Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([C:8]2[O:9][CH:10]=[CH:11][CH:12]=2)[C:5]([C:13]#[N:14])=[C:4](S(C)(=O)=O)[N:3]=1.[CH:19]([OH:22])([CH3:21])[CH3:20].C1CCN2C(=NCCC2)CC1>COCCOC>[NH2:1][C:2]1[N:7]=[C:6]([C:8]2[O:9][CH:10]=[CH:11][CH:12]=2)[C:5]([C:13]#[N:14])=[C:4]([O:22][CH:19]([CH3:21])[CH3:20])[N:3]=1
Reactant: CS(=O)(=O)c1nc(N)nc(-c2ccco2)c1C#N
Reactant: CC(C)O
Solvent: C1CCC2=NCCCN2CC1
Solvent: COCCOC
Product: CC(C)Oc1nc(N)nc(-c2ccco2)c1C#N

Procedure:
From 2-amino-4-furan-2-yl-6-methanesulfonyl-pyrimidine-5-carbonitrile, isopropyl alcohol and DBU in DME. EI-MS m/e (%): 244 (M+, 40), 202 ([M—C3H6]+, 100).
Reaction SMILES: O.[NH2:2][NH2:3].[CH3:4][O:5][CH2:6][C:7](=O)[CH2:8][C:9]#[N:10]>C(O)C>[CH3:4][O:5][CH2:6][C:7]1[CH:8]=[C:9]([NH2:10])[NH:2][N:3]=1
Reactant: NN
Reactant: COCC(=O)CC#N
Solvent: O
Solvent: CCO
Product: COCc1cc(N)[nH]n1
Temperature: 25 °C
Yield: 53 %

Procedure:
Hydrazine monohydrate (0.49 ml) was added to a solution of the thus obtained 4-methoxy-3-oxobutyronitrile (1.14 g) in ethanol (50 ml), and refluxed for 17 hours. The reaction mixture was cooled to room temperature and concentrated under reduced pressure. The residue was purified by column chromatography (eluting solvent; dichloromethane:methanol 50:1) to give 5-methoxymethyl-2H-pyrazol-3-ylamine (684 mg, Y.:53%).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:22])[C:5]1[CH:10]=[CH:9][C:8]([N:11]2[C:19]3[C:14](=[CH:15][CH:16]=[C:17]([CH:20]=[O:21])[CH:18]=3)[CH:13]=[CH:12]2)=[CH:7][CH:6]=1)[CH3:2].O1CCCC1.[BH4-].[Na+].[Cl-].[NH4+]>CO>[CH2:1]([O:3][C:4](=[O:22])[C:5]1[CH:10]=[CH:9][C:8]([N:11]2[C:19]3[C:14](=[CH:15][CH:16]=[C:17]([CH2:20][OH:21])[CH:18]=3)[CH:13]=[CH:12]2)=[CH:7][CH:6]=1)[CH3:2]
Reactant: CCOC(=O)c1ccc(-n2ccc3ccc(C=O)cc32)cc1
Agent: [BH4-]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CO
Solvent: C1CCOC1
Product: CCOC(=O)c1ccc(-n2ccc3ccc(CO)cc32)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 4-(6-formylindol-1-yl)benzoic acid ethyl ester in a mixed solvent of tetrahydrofuran (3 mL) and methanol (10 mL) was added sodium borohydride (0.075 g) at 0° C., and this mixture was stirred at room temperature for 0.5 hours. This reaction mixture was poured into a saturated aqueous ammonium chloride solution and this mixture was extracted with ethyl acetate. This organic layer was washed with brine, and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure to give 4-(6-hydroxymethyl-indol-1-yl)benzoic acid ethyl ester (0.38 g). To a solution of 4-(6-hydroxymethyl-indol-1-yl)benzoic acid ethyl ester (0.09 g) in dichloromethane (1 mL) were added acetic anhydride (0.093 g) and pyridine (0.024 g), and this mixture was stirred at room temperature for 2 days. This mixture was poured into water and the resulting mixture was extracted with ethyl acetate. This organic layer was washed with brine, and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure. The residue was purified by column chromatography on silica gel (eluent: n-hexane/ethyl acetate) to give the title compound (0.068 g).
Reaction SMILES: [N:1]1([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[C:5]2=[CH:6][N:7]=[CH:8][CH:9]=[C:4]2[CH:3]=[CH:2]1.CCO>O=[Pt]=O.CC(O)=O>[N:1]1([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH:5]2[CH2:6][NH:7][CH2:8][CH2:9][CH:4]2[CH2:3][CH2:2]1
Reactant: CC(C)(C)OC(=O)n1ccc2ccncc21
Agent: O=[Pt]=O
Solvent: CCO
Solvent: CC(=O)O
Product: CC(C)(C)OC(=O)N1CCC2CCNCC21
Yield: 95.5 %

