Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [BH4-].[Na+].[H][H].[Cl:5][C:6]1[CH:11]=[C:10]([Cl:12])[CH:9]=[CH:8][C:7]=1/[CH:13]=[C:14](/[N:21]1[CH:25]=[N:24][CH:23]=[N:22]1)\[C:15](=[O:20])[C:16]([CH3:19])([CH3:18])[CH3:17].Cl>ClCCCl.CN(C)C=O>[Cl:5][C:6]1[CH:11]=[C:10]([Cl:12])[CH:9]=[CH:8][C:7]=1/[CH:13]=[C:14](/[N:21]1[CH:25]=[N:24][CH:23]=[N:22]1)\[CH:15]([OH:20])[C:16]([CH3:17])([CH3:18])[CH3:19]
Reactant: CC(C)(C)C(=O)/C(=C\c1ccc(Cl)cc1Cl)n1cncn1
Reactant: [H][H]
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: ClCCCl
Solvent: CN(C)C=O
Product: CC(C)(C)C(O)/C(=C\c1ccc(Cl)cc1Cl)n1cncn1
Temperature: -30 °C
Reaction time: 23 h
Yield: 99.6 %

Procedure:
In a nitrogen atmosphere, 0.338 g (1.8 mmoles) of (+)-norephedrine hydrochloride was suspended in 5 ml of 1,2-dichloroethane, and after cooling to -30° C., a solution of 0.0681 g (1.8 mmoles) of sodium borohydride in 1 ml of dimethylformamide was added. On raising the temperature of the resulting suspension from -30° C. to room temperature over 2 hours, 87 ml of hydrogen gas was generated. Thereafter, a solution of 0.39 g (1.2 mmoles) of (E)-1-(2,4-dichlorophenyl)-2-(1,2,4-triazol-1-yl)-4,4-dimethyl-1-penten-3-one (E/Z=99.9/0.1) in 4 ml of 1,2-dichloroethane was added to this suspension at room temperature, and then stirring was carried out for 23 hours. Thereafter, 6 ml of 2M hydrochloric acid was added, followed by stirring for 2 hours. The organic layer was washed with water, dried and concentrated under reduced pressure. The residue was purified on a column packed with 2 g of silica gel with a chloroform solvent and then concentrated under reduced pressure to obtain 0.39 g of (-)-(E)-1-(2,4-dichlorophenyl)-2-(1,2,4-triazol-1-yl)-4,4-dimethyl-1-penten-3-ol as a crude crystal. By gas-chromatographic analysis, it was found that the conversion was 96.4%, and the composition of the reaction product was: E-form alcohol, 98.3% and Z-form alcohol, 1.7% (Z-form alcohol was produced through isomerization of the ketone compound to the Z-form, followed by reduction of the carbonyl group).
Reaction SMILES: [H-].[Na+].[CH3:3][O:4][C:5](=[O:23])[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][N:13]1[C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=2[NH:15][C:14]1=[O:22].COC(=O)[CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33]Br>CN(C=O)C>[CH3:3][O:4][C:5](=[O:23])[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][N:13]1[C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=2[N:15]([CH2:33][C:32]2[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=2)[C:14]1=[O:22]
Reactant: COC(=O)CCCCCCCn1c(=O)[nH]c2ccccc21
Reactant: COC(=O)CCCCCCCBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)CCCCCCCn1c(=O)n(Cc2ccccc2)c2ccccc21

Procedure:
The product is produced as described in example 1 from 0.75 g. of NaH (80% suspension in mineral oil), 5.6 g. of 1-benzylbenzimidazolin-2-one (produced in usual manners by alkylation of benzimidazolin-2-one with benzylchloride according to example 8), 50 cc. of DMF, 5.9 g. of 8-bromocaprylic acid methyl ester and 0.75 g. of NaJ.
Reaction SMILES: [OH:1][CH:2]([C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([Cl:11])[CH:6]=1)[CH2:3][NH2:4].[C:12](/[CH:16]=[CH:17]/[C:18]1[CH:23]=[CH:22][C:21]([CH2:24][C:25](=O)[CH3:26])=[CH:20][CH:19]=1)([O:14][CH3:15])=[O:13]>>[C:12](/[CH:16]=[CH:17]/[C:18]1[CH:19]=[CH:20][C:21]([CH2:24][CH:25]([NH:4][CH2:3][CH:2]([OH:1])[C:5]2[CH:10]=[CH:9][CH:8]=[C:7]([Cl:11])[CH:6]=2)[CH3:26])=[CH:22][CH:23]=1)([O:14][CH3:15])=[O:13]
Reactant: NCC(O)c1cccc(Cl)c1
Reactant: COC(=O)/C=C/c1ccc(CC(C)=O)cc1
Product: COC(=O)/C=C/c1ccc(CC(C)NCC(O)c2cccc(Cl)c2)cc1

