[CH:43]=[CH:42][C:41]([F:44])=[CH:40][CH:39]=1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>C1COCC1>[CH2:19]([O:26][CH2:27][C@H:28]1[CH2:37][CH2:36][C@:30]2([O:34][CH2:33][C@@:32]([OH:35])([C:2]3[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[CH:4][C:3]=3[O:12][CH3:13])[CH2:31]2)[C@@H:29]1[C:38]1[CH:39]=[CH:40][C:41]([F:44])=[CH:42][CH:43]=1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: COc1ccc(C(F)(F)F)cc1Br
Reactant: O=C1CO[C@]2(CC[C@H](COCc3ccccc3)[C@H]2c2ccc(F)cc2)C1
Agent: [Li]C(C)(C)C
Solvent: C1CCOC1
Product: COc1ccc(C(F)(F)F)cc1[C@]1(O)CO[C@]2(CC[C@H](COCc3ccccc3)[C@H]2c2ccc(F)cc2)C1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 51.8 %

Procedure:
2-Bromo-4-(trifluoromethyl)anisole (227 mg, 0.89 mmol), prepared according to the procedure of J. Alexander (Org. Prep. Proced. Int., 1986, 18, 213-215), was dissolved in 3.7 mL of THF and cooled in a -78° C. bath. A solution of t-butyllithium (1.0 mL, 1.7M in hexane, 1.7 mmol) was added over a period of 2 min. After 30 min., a solution of 200 mg (0.56 mmol) of (5R,6S,7S)-7-(benzyloxymethyl)-6-(4-fluorophenyl)-1-oxaspiro[4.4]nonane-3-one (prepared from methyl (5R,6S,7S)-6-(4-fluorophenyl)-3-(methylene)-1-oxaspiro[4.4]nonane-7-carboxylate (from Example 9) by DIBALH reduction, benzylation with sodium hydride and benzyl bromide, and oxidation as described in Example 6, Step C) in 1.0 mL of THF was added, and the reaction was stirred for 45 min. at -78° C. followed by warming to -35° C. over 20 min. The reaction was quenched by the addition of 10 mL of saturated aqueous ammonium chloride and partioned between 30 mL of ethyl acetate and 10 mL of water. The organic layer was washed with 10 mL of saturated aqueous sodium bicarbonate and 10 mL of saturated aqueous sodium chloride, dried over sodium sulfate, decanted, and evaporated. The crude product was purified by flash column chromatography, eluting with 1.5-5% ethyl ether in toluene to give 154 mg of the title compound.
Reaction SMILES: [Cl:1][C:2]1[O:6][N:5]=[C:4]([C:7]([OH:9])=O)[CH:3]=1.O=S(Cl)[Cl:12]>C(Cl)(Cl)Cl>[Cl:1][C:2]1[O:6][N:5]=[C:4]([C:7]([Cl:12])=[O:9])[CH:3]=1
Reactant: O=C(O)c1cc(Cl)on1
Reactant: O=S(Cl)Cl
Solvent: ClC(Cl)Cl
Product: O=C(Cl)c1cc(Cl)on1

Procedure:
To solution of 5-chloroisoxazole-3-carboxylic acid (Example 22, 0.253 g, 1.71 mmol, 2.0 equiv) in CHCl3 (21 mL) was added SOCl2 (9 mL). The reaction mixture was heated to reflux for 26 h. The volatiles were removed under reduced pressure to give crude 5-chloroisoxazole-3-carbonyl chloride.
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[CH2:14][NH:13][CH2:12][CH:11]([C:15]([NH:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[O:16])[CH2:10]2)=[CH:5][CH:4]=1)[CH3:2].[C:24]([O:28][C:29]([NH:31][C:32]1([C:35](O)=[O:36])[CH2:34][CH2:33]1)=[O:30])([CH3:27])([CH3:26])[CH3:25]>>[CH2:1]([C:3]1[CH:4]=[CH:5][C:6]([CH:9]2[CH2:10][CH:11]([C:15](=[O:16])[NH:17][C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=3)[CH2:12][N:13]([C:35]([C:32]3([NH:31][C:29](=[O:30])[O:28][C:24]([CH3:26])([CH3:25])[CH3:27])[CH2:34][CH2:33]3)=[O:36])[CH2:14]2)=[CH:7][CH:8]=1)[CH3:2]
Reactant: CC(C)(C)OC(=O)NC1(C(=O)O)CC1
Reactant: CCc1ccc(C2CNCC(C(=O)Nc3ccccc3)C2)cc1
Product: CCc1ccc(C2CC(C(=O)Nc3ccccc3)CN(C(=O)C3(NC(=O)OC(C)(C)C)CC3)C2)cc1