Procedure:
tert-Butyl 1H-pyrrolo[2,3-c]pyridine-1-carboxylate (1.0 g, 4.58 mmol) and PtO2 (0.208 g, 0.916 mmol) were placed in 1:1 EtOH:AcOH (10 mL) and hydrogenated at 50 PSI of H2 for 8 hours (Parr shaker). The reaction was then concentrated, and the crude oil was dissolved in DCM and poured into saturated Na2CO3 and extracted into DCM. The combined organic fractions were dried, filtered, and concentrated to give tert-butyl octahydro-1H-pyrrolo[2,3-c]pyridine-1-carboxylate (0.99 g, 95% yield) as an oil.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([CH2:10][CH2:11][NH:12][CH2:13][CH2:14][N:15]2[CH2:20][CH2:19][N:18]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[CH2:17][CH2:16]2)=[CH:6][CH:5]=1)([O-:3])=[O:2].CCN(CC)CC.[C:34](Cl)(=[O:37])[CH2:35][CH3:36]>C(Cl)Cl>[N+:1]([C:4]1[CH:9]=[CH:8][C:7]([CH2:10][CH2:11][N:12]([CH2:13][CH2:14][N:15]2[CH2:16][CH2:17][N:18]([C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=3)[CH2:19][CH2:20]2)[C:34](=[O:37])[CH2:35][CH3:36])=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: CCC(=O)Cl
Reactant: O=[N+]([O-])c1ccc(CCNCCN2CCN(c3ccccc3)CC2)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCC(=O)N(CCc1ccc([N+](=O)[O-])cc1)CCN1CCN(c2ccccc2)CC1
Reaction time: 2 h
Yield: 89 %

Procedure:
To a stirred solution of [2-(4-nitro-phenyl)-ethyl]-[2-(4-phenyl-piperazin-1-yl)-ethyl]-amine 27a (0.375 g, 1.05 mmol), Et3N (0.267 g, 2.64 mmol) in 25 mL of dry CH2Cl2 under nitrogen at 0° C. was added a solution of propionyl chloride (0.137 g, 1.48 mmol). The temperature was allowed to rise to room temperature, the mixture stirred for 2 h, and then washed with water. The aqueous layer was extracted with dichloromethane. The combined organic phase was dried (Na2SO4) and concentrated. The crude product was purified by column chromatography over silica gel (EtOAc/Hex=9/1) to give 28a as a colorless oil: 0.39 g (89% yield). 1H NMR (CDCl3, 400 MHz): δ 1.16 (3H, t, J=7.2, CH3), 2.38 (2H, q, J=7.2, CH2), 2.51 (2H, t, J=7.2 Hz, CH2Ar), 2.62 (4H, t, J=4.8, (CH2)2N), 2.99 (2H, t, J=7.2, CH2—CH2NCO), 3.15-3.20 (4H, m, (CH2)2NHPh, 3.32 (2H, t, J=7.2, CH2—CH2Ar), 3.58 (2H, t, J=7.2, CH2NCO), 6.83-6.93 (3H, m, ArH), 7.23-7.28 (2H, m, ArH), 7.34 (1H, d, J=8.0, ArH), 7.38 (1H, d, J=8.8, ArH, 8.15 (1H, d, J=8.8, ArH), 8.18 (1H, d, J=8.4, ArH).
Reaction SMILES: [C:1]1([CH2:7][CH2:8][NH2:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Cl:10][CH2:11][C:12](Cl)=[O:13].C(=O)(O)[O-].[Na+]>>[Cl:10][CH2:11][C:12]([NH:9][CH2:8][CH2:7][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)=[O:13]
Reactant: O=C(Cl)CCl
Reactant: NCCc1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Product: O=C(CCl)NCCc1ccccc1