Procedure:
This was prepared in an identical manner to the compound described in Example 1 using 2-hydroxy-2-(3-chlorophenyl) ethanamine (5.45 g) and 4-{(E)-2-carbomethoxyethenyl}phenylpropan-2-one (7.11 g). The resulting oil was chromatographed on Kieselgel 60. Elution with 5% methanol-chloroform gave the title compound, 9.8 g τ (CDCl3) 8.9 (3H, d, J=6 Hz), 6.8-7.5 (7H, m, 2H disappears with D2O), 6.25 (3H, s), 5.4 (1H, m), 3.6 (1H, d, J=16 Hz), 2.5-2.9 (8H, m), 2.35 (1H, d, J=16 Hz).
Reaction SMILES: [I-].[C:2]1([CH:8]([C:50]2[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=2)[O:9][C:10]([C:12]2[N:17]3[C:18](=[O:29])[C@@H:19]([NH:20][C:21](=[O:28])[CH2:22][C:23]4[S:24][CH:25]=[CH:26][CH:27]=4)[C@H:16]3[S:15][CH2:14][C:13]=2[CH2:30][P+:31]([C:44]2[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=2)([C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)[C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)=[O:11])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+]>CC(C)=O.O>[S:24]1[CH:25]=[CH:26][CH:27]=[C:23]1[CH2:22][C:21]([NH:20][C@@H:19]1[C:18](=[O:29])[N:17]2[C:12]([C:10]([O:9][CH:8]([C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)[C:50]3[CH:51]=[CH:52][CH:53]=[CH:54][CH:55]=3)=[O:11])=[C:13]([CH:30]=[P:31]([C:38]3[CH:39]=[CH:40][CH:41]=[CH:42][CH:43]=3)([C:44]3[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=3)[C:32]3[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=3)[CH2:14][S:15][C@H:16]12)=[O:28]
Reactant: O=C(Cc1cccs1)N[C@@H]1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(C[P+](c3ccccc3)(c3ccccc3)c3ccccc3)CS[C@H]12
Agent: [I-]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC(C)=O
Product: O=C(Cc1cccs1)N[C@@H]1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(C=P(c3ccccc3)(c3ccccc3)c3ccccc3)CS[C@H]12
Yield: 79.4 %

Procedure:
A solution of [4-diphenylmethoxycarbonyl-7β-(2-thienylacetamido)ceph-3-em-3-ylmethyl] triphenylphosphonium iodide (25 g.) in acetone (300 ml.) with water (40 ml.) was cooled to 0° and taken to pH 11 with 2N-sodium hydroxide. The mixture, containing a precipitated yellow solid, was diluted with acetone (200 ml.) and water (50 ml.), and filtered. The collected solid was washed with acetone and ether, and dried in vacuo to give diphenylmethyl 7β-(2-thienylacetamido)-3-(triphenylphosphoranylidenemethyl)ceph-3-em-4-carboxylate (17 g., 78.5%) as a yellow crystalline solid, m.p. 133°-138° (Decomp), [α]D - 35° (CHCl3), λmax (CHCl3) 388 nm. (ε 18,500), 273 nm (ε6,240) and 267 nm (ε6,940), νmax (CHBr3) 3360 (NH), 1746 (β-lactam), 1670 (CO2R), 1642 and 1500 (CONH), and 1438 (P-C aryl) cm-1 ; τ(CDCl3) 4.82 (C(7) --H, dd, J 4.5, 9Hz), 4.95 (C(6) --H,d, J 4.5 Hz), 7.11 and 7.55 (C(2) --CH2, two dd. J 14 Hz., JP-H 1-2 Hz) and 4.5 ##STR34## [Found: C, 66.6; H, 4.7, N, 2.9; P, 3.9; S, 7.8. C45H37N2O4S2P (764.8) requires C, 70.6; H, 4.8; N, 3.6; P, 4.0; S, 8.4%[.
Reaction SMILES: [CH2:1]([O:3][C:4]1[C:5]([O:23][CH3:24])=[CH:6][C:7]2[O:12][C:11](=[O:13])[C:10]([CH2:14][CH2:15]OS(C)(=O)=O)=[C:9]([CH3:21])[C:8]=2[CH:22]=1)[CH3:2].[C:25]1([CH:31]2[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]2)[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>C(O)C>[CH2:1]([O:3][C:4]1[C:5]([O:23][CH3:24])=[CH:6][C:7]2[O:12][C:11](=[O:13])[C:10]([CH2:14][CH2:15][N:34]3[CH2:35][CH2:36][CH:31]([C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=4)[CH2:32][CH2:33]3)=[C:9]([CH3:21])[C:8]=2[CH:22]=1)[CH3:2]
Reactant: CCOc1cc2c(C)c(CCOS(C)(=O)=O)c(=O)oc2cc1OC
Reactant: c1ccc(C2CCNCC2)cc1
Solvent: CCO
Product: CCOc1cc2c(C)c(CCN3CCC(c4ccccc4)CC3)c(=O)oc2cc1OC
Yield: 69 %