Procedure:
169 mg (0.50 mmol) of 5-(4-ethylphenyl)-N-phenylpiperidine-3-carboxamide (Example 17A) and 111 mg (0.55 mmol, 1.1 eq.) of 1-[(tert-butoxycarbonyl)amino]cyclopropanecarboxylic acid were reacted according to General Method 1. Yield: 119 mg (48% of theory)
Reaction SMILES: N[C:2]1[C:3]([N+:14]([O-:16])=[O:15])=[CH:4][C:5]2[O:10][C:9]([CH3:12])([CH3:11])[CH:8]=[CH:7][C:6]=2[CH:13]=1.N([O-])=O.[Na+].O.[BrH:22]>C(O)(=O)C.OS(O)(=O)=O>[Br:22][C:2]1[C:3]([N+:14]([O-:16])=[O:15])=[CH:4][C:5]2[O:10][C:9]([CH3:12])([CH3:11])[CH:8]=[CH:7][C:6]=2[CH:13]=1
Reactant: Br
Reactant: CC1(C)C=Cc2cc(N)c([N+](=O)[O-])cc2O1
Agent: O=N[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: CC1(C)C=Cc2cc(Br)c([N+](=O)[O-])cc2O1
Reaction time: 0.5 h

Procedure:
A suspension of 6-amino-2,2-dimethyl-7-nitro-2H-1-benzopyran (5.0 g, the preparation of which was described in J. Med. Chem., 26, 1582 (1983)) in glacial acetic acid (19 mL) was added dropwise to a stirred solution of sodium nitrite (1.6 g) in conc. H2SO4 (19 mL) while maintaining the temperature below 10° C. After an additional 0.5 h, the dark brown solution was added to a stirred solution of CuBr (6.5 g) in 47% HBr (53 mL). After 1 h, water was added to the solution and it was extracted with ethyl acetate. The organic extract was washed with water, saturated sodium bicarbonate solution, and dried over anh. MgSO4. The organic layer was filtered, evaporated, and chromatographed on silica gel. Elution with 3% ethyl acetate--60°-80° C. petroleum ether gave the compound of description 1 as a crude solid (3.5 g). Mass spectrum (E.I.) M+ at m/z 282.9848. Calcd. for C11H10NO3Br: 282.9845.
Reaction SMILES: Cl.[CH3:2][NH:3][OH:4].CO[Na].[C:8]([C:10]1[CH:11]=[C:12]([C:16]2[CH:17]=[C:18]3[C:23](=[CH:24][CH:25]=2)[O:22][CH:21]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][N:27]=2)[CH2:20]/[C:19]/3=[N:32]/[C:33]#[N:34])[CH:13]=[CH:14][CH:15]=1)#[N:9]>CO>[NH2:34][C:33]1[N:3]([CH3:2])[O:4][C:19]2([C:18]3[C:23](=[CH:24][CH:25]=[C:16]([C:12]4[CH:11]=[C:10]([CH:15]=[CH:14][CH:13]=4)[C:8]#[N:9])[CH:17]=3)[O:22][CH:21]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][N:27]=3)[CH2:20]2)[N:32]=1
Reactant: CNO
Reactant: N#C/N=C1/CC(c2ccccn2)Oc2ccc(-c3cccc(C#N)c3)cc21
Agent: CO[Na]
Agent: Cl
Solvent: CO
Product: CN1OC2(CC(c3ccccn3)Oc3ccc(-c4cccc(C#N)c4)cc32)N=C1N
Reaction time: 0.17 h
Yield: 7.7 %