Procedure:
Eur. J. Org. Chem. 2008, 895-913 describes a process comprising: a) reacting phenylethylamine with chloroacetyl chloride in presence of sodium bicarbonate to obtain 2-chloro-N-phenethylacetamide, b) treating 2-chloro-N-phenethylacetamide with aminoacetaldehyde dimethylacetal to give 2-[2,2-dimethoxyethyl)amino]-N-(2-phenylethyl)acetamide, c) making hydrochloride salt of 2-[(2,2-dimethoxyethyl)amino]-N-(2-phenylethyl)acetamide, and d) cyclising using sulphuric acid to form praziquanamine (i.e.4-oxo-1,2,3,6,7,11b-hexahydro-4H-pyrazino[2,1-a]isoquinoline).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH2:5][NH2:6].Cl[C:11]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[C:14]([CH2:21][C:22]2[CH:27]=[CH:26][N:25]=[CH:24][CH:23]=2)=[CH:13][N:12]=1.N>C(OCC)(=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH2:5][NH:6][C:11]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[C:14]([CH2:21][C:22]2[CH:27]=[CH:26][N:25]=[CH:24][CH:23]=2)=[CH:13][N:12]=1
Reactant: Clc1ncc(Cc2ccncc2)c2ccccc12
Reactant: NCc1cccc(Cl)c1
Agent: N
Solvent: CCOC(C)=O
Product: Clc1cccc(CNc2ncc(Cc3ccncc3)c3ccccc23)c1

Procedure:
With the exclusion of moisture, 1.6 ml (13.1 mmol) of 3-chlorobenzylamine and 800 mg (3.14 mmol) of 1-chloro-4-(pyridin-4-ylmethyl)-isoquinoline (Example 1e) are stirred for 2 hours at 150° C. The mixture is suspended in ethyl acetate, 1 ml of concentrated ammonia solution is added, washing with water and brine is carried out, and the organic phase is dried (Na2SO4) and concentrated by evaporation. Column chromatography (SiO2; ethyl acetate) yields the title compound: m.p. 141-142° C.; 1H NMR (DMSO-d6) 8.39 (d, 2H), 8.31 (d, 1H), 8.03 (t, HN), 7.82 (s, 1H), 7.69 (d, 1H), 7.61 (t, 1H), 7.50 (t, 1H), 7.40 (s, 1H), 7.33 (m, 2H), 7.26 (m, 1H), 7.20 (d, 2H), 4.73 (d, 2H), 4.14 (s, 2H); FAB-MS: (M+H)+=360; Anal. calc. (C22H18N3Cl) C 73.43%, H 5.04%, N 11.68%, Cl 9.85%; found C 73.2%, H 5.1%, N 11.6%, Cl 9.9%.
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]([C:11]#[N:12])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.[F:13][C:14]1([F:29])[CH2:19][CH2:18][C:17]([CH2:27][NH2:28])([C:20]2[CH:21]=[N:22][C:23]([F:26])=[CH:24][CH:25]=2)[CH2:16][CH2:15]1>>[C:11]([C:9]1[CH:8]=[CH:7][C:3]([C:4]([NH:28][CH2:27][C:17]2([C:20]3[CH:21]=[N:22][C:23]([F:26])=[CH:24][CH:25]=3)[CH2:18][CH2:19][C:14]([F:13])([F:29])[CH2:15][CH2:16]2)=[O:6])=[C:2]([F:1])[CH:10]=1)#[N:12]
Reactant: N#Cc1ccc(C(=O)O)c(F)c1
Reactant: NCC1(c2ccc(F)nc2)CCC(F)(F)CC1
Product: N#Cc1ccc(C(=O)NCC2(c3ccc(F)nc3)CCC(F)(F)CC2)c(F)c1

Procedure:
From 2-fluoro-4-cyanobenzoic acid and C-[4,4-difluoro-1-(6-fluoro-pyridin-3-yl)-cyclohexyl]-methylamine. LCMS (MH+): m/z=392.1, tR (minutes, Method D)=0.68
Reaction SMILES: [Na].[N:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:13](C(O)=O)=[CH:12][CH:11]=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.C[C:18]([OH:20])=[O:19].CO>O=[Pt]=O>[NH:2]1[CH2:3][CH2:4][CH:5]([C:8]2[CH:9]=[CH:10][C:11]([C:18]([OH:20])=[O:19])=[CH:12][CH:13]=2)[CH2:6][CH2:7]1
Reactant: CC(=O)O
Reactant: O=C(O)c1ccccc1-c1ccncc1
Agent: O=[Pt]=O
Agent: [Na]
Solvent: CO
Product: O=C(O)c1ccc(C2CCNCC2)cc1
Reaction time: 4 h