Procedure:
Process A; starting materials: 6-ethoxy-3-[2-(methanesulphonyloxy)ethyl]-7-methoxy-4-methyl-2H-1-benzopyran-2-one (Example 29) and 4-phenylpiperidine; yield 69%; m.p. 195°-196° C. (from ethanol).
Reaction SMILES: [NH2:1][C:2]1[CH:6]=[CH:5][NH:4][N:3]=1.[CH3:7][O:8][C:9]1[CH:10]=[C:11]([CH:20]=[CH:21][C:22]=1[O:23][CH3:24])[C:12]([CH2:14][C:15](OCC)=[O:16])=O>C(O)(=O)C>[CH3:7][O:8][C:9]1[CH:10]=[C:11]([C:12]2[CH:14]=[C:15]([OH:16])[N:3]3[N:4]=[CH:5][CH:6]=[C:2]3[N:1]=2)[CH:20]=[CH:21][C:22]=1[O:23][CH3:24]
Reactant: Nc1cc[nH]n1
Reactant: CCOC(=O)CC(=O)c1ccc(OC)c(OC)c1
Solvent: CC(=O)O
Product: COc1ccc(-c2cc(O)n3nccc3n2)cc1OC
Yield: 41.5 %

Procedure:
3-Aminopyrazole (33.2 g) and 110 g of ethyl 3,4-dimethoxybenzoylacetate are stirred in 500 ml of glacial acetic acid for 6 hours at 80° C. After cooling the crystallized-out product is filtered off under suction, washed with diethyl ether and dried. There are obtained 45 g of 5-(3,4-dimethoxyphenyl)pyrazolo[1,5-a]pyrimidin-7-ol of m.p. 268°-270° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([CH2:12][N:13]([CH3:15])[CH3:14])=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH:7]=[CH:6]2.CN(C=O)C.[N:21]1[S:22][N:23]=[C:24]2[C:29]([S:30](Cl)(=[O:32])=[O:31])=[CH:28][CH:27]=[CH:26][C:25]=12>>[N:21]1[S:22][N:23]=[C:24]2[C:29]([S:30]([N:8]3[C:9]4[C:5](=[C:4]([CH2:12][N:13]([CH3:14])[CH3:15])[C:3]([O:2][CH3:1])=[CH:11][CH:10]=4)[CH:6]=[CH:7]3)(=[O:32])=[O:31])=[CH:28][CH:27]=[CH:26][C:25]=12
Reactant: COc1ccc2[nH]ccc2c1CN(C)C
Reactant: O=S(=O)(Cl)c1cccc2nsnc12
Solvent: CN(C)C=O
Product: COc1ccc2c(ccn2S(=O)(=O)c2cccc3nsnc23)c1CN(C)C
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 10.6 %