Procedure:
To a solution of N-methyl-hydroxylamine hydrochloride (14 mg, 0.14 mmol) in MeOH (4 mL) was added MeONa (0.03 mL, 25% (Wt.) in MeOH), followed (Z)—N-(6-(3-cyanophenyl)-2-(pyridin-2-yl)chroman-4-ylidene)cyanamide (50 mg, crude). After stirring for 10 minutes, the solvent was removed in vacuo to give a residue. The residue was purified by preparative TLC to give 3-(3′-amino-2′-methyl-2-(pyridin-2-yl)-2′H-spiro[chroman-4,5′-[1,2,4]oxadiazole]-6-yl)benzonitrile (4.3 mg, 8%). 1H-NMR (MeOD): 2.11 (m, 1H), 2.51 (m, 1H), 3.02 (s, 2H), 3.28 (s, 1H), 4.12 (m, 1H), 5.32 (m, 1H), 6.97 (m, 1H), 7.32 (m, 1H), 7.55 (m, 5H), 7.82 (m, 3H), 8.46 (m, 1H).
Reaction SMILES: [CH3:1][O:2][C:3]([CH:5]1[CH2:9][CH:8]([OH:10])[CH:7]([C:11]#[N:12])[CH2:6]1)=[O:4].[CH3:13]I>C1COCC1>[CH3:1][O:2][C:3]([CH:5]1[CH2:9][CH:8]([O:10][CH3:13])[CH:7]([C:11]#[N:12])[CH2:6]1)=[O:4]
Reactant: COC(=O)C1CC(O)C(C#N)C1
Reactant: CI
Solvent: C1CCOC1
Product: COC(=O)C1CC(C#N)C(OC)C1
Temperature: 60 °C
Reaction time: 8 h

Procedure:
A solution of (1SR,3RS,4SR)-3-cyano-4-hydroxy-cyclopentanecarboxylic acid methyl ester (878 mg; example 15A) in THF (15 ml) was transferred to a sealed tube and treated with Ag2O (3.6 g) and methyl iodide (3.23 ml) and stirred at 60° C. overnight. The reaction mixture was filtered, and the cake was rinsed with plenty of THF. The filtrate was concentrated. The crude product was purified by column chromatography (silica gel; gradient: cyclohexane→cyclohexane/EtOAc 65:35) to give (1SR,3RS,4SR)-3-cyano-4-methoxy-cyclopentanecarboxylic acid methyl ester (600 mg) as light yellow oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([O:9][CH3:10])[C:4]=1[N+:11]([O-])=O.C([O-])([O-])=O.[Na+].[Na+]>CC(O)=O.CCO.O.[Fe]>[CH3:10][O:9][C:5]1[CH:6]=[CH:7][CH:8]=[C:3]([O:2][CH3:1])[C:4]=1[NH2:11]
Reactant: COc1cccc(OC)c1[N+](=O)[O-]
Agent: [Fe]
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Solvent: CC(=O)O
Product: COc1cccc(OC)c1N
Temperature: 90 °C
Yield: 97.6 %

Procedure:
To a solution of 78 (170 mg, 0.93 mmol) in AcOH (5 mL), EtOH (5 mL) and H2O (2.5 mL) was added iron powder (311 mg, ˜325 mesh, 5.57 mmol) portion wise. The mixture was then heated at 90° C. under N2 overnight. After cooling to room temperature, the mixture was poured onto ice, basified using solid Na2CO3 and extracted with EtOAc (3×). The combined organic layers were washed with brine, dried over Na2SO4 and concentrated in vacuo to yield 79 as a pale yellow solid (139 mg, 98%). MS (APCI): m/z 154 (100%, [M+H]+) which was used in the next step without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]2[NH:8][C:9]3[C:15](=O)[N:14]([CH3:17])[C:13]4[CH:18]=[CH:19][CH:20]=[CH:21][C:12]=4[O:11][C:10]=3[C:5]2=[CH:4][CH:3]=1.P(Cl)(Cl)(Cl)(Cl)Cl.[CH2:28]([NH:30][CH2:31][CH3:32])[CH3:29]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[C:6](=[N:8][C:9]3[C:10]=2[O:11][C:12]2[CH:21]=[CH:20][CH:19]=[CH:18][C:13]=2[N:14]([CH3:17])[C:15]=3[N:30]([CH2:31][CH3:32])[CH2:28][CH3:29])[CH:7]=1
Reactant: CN1C(=O)c2[nH]c3cc(Cl)ccc3c2Oc2ccccc21
Reactant: CCNCC
Agent: ClP(Cl)(Cl)(Cl)Cl
Product: CCN(CC)C1=C2N=c3cc(Cl)ccc3=C2Oc2ccccc2N1C