Procedure:
To the sodium salt of 4-pyridine benzoic acid (500 mg, 2.25 mmol) suspended in 20% AcOH/MeOH (20 ml) was added PtO2 (250 mg) and the mixture was hydrogenated at 50 psi with agitation (Parr) for 4 h. The solution was filtered through celite, washed with MeOH (3×5 ml), evaporated with hexane (4×) to azeotrope the acetic acid. TLC of the crude (EtOH/H2O/NH4OH 10:1:1) shows no starting material, but did show 2 more polar spots. After evaporation from hexane, the white solid (596 mg crude, still with residual HOAc) was dried in a vacuum overnight, and used without further purification in subsequent steps. MS m/z [M+H]+.
Reaction SMILES: CO[C:3](=[O:22])[C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:11][C:12]2[C:13]([CH2:18][CH2:19][CH2:20][CH3:21])=[N:14][O:15][C:16]=2[CH3:17])=[N:6][CH:5]=1.[NH2:23][C:24]([CH3:28])([CH3:27])[CH2:25][OH:26]>>[CH2:18]([C:13]1[C:12]([CH2:11][O:10][C:7]2[CH:8]=[CH:9][C:4]([C:3]([NH:23][C:24]([CH3:28])([CH3:27])[CH2:25][OH:26])=[O:22])=[CH:5][N:6]=2)=[C:16]([CH3:17])[O:15][N:14]=1)[CH2:19][CH2:20][CH3:21]
Reactant: CC(C)(N)CO
Reactant: CCCCc1noc(C)c1COc1ccc(C(=O)OC)cn1
Product: CCCCc1noc(C)c1COc1ccc(C(=O)NC(C)(C)CO)cn1
Yield: 29 %

Procedure:
As described for example 5d, 6-(3-butyl-5-methyl-isoxazol-4-ylmethoxy)-nicotinic acid methyl ester (537 mg, 1.5 mmol) was converted, using 2-amino-2-methyl-1-propanol instead of isopropylamine, to the title compound (155 mg, 29%) which was obtained as a white solid after purification by chromatography (silica, 0 to 60% ethyl acetate in heptane). MS: m/e=362.4 [M+H]+.
Reaction SMILES: [C:1]1(O)C=CC=C[CH:2]=1.[OH:8][C:9]([C:17]1[CH:18]=[C:19]([O:23][Si](C(C)(C)C)(C)C)[CH:20]=[CH:21][CH:22]=1)([C:12]1S[CH:14]=[CH:15][N:16]=1)[CH2:10][CH3:11]>>[OH:8][C:9]([C:17]1[CH:18]=[C:19]([OH:23])[CH:20]=[CH:21][CH:22]=1)([C:12]1[CH:2]=[CH:1][CH:14]=[CH:15][N:16]=1)[CH2:10][CH3:11]
Reactant: Oc1ccccc1
Reactant: CCC(O)(c1cccc(O[Si](C)(C)C(C)(C)C)c1)c1nccs1
Product: CCC(O)(c1cccc(O)c1)c1ccccn1

Procedure:
Following the procedure described for Phenol 6, Step 3 but substituting 3-[1-hydroxy-1-(pyridin-2-yl)propyl](O-tert-butyldiphenylsilyl)phenol from Step 4 for 3-[1-hydroxy-1-(thiazol-2-yl)propyl](O-tert-butyldimethylsilyl)phenol, the title compound was obtained.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2([C:14]3[CH:19]=[CH:18][C:17]([Cl:20])=[C:16]([F:21])[CH:15]=3)[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)=[CH:4][CH:3]=1.CC1(C)C(C)(C)OB([C:30]2[CH:31]=[N:32][NH:33][CH:34]=2)O1>[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[Cl:20][C:17]1[CH:18]=[CH:19][C:14]([C:8]2([C:5]3[CH:6]=[CH:7][C:2]([C:30]4[CH:31]=[N:32][NH:33][CH:34]=4)=[CH:3][CH:4]=3)[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)=[CH:15][C:16]=1[F:21]
Reactant: Fc1cc(C2(c3ccc(Br)cc3)CCNCC2)ccc1Cl
Reactant: CC1(C)OB(c2cn[nH]c2)OC1(C)C
Agent: [Pd]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: Fc1cc(C2(c3ccc(-c4cn[nH]c4)cc3)CCNCC2)ccc1Cl