Procedure:
To a solution of 1-(5-methoxy-11H-indol-4-yl)-N,N-dimethylmethanamine (15 mg, 0.07 mmol; Intermediate 97) in DMF (1 mL) NaH (4 mg, 0.15 mmol) was added at rt. The reaction mixture was stirred at rt for 15 min and 2,1,3-benzothiadiazole-4-sulfonyl chloride (26 mg, 0.11 mmol) was added. The reaction mixture was allowed to stir at rt over night. The reaction was quenched by addition of water. Purification by preparative HPLC/UV (System B) afforded the title product (3 mg, 11%) as a yellow solid. MS (ESI+) for C18H18N4O3S2 m/z 403 (M+H)+.
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[O:3][C:4]1[CH:5]=[C:6]([OH:10])[CH:7]=[CH:8][CH:9]=1.Cl[CH2:14][CH2:15][C:16](Cl)=[O:17].OS(C(F)(F)F)(=O)=O>FC(F)(F)C(O)=O.CC(OC)(C)C>[F:1][C:2]([F:11])([F:12])[O:3][C:4]1[CH:5]=[C:6]2[C:7]([C:16](=[O:17])[CH2:15][CH2:14][O:10]2)=[CH:8][CH:9]=1
Reactant: O=C(Cl)CCCl
Reactant: Oc1cccc(OC(F)(F)F)c1
Agent: O=S(=O)(O)C(F)(F)F
Solvent: COC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Product: O=C1CCOc2cc(OC(F)(F)F)ccc21
Temperature: 50 °C
Reaction time: 8 h
Yield: 38.7 %

Procedure:
A solution of 3-(trifluoromethoxy)phenol (7.13 mL, 55.0 mmol) and 3-chloropropanoyl chloride (5.5 mL, 57.6 mmol) in trifluoroacetic acid (25 mL) was stirred 15 minutes at ambient temperature, and then heated at 50° C. for 90 minutes. After stirring at ambient temperature overnight, the solution was added over 5 minutes to preheated triflic acid (20 mL) at 50° C. After 20 minutes, the mixture was removed from the oil bath, then cooled in an ice water bath. Crushed ice was added, slowly at first, keeping the temperature of the orange solution below 25° C. Eventually a solid precipitate formed, and the suspension was diluted with MTBE (200 mL). The mixture was cooled in an ice water bath. It was washed with brine and then four times with water, partially dried (Na2SO4), filtered, and concentrated. After standing overnight, the yellow mixture was dissolved in ethanol (180 mL) and added slowly over 22 minutes to 1.5 M aqueous Na2CO3 (180 mL) cooled with a water ice bath (internal temp did not exceed 15° C.). The suspension was permitted to come to ambient temperature overnight, and was then diluted with 2:1 EtOAc/hexanes (300 mL) and filtered. The solids were rinsed with more 2:1 solution (105 mL), and the aqueous phase of the filtrate was separated and extracted with 1:1 EtOAc/hexanes (3×100 mL). The combined organic phases were washed once with water (200 mL), and the aqueous phase was back-extracted once with 1:1 solution (40 mL). The organic phases were combined and washed with brine (30 mL), dried (Na2SO4), filtered, and concentrated, chromatographed on silica (gradient elution, 5-20% Et2O/hexanes) to give the title compound (4.95 g, 21.3 mmol, 39% yield). 1H NMR (300 MHz, DMSO-d6) δ 7.90-7.85 (m, 1H), 7.08-7.01 (m, 2H), 4.61 (dd, 2H), 2.83 (dd, 2H).
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[C:12]([N:14]([CH3:16])[CH3:15])[C:11]([C:17]([F:20])([F:19])[F:18])=[CH:10][C:9]=1[NH:21][C:22](=[O:45])[CH2:23][C:24](=O)[C:25]1[CH:30]=[CH:29][CH:28]=[C:27]([C:31]2[O:35][N:34]=[C:33]([CH2:36][O:37]C3CCCCO3)[CH:32]=2)[CH:26]=1)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH3:16][N:14]([CH3:15])[C:12]1[C:11]([C:17]([F:18])([F:19])[F:20])=[CH:10][C:9]2[NH:21][C:22](=[O:45])[CH2:23][C:24]([C:25]3[CH:30]=[CH:29][CH:28]=[C:27]([C:31]4[O:35][N:34]=[C:33]([CH2:36][OH:37])[CH:32]=4)[CH:26]=3)=[N:7][C:8]=2[CH:13]=1
Reactant: CN(C)c1cc(NC(=O)OC(C)(C)C)c(NC(=O)CC(=O)c2cccc(-c3cc(COC4CCCCO4)no3)c2)cc1C(F)(F)F
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CN(C)c1cc2c(cc1C(F)(F)F)NC(=O)CC(c1cccc(-c3cc(CO)no3)c1)=N2