Procedure:
In the same way as described in example 1, 3-chloro-7-methyl-7H-indolo[3,2-b][1,5]benzoxazepine-6(5H)-one, phosphorous pentachloride and diethylamine were reacted and the solid product recrystallized from methanol for analysis, mp. 127°-8°.
Reaction SMILES: C(OC([N:11]1[CH:17]([CH3:18])[CH2:16][C:15](=[O:19])[NH:14][CH2:13][CH2:12]1)=O)C1C=CC=CC=1>C(O)C.[Pd]>[CH3:18][CH:17]1[NH:11][CH2:12][CH2:13][NH:14][C:15](=[O:19])[CH2:16]1
Reactant: CC1CC(=O)NCCN1C(=O)OCc1ccccc1
Agent: [Pd]
Solvent: CCO
Product: CC1CC(=O)NCCN1
Temperature: 25 °C
Reaction time: 20 h
Yield: 82.1 %

Procedure:
A mixture of 7-methyl-5-oxo-[1,4]diazepane-1-carboxylic acid benzyl ester (201 mg, 0.77 mmol) and palladium (10% on activated charcoal, 80 mg) in ethanol (2 ml) was stirred at room temperature under a hydrogen atmosphere (3 bar). After 20 h, the catalyst was removed by filtration and the filtrate evaporated to afford the title compound (81 mg, 82%). White solid,
Reaction SMILES: [I-:1].[Na+].Cl[CH2:4][CH2:5][CH2:6][Si:7]([O:14][CH2:15][CH3:16])([O:11][CH2:12][CH3:13])[O:8][CH2:9][CH3:10]>CC(C)=O>[I:1][CH2:4][CH2:5][CH2:6][Si:7]([O:14][CH2:15][CH3:16])([O:11][CH2:12][CH3:13])[O:8][CH2:9][CH3:10]
Reactant: [I-]
Reactant: CCO[Si](CCCCl)(OCC)OCC
Agent: [Na+]
Solvent: CC(C)=O
Product: CCO[Si](CCCI)(OCC)OCC
Temperature: 25 °C
Yield: 10 %

Procedure:
Sodium iodide (15 g, 93.325 mmol) was dissolved in acetone and (3-chloropropyl)triethoxysilane (22 mL, 45.63 mmol) was added dropwise. The resultant mixture was shaken at 80° C. for 48 hours in argon. The reaction crude was cooled to room temperature, filtered and the solvent was removed under reduced pressure. A yellowish liquid (28.476 g) containing 90% of iodinated compound and 10% of the chlorinated reagent was obtained. Said liquid was kept for further use without purification.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH2:11][CH2:12][CH2:13]Cl)[N:6]=[CH:5]2.[I-].[K+].C([O-])([O-])=O.[K+].[K+].[NH:23]1[CH2:27][CH2:26][CH2:25][CH2:24]1>CN(C=O)C.CCOC(C)=O>[Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH2:11][CH2:12][CH2:13][N:23]1[CH2:27][CH2:26][CH2:25][CH2:24]1)[N:6]=[CH:5]2
Reactant: ClCCCn1ncc2cc(Br)ccc21
Reactant: C1CCNC1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: Brc1ccc2c(cnn2CCCN2CCCC2)c1
Temperature: 50 °C
Yield: 102.6 %