Procedure:
The title compound was prepared from (RS)-[5-dimethylamino-2-(3-oxo-3-{3-[3-(tetrahydro-pyran-2-yloxymethyl)-isoxazol-5-yl]-phenyl}-propionylamino)-4-trifluoromethyl-phenyl]-carbamic acid tert.-butyl ester (Example M41) (680 mg, 1.05 mmol) by treatment with TFA in CH2Cl2 according to the general procedure N. Obtained as a yellow solid (294 mg).
Reaction SMILES: C([O:9][CH:10]([C:27]([NH:29][C@@H:30]([C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)[CH3:31])=[O:28])[C@@H:11]([NH:16]C(OCC1C=CC=CC=1)=O)[CH2:12][CH2:13][CH2:14][CH3:15])(=O)C1C=CC=CC=1.[OH-].[Na+]>O1CCOCC1.O>[NH2:16][C@@H:11]([CH2:12][CH2:13][CH2:14][CH3:15])[CH:10]([OH:9])[C:27]([NH:29][C@@H:30]([C:32]1[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=1)[CH3:31])=[O:28]
Reactant: CCCC[C@H](NC(=O)OCc1ccccc1)C(OC(=O)c1ccccc1)C(=O)N[C@H](C)c1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: CCCC[C@H](N)C(O)C(=O)N[C@H](C)c1ccccc1
Temperature: 25 °C
Yield: 95.2 %

Procedure:
A mixture of 8.75 g (17.4 mmol) of (2S)-2-{[(benzyloxy)carbonyl]amino}-1-({[(1R)-1-phenylethyl]amino}carbonyl)hexyl benzoate and 6.97 g (174 mmol) of sodium hydroxide in 175 mL of dioxane and 75 mL of water was heated at reflux for 3 h. Upon cooling to room temperature, the reaction mixture was diluted with 100 mL of water and extracted with ethyl acetate. The combined ethyl acetate layers were dried over potassium carbonate and concentrated to afford 4.38 g (95%) of (3S)-3-amino-2-hydroxy-N-[(1R)-1-phenylethyl]heptanamide as a white solid. 1H NMR (300 MHz, DMSO-d6) δ 8.08 (d, J=8 Hz, 1H), 7.39-7.20 (m, 5H), 4.99 (m, 1H), 4.51 (br s, 1H), 3.71 (d, J=3 Hz, 1H), 2.81 (m, 1H), 1.50-1.05 (m, 9H), 0.87 (t, 3H). ES-LCMS m/z 265 (M+H).
Reaction SMILES: C[O:2][C:3](=[O:12])[C:4]1[CH:9]=[C:8]([Br:10])[CH:7]=[CH:6][C:5]=1[OH:11].I[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20].C(=O)([O-])[O-].[K+].[K+]>>[Br:10][C:8]1[CH:7]=[CH:6][C:5]([O:11][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])=[C:4]([CH:9]=1)[C:3]([OH:2])=[O:12]
Reactant: COC(=O)c1cc(Br)ccc1O
Reactant: CCCCCCCI
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CCCCCCCOc1ccc(Br)cc1C(=O)O

Procedure:
5-Bromo-2-heptyloxy-benzoic acid was prepared by reacting 5-Bromo-2-hydroxy-benzoic acid methyl ester (1.0 g, 4.32 mmol) with Iodoheptane (1.46 g, 6.49 mmol) as per general procedure G with potassium carbonate (1.5 g, 10.8 mmol) added to it. The ester thus obtained was subjected to hydrolysis as per general procedure C to yield the 5-Bromo-2-heptyloxy-benzoic acid (0.950 g).
Reaction SMILES: C1C2C(COC([N:18]3[CH2:23][C@@H:22]([C:24](=[O:44])[N:25]([CH:41]4[CH2:43][CH2:42]4)[CH2:26][C:27]4[C:35]5[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=5)[N:29]([CH2:36][CH2:37][CH2:38][O:39][CH3:40])[CH:28]=4)[CH2:21][C@@H:20]([NH2:45])[CH2:19]3)=O)C3C(=CC=CC=3)C=2C=CC=1.ClC(Cl)C.[CH2:50]([N:57]=[C:58]=[O:59])[C:51]1[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=1>>[CH:41]1([N:25]([CH2:26][C:27]2[C:35]3[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=3)[N:29]([CH2:36][CH2:37][CH2:38][O:39][CH3:40])[CH:28]=2)[C:24]([C@H:22]2[CH2:21][C@@H:20]([NH:45][C:58]([NH:57][CH2:50][C:51]3[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=3)=[O:59])[CH2:19][NH:18][CH2:23]2)=[O:44])[CH2:43][CH2:42]1
Reactant: O=C=NCc1ccccc1
Reactant: COCCCn1cc(CN(C(=O)[C@H]2C[C@@H](N)CN(C(=O)OCC3c4ccccc4-c4ccccc43)C2)C2CC2)c2ccccc21
Solvent: CC(Cl)Cl
Product: COCCCn1cc(CN(C(=O)[C@@H]2CNC[C@H](NC(=O)NCc3ccccc3)C2)C2CC2)c2ccccc21
Temperature: 50 °C
Reaction time: 14 h

Procedure:
A mixture of (3R*,5S*)-3-amino-5-{cyclopropyl-[1-(3-methoxy-propyl)-1H-indol-3-ylmethyl]-carbamoyl}-piperidine-1-carboxylic acid 9H-fluoren-9-ylmethyl ester (91 mg, 0.15 mmol), dichloroethane (2 mL) and benzyl isocyanate (18.4 μL, 0.15 mmol) is shaken for 14 h at 50° C. A second portion of benzyl isocyanate (9.2 μL, 0.075 mmol) is added and shaking is continued for 5 h at 60° C. The mixture is evaporated in vacuo. The crude product is stirred with a solution of CH2Cl2/piperidine 4:1 (5 mL) for 2 h, the mixture is evaporated and the residue purified by preparative HPLC (C18 column, 10-100% CH3CN+0.1% TFA/H2O+0.1% TFA, 20 min, flow 20 mL/min). The combined pure fractions are treated with K2CO3, CH3CN is removed in vacuo and the residual aqueous phase extracted three times with CH2Cl2. The combined organic layers are dried (Na2SO4) and evaporated to afford the title compound as a yellow resin. MS: 518.3 [M+H]+; tR (HPLC, Nucleosil C18; 5-100% CH3CN+0.1% TFA/H2O+0.1% TFA for 8 min, flow 1.5 ml/min): 5.05 min.
Reaction SMILES: [F:1][C:2]1([F:14])[O:6][C:5]2[CH:7]=[CH:8][C:9]([CH2:11][C:12]#[N:13])=[CH:10][C:4]=2[O:3]1.[OH-].[K+].[CH3:17][C:18](OC)(C)C>O>[F:14][C:2]1([F:1])[O:6][C:5]2[CH:7]=[CH:8][C:9]([C:11]3([C:12]#[N:13])[CH2:18][CH2:17]3)=[CH:10][C:4]=2[O:3]1
Reactant: COC(C)(C)C
Reactant: N#CCc1ccc2c(c1)OC(F)(F)O2
Agent: [K+]
Agent: [OH-]
Solvent: O
Product: N#CC1(c2ccc3c(c2)OC(F)(F)O3)CC1
Temperature: 70 °C

Procedure:
A mixture of (2,2-difluoro-1,3-benzodioxol-5-yl)-acetonitrile (1.0 eq), 50 wt % aqueous KOH (5.0 eq) 1-bromo-2-chloroethane (1.5 eq), and Oct4NBr (0.02 eq) was heated at 70° C. for 1 hour. The reaction mixture was cooled, then worked up with MTBE and water. The organic phase was washed with water and brine. The solvent was removed to afford (2,2-difluoro-1,3-benzodioxol-5-yl)-cyclopropanecarbonitrile.
Reaction SMILES: [C:1]([C:9]1[S:13][C:12]2[CH:14]=[CH:15][CH:16]=[CH:17][C:11]=2[C:10]=1[OH:18])(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.P(Cl)(Cl)(Cl)(Cl)Cl.[CH3:25][N:26]([CH3:31])[CH2:27][CH2:28][CH2:29][NH2:30]>>[CH3:25][N:26]([CH3:31])[CH2:27][CH2:28][CH2:29][NH:30]/[C:1](/[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)=[C:9]1\[C:10](=[O:18])[C:11]2[CH:17]=[CH:16][CH:15]=[CH:14][C:12]=2[S:13]\1
Reactant: CN(C)CCCN
Reactant: O=C(c1ccccc1)c1sc2ccccc2c1O
Agent: ClP(Cl)(Cl)(Cl)Cl
Product: CN(C)CCCN/C(=C1/Sc2ccccc2C1=O)c1ccccc1
Yield: 26 %