Procedure:
To a solution of 5-bromo-1-(3-chloropropyl)-1H-indazole (2.14 g, 7.84 mmol) in DMF (40 mL) was added potassium iodide (1.3 mg, 7.8 mmol) and K2CO3 (5.40 g, 39.2 mmol) under N2 (g). Then pyrrolidine (17.2 ml, 26.6 mmol) was added. The reaction was heated to 50° C. for 20 h. The reaction was diluted with EtOAc (100 mL) and washed with a 5% LiCl solution (4×). The organics were dried (Na2SO4), filtered, and concentrated to give the title compound (2.48 g, quant.) as a brown oil: 1H NMR (300 MHz, CDCl3) δ 7.93 (s, 1H), 7.85 (d, J=1.2 Hz, 1H), 7.45-7.41 (dd, J=8.9, 1.7 Hz, 1H), 7.36 (d, J=8.9 Hz, 1H), 4.45 (t, J=6.7 Hz, 1H), 2.44-2.36 (m, 6H), 2.15-2.07 (m, 2H), 1.78-1.74 (m, 4H); ESI MS m/z 308 [M+H]+.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@:9]1([C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH2:11][C@H:10]1[CH:12]=[CH2:13])=[O:7])([CH3:4])([CH3:3])[CH3:2].B1C2CCCC1CCC2.[Na].[OH:29]O>C1COCC1.CCCCCC.CCOC(C)=O.C(O)(=O)C>[C:1]([O:5][C:6]([NH:8][C@:9]1([C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH2:11][C@H:10]1[CH2:12][CH2:13][OH:29])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: OO
Reactant: C=C[C@@H]1C[C@]1(NC(=O)OC(C)(C)C)C(=O)OCC
Agent: B1C2CCCC1CCC2
Agent: [Na]
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Solvent: CCCCCC
Product: CCOC(=O)[C@@]1(NC(=O)OC(C)(C)C)C[C@H]1CCO
Temperature: 25 °C
Reaction time: 2 h
Yield: 70.3 %

Procedure:
To a solution of (1R,2S)-ethyl 1-(tert-butoxycarbonylamino)-2-vinylcyclopropanecarboxylate (15.3 g, 59.9 mmol) in THF (100 ml) was added 9-BBN (180 ml, 90 mmol) dropwise at 0° C. The formed solution was stirred at room temperature for 2 hr. The final solution was cooled back to 0° C. while 3 M acetic acid, sodium salt (180 ml, 540 mmol) was added. To this well stirred mixture, hydrogen peroxide (89 ml, 869 mmol) was added dropwise (Caution should be exercised since the addition was exothermic). The formed warm two layer mixture was stirred overnight. Separated the upper organic layer. The aqueous layer was extracted with EtOAc. The combined organic layers were washed with brine. Dried over MgSO4, filtered, evaporated. The residue was purified by silica gel column, eluted with 4:1, 3:1, 2:1, then 3:2 Hexane-EtOAc to afford the desired product (1R,2S)-ethyl 1-(tert-butoxycarbonylamino)-2-(2-hydroxyethyl)cyclopropanecarboxylate (11.50 g, 42.1 mmol, 70.2% yield) as a viscous oil, which solidified upon standing on the bench. 1H NMR (CDCl3) δ 1.18-1.21 (m, 1H), 1.25 (t, J=7 Hz, 3H), 1.35-1.40 (m, 1H), 1.44 (s, 9H), 1.61-1.65 (m, 1H), 1.70-1.75 (m 1H), 1.91-1.98 (m, 1H), 3.61-3.65 (m, 1H), 3.71-3.75 (m, 1H), 4.10-4.21 (m, 2H), 5.17 (b, 1H).
Reaction SMILES: [CH3:1][O:2][CH2:3][N:4]1[N:8]=[N:7][C:6]([CH2:9][N:10]2[C:15]3[CH:16]=[C:17]([C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=4)[S:18][C:14]=3[C:13](=[O:25])[N:12]([CH:26]3[CH2:31][CH2:30][N:29](C(OC(C)(C)C)=O)[CH2:28][CH2:27]3)[C:11]2=[O:39])=[N:5]1.[F:40][C:41]([F:46])([F:45])[C:42]([OH:44])=[O:43]>C(Cl)Cl>[F:40][C:41]([F:46])([F:45])[C:42]([OH:44])=[O:43].[CH3:1][O:2][CH2:3][N:4]1[N:8]=[N:7][C:6]([CH2:9][N:10]2[C:15]3[CH:16]=[C:17]([C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=4)[S:18][C:14]=3[C:13](=[O:25])[N:12]([CH:26]3[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]3)[C:11]2=[O:39])=[N:5]1
Reactant: COCn1nnc(Cn2c(=O)n(C3CCN(C(=O)OC(C)(C)C)CC3)c(=O)c3sc(-c4ccccc4)cc32)n1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COCn1nnc(Cn2c(=O)n(C3CCNCC3)c(=O)c3sc(-c4ccccc4)cc32)n1
Temperature: 0 °C
Reaction time: 0.83 h