Procedure:
Prepared as in Example 1 from 2-benzoyl-benzo[b]-thiophen-3-ol, phosphorus(V) chloride and an aqueous solution of 3-(dimethylamino)-propylamine (prepared from 51 gm of diamine and 70 cc of water) with a yield of 26% of theory.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:19]=[CH:18][C:6]([CH2:7][NH:8][CH2:9][C:10]2[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][CH:11]=2)=[CH:5][CH:4]=1.Cl[S:21]([C:24]1[CH:33]=[CH:32][C:27]([C:28]([O:30]C)=[O:29])=[CH:26][CH:25]=1)(=[O:23])=[O:22]>>[CH3:17][O:16][C:13]1[CH:14]=[CH:15][C:10]([CH2:9][N:8]([CH2:7][C:6]2[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:19][CH:18]=2)[S:21]([C:24]2[CH:25]=[CH:26][C:27]([C:28]([OH:30])=[O:29])=[CH:32][CH:33]=2)(=[O:23])=[O:22])=[CH:11][CH:12]=1
Reactant: COc1ccc(CNCc2ccc(OC)cc2)cc1
Reactant: COC(=O)c1ccc(S(=O)(=O)Cl)cc1
Product: COc1ccc(CN(Cc2ccc(OC)cc2)S(=O)(=O)c2ccc(C(=O)O)cc2)cc1

Procedure:
Prepared as in example 5-27 from bis(4-methoxybenzyl)amine and methyl 4-(chlorosulfonyl)-benzoate (Example 5-10c). MS (M−H, 440.1); 1H NMR (400 MHz, DMSO-d6): δ, ppm: 3.68 (s, 6H), 4.20 (s, 4H), 6.77 (d, 4H, J=10 Hz), 6.98 (d, 4H, J=10 Hz), 7.92 (dd, 2H J=8 Hz), 8.06 (dd, 2H, J=8 Hz). Elemental analysis: (found): C, 62.45%; H, 5.19%; and N, 3.06%. (theoretical): C, 62.57%; H, 5.25%; and N, 3.17%.
Reaction SMILES: [CH3:1][C:2]([Si:5]([CH3:26])([CH3:25])[O:6][C@H:7]1[CH2:12][C@@H:11]([CH2:13]O)[CH2:10][N:9]([C:15]([O:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[O:16])[CH2:8]1)([CH3:4])[CH3:3].[C:27]1(=[O:37])[NH:31][C:30](=[O:32])[C:29]2=[CH:33][CH:34]=[CH:35][CH:36]=[C:28]12.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>C1COCC1>[CH3:1][C:2]([Si:5]([CH3:25])([CH3:26])[O:6][C@H:7]1[CH2:12][C@@H:11]([CH2:13][N:31]2[C:27](=[O:37])[C:28]3[C:29](=[CH:33][CH:34]=[CH:35][CH:36]=3)[C:30]2=[O:32])[CH2:10][N:9]([C:15]([O:17][CH2:18][C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)=[O:16])[CH2:8]1)([CH3:4])[CH3:3]
Reactant: O=C1NC(=O)c2ccccc21
Reactant: CC(C)(C)[Si](C)(C)O[C@H]1C[C@@H](CO)CN(C(=O)OCc2ccccc2)C1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(C)(C)[Si](C)(C)O[C@H]1C[C@@H](CN2C(=O)c3ccccc3C2=O)CN(C(=O)OCc2ccccc2)C1
Temperature: 25 °C
Reaction time: 16 h
Yield: 96.9 %

Procedure:
To cis-phenylmethyl (3RS,5RS)-3-{[(1,1-dimethylethyl)(dimethyl)silyl]oxy}-5-(hydroxymethyl)-1-piperidinecarboxylate (550 mg; 1.4 mmol) in THF (25 ml) was added phthalimide (250 mg; 1.7 mmol), triphenylphosphine (450 mg; 1.7 mmol), and diethyl azodicarboxylate (300 mg; 1.7 mmol). The reaction was allowed to stir at room temperature under N2 for 16 hours. The reaction was partitioned between EtOAc (150 ml) and water (50 ml), the layers were separated, the organic layer was washed with brine and dried with Na2SO4. The solvents were removed and the crude residue was purified by chromatography on silica gel using a 10%-100% EtOAc/hexanes gradient to provide the desired compound (690 mg; 93%) as a yellow oil.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[N:25]=[C:24]([O:26][C@H:27]3[C@H:31]4[O:32][CH2:33][C@@H:34]([OH:35])[C@H:30]4[O:29][CH2:28]3)[N:23]([CH2:36][O:37][CH2:38][CH2:39][Si:40]([CH3:43])([CH3:42])[CH3:41])[C:5]2=[N:6][C:7]=1[C:8]1[CH:13]=[CH:12][C:11](B2OC(C)(C)C(C)(C)O2)=[CH:10][CH:9]=1.Br[C:45]1[CH:50]=[CH:49][C:48]([S:51](=[N:56][CH3:57])([N:53]([CH3:55])[CH3:54])=[O:52])=[CH:47][CH:46]=1>O1CCOCC1>[OH:35][C@H:34]1[C@H:30]2[O:29][CH2:28][C@@H:27]([O:26][C:24]3[N:23]([CH2:36][O:37][CH2:38][CH2:39][Si:40]([CH3:41])([CH3:42])[CH3:43])[C:5]4=[N:6][C:7]([C:8]5[CH:13]=[CH:12][C:11]([C:45]6[CH:46]=[CH:47][C:48]([S:51](=[N:56][CH3:57])([N:53]([CH3:54])[CH3:55])=[O:52])=[CH:49][CH:50]=6)=[CH:10][CH:9]=5)=[C:2]([Cl:1])[CH:3]=[C:4]4[N:25]=3)[C@H:31]2[O:32][CH2:33]1
Reactant: CC1(C)OB(c2ccc(-c3nc4c(cc3Cl)nc(O[C@@H]3CO[C@H]5[C@@H]3OC[C@H]5O)n4COCC[Si](C)(C)C)cc2)OC1(C)C
Reactant: CN=S(=O)(c1ccc(Br)cc1)N(C)C
Solvent: C1COCCO1
Product: CN=S(=O)(c1ccc(-c2ccc(-c3nc4c(cc3Cl)nc(O[C@@H]3CO[C@H]5[C@@H]3OC[C@H]5O)n4COCC[Si](C)(C)C)cc2)cc1)N(C)C

Procedure:
The title compound is prepared from (3R,3aR,6R,6aR)-6-(6-chloro-5-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-3-(2-trimethylsilanyl-ethoxymethyl)-3H-imidazo[4,5-b]pyridin-2-yloxy)hexahydrofuro[3,2-b]furan-3-ol and 4-bromo-N,N,N′-trimethyl-benzenesulfonimidamide following a procedure analogous to that described for Intermediate 3 (Step 3) using 1,4-dioxane as a solvent. LC (method 1): tR=1.06 min; Mass spectrum (ESI+): m/z=700 [M+H]+.
Reaction SMILES: [F:1][C:2]1[CH:20]=[CH:19][CH:18]=[CH:17][C:3]=1[CH2:4][N:5]1[C:9]2=[N:10][CH:11]=[CH:12][CH:13]=[C:8]2[C:7]([C:14](=[NH:16])[NH2:15])=[N:6]1.[C:21]([CH:23](/[N:29]=[N:30]/[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)[C:24](OCC)=[O:25])#[N:22]>>[NH2:22][C:21]1[N:15]=[C:14]([C:7]2[C:8]3[C:9](=[N:10][CH:11]=[CH:12][CH:13]=3)[N:5]([CH2:4][C:3]3[CH:17]=[CH:18][CH:19]=[CH:20][C:2]=3[F:1])[N:6]=2)[N:16]=[C:24]([OH:25])[C:23]=1/[N:29]=[N:30]/[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1
Reactant: N=C(N)c1nn(Cc2ccccc2F)c2ncccc12
Reactant: CCOC(=O)C(C#N)/N=N/c1ccccc1
Product: Nc1nc(-c2nn(Cc3ccccc3F)c3ncccc23)nc(O)c1/N=N/c1ccccc1
Temperature: 25 °C

Procedure:
2.43 g (9.02 mmol) of 1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridine-3-carboximidamide from example I and ethyl cyano[(E)-phenyldiazenyl]acetate (1.96 g, 9.02 mmol) were heated under reflux for 12 h. After cooling to room temperature, the precipitate which had separated out was filtered off and washed several times with toluene. Flash chromatography (CH2Cl2/ethyl acetate 50:1→EA) afforded the desired product.