Procedure:
To a solution of tert-butyl 4-[1-{[2-(methoxymethyl)-2H-tetrazol-5-yl]methyl}-2,4-dioxo-6-phenyl-1,4-dihydrothieno[3,2-d]pyrimidin-3(2H)-yl]piperidine-1-carboxylate (270 mg; compound B24) in DCM (1.69 ml) is slowly added trifluoroacetic acid (0.56 ml) at 0° C. The reaction mixture is stirred for 10 min at 0° C. and for 50 min at RT. All volatiles are removed in vacuo to give the title compound as a solid, which is used for the next step without further purification.
Reaction SMILES: [CH2:1]([CH:7]1[CH2:11][O:10][C:9]([CH3:13])([CH3:12])[O:8]1)[CH2:2][CH2:3][CH2:4][CH:5]=[CH2:6].CC[O:16]CC>>[OH:16][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][CH2:1][CH:7]1[CH2:11][O:10][C:9]([CH3:13])([CH3:12])[O:8]1
Reactant: CCOCC
Reactant: C=CCCCCC1COC(C)(C)O1
Product: CC1(C)OCC(CCCCCCO)O1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Alkene ketal, 4(5-hexenyl)-2,2-dimethyl-1,3-dioxolane, (0.01 mole) was dissolved in ether (50 mL) in a flask equipped with dropping funnel, condenser and magnetic stirrer. A steady stream of dry nitrogen was bubbled through the solution. The dropping funnel was charged with borane methylsulfide (Aldrich Chemical Co., Milwaukee, Wis.) (5 mL) in ether (25 mL) and added dropwise to the alkene ketal solution over 30 mins. and the resulting mixture allowed to warm to room temperature and stirred for 3 hrs. Ethanol was then added to scavenge excess borane followed by sodium hydroxide (5 mL of 3 molar solution) and the resulting solution cooled in an ice bath before hydrogen peroxide (19 mL 30% solution) was added at such a rate that the reaction temperature did not exceed 35° C. After addition of the hydrogen peroxide was completed the reaction mixture was refluxed for 1 hr before it was poured over an ice/water (120 mL) mixture. The mixture was saturated with sodium chloride and extracted with ether. The extract was then dried over anhydrous sodium carbonate. The desired product (1.3 g) was obtained on evaporation of ether.
Reaction SMILES: B.CSC.[CH:5]1([O:11][C:12]2[CH:13]=[CH:14][C:15]([C:18]#[N:19])=[N:16][CH:17]=2)[CH2:10][CH2:9][CH2:8][CH2:7][CH2:6]1.CO.Cl>C1COCC1>[NH2:19][CH2:18][C:15]1[CH:14]=[CH:13][C:12]([O:11][CH:5]2[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10]2)=[CH:17][N:16]=1
Reactant: N#Cc1ccc(OC2CCCCC2)cn1
Agent: B
Agent: Cl
Solvent: CSC
Solvent: CO
Solvent: C1CCOC1
Product: NCc1ccc(OC2CCCCC2)cn1
Temperature: 25 °C
Reaction time: 8 h
Yield: 35.8 %

Procedure:
Under a nitrogen atmosphere, add borane-dimethylsulfide complex (20.3 mL, 40.6 mmol, 2M solution in THF) to a solution of 5-cyclohexyloxy-pyridine-2-carbonitrile (0.82 g, 4.06 mmol) in THF (800 mL) at 0° C. Warm the mixture to room temperature and stir overnight. Cool the mixture in an ice-bath, add methanol (15 mL) and concentrated HCl (2 mL). Stir for 2 h, and concentrate in vacuo. Dissolve the residue in saturated aqueous K2CO3. Extract with DCM and wash the organic phase with water and brine. Dry the organic phase over Na2SO4, filter, and concentrate in vacuo to obtain the title compound (0.3 g, 36%). MS (ES+) m/z: 207 (M+H)+.