Procedure:
4-(4-Bromo-phenyl)-4-(4-chloro-3-fluoro-phenyl)-piperidine was reacted with 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole following the procedure set out in Example 1, but using tetrakis(triphenylphosphine) palladium (0) as the catalyst, to obtain the title compound. LCMS (PS-A3) Rt 7.11 min [M+H]+ 356. 1H NMR (Me-d3-OD) δ 2.62-2.80 (4H, m), 3.18-3.30 (partially overlaps with solvent, 4H, m), 7.23 (1H, t), 7.34-7.39 (1H, m), 7.22 (1H, dd), 7.30 (1H, dd), 7.43-7.49 (3H, m), 7.71 (2H, d), 8.55 (2H, s).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([C:8](=[O:10])[CH3:9])[CH:5]=[CH:6][CH:7]=1.Br[CH2:12][CH2:13][CH2:14][Cl:15]>>[Cl:15][CH2:14][CH2:13][CH2:12][O:1][C:2]1[CH:3]=[C:4]([C:8](=[O:10])[CH3:9])[CH:5]=[CH:6][CH:7]=1
Reactant: ClCCCBr
Reactant: CC(=O)c1cccc(O)c1
Product: CC(=O)c1cccc(OCCCCl)c1

Procedure:
Prepared by Procedure U and Scheme AK using 1-(3-hydroxyphenyl)ethanone and 1-bromo-3-chloropropane.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH2:11][CH:10]([NH:14][C:15]([CH:17]2[C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[N:19]([S:26]([C:29]3[C:38]4[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=4)[C:32]([O:39][CH3:40])=[CH:31][CH:30]=3)(=[O:28])=[O:27])[CH2:18]2)=[O:16])[CH2:9]1)=O)(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[NH:8]1[CH2:13][CH2:12][CH2:11][CH:10]([NH:14][C:15]([CH:17]2[C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[N:19]([S:26]([C:29]3[C:38]4[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=4)[C:32]([O:39][CH3:40])=[CH:31][CH:30]=3)(=[O:28])=[O:27])[CH2:18]2)=[O:16])[CH2:9]1
Reactant: COc1ccc(S(=O)(=O)N2CC(C(=O)NC3CCCN(C(=O)OC(C)(C)C)C3)c3ccccc32)c2ccccc12
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COc1ccc(S(=O)(=O)N2CC(C(=O)NC3CCCNC3)c3ccccc32)c2ccccc12
Yield: 77.8 %

Procedure:
To a solution of (A) (500 mg, 0.99 mmol) in dichloromethane (12 cm3) was added, with stirring, trifluoroacetic acid (2 cm3). The reaction was then allowed to stir at room temperature for 3 h, after which the solvents were removed by evaporation under reduced pressure. Dichloromethane (40 cm3) was added to the residue and the mixture was then washed with saturated aqueous sodium bicarbonate solution (30 cm3) followed by water (30 cm3) and saturated sodium chloride solution (50 cm3). The resulting organic mixture was then dried over sodium sulfate and evaporated under reduced pressure to afford the title compound as a pale yellow solid (310 mg, 0.77 mmol; 77%). Positive ion ESI (M+H)+ 466.6.
Reaction SMILES: [CH:1]([N:4]1[C:12]2[C:7](=[CH:8][C:9]([O:13][C@H:14]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[C@@H:15]([NH2:17])[CH3:16])=[CH:10][CH:11]=2)[CH:6]=[N:5]1)([CH3:3])[CH3:2].[CH3:24][S:25](Cl)(=[O:27])=[O:26]>>[C:18]1([C@@H:14]([O:13][C:9]2[CH:8]=[C:7]3[C:12](=[CH:11][CH:10]=2)[N:4]([CH:1]([CH3:2])[CH3:3])[N:5]=[CH:6]3)[C@@H:15]([NH:17][S:25]([CH3:24])(=[O:27])=[O:26])[CH3:16])[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)n1ncc2cc(O[C@H](c3ccccc3)[C@H](C)N)ccc21
Product: CC(C)n1ncc2cc(O[C@H](c3ccccc3)[C@H](C)NS(C)(=O)=O)ccc21

Procedure:
The title compound was prepared from (1R,2S)-1-[(1-isopropyl-1H-indazol-5-yl)oxy]-1-phenylpropan-2-amine (30b, 31 mg, 100 μmol) and methanesulfonyl chloride (34 mg, 300 μmol) as described in Example 2b. Yield 28 mg (72%).
Reaction SMILES: C([S:4][C@H:5]1[CH2:9][CH2:8][N:7]([C:10]2[S:11][CH:12]=[C:13]([C:15](=[O:17])[NH2:16])[N:14]=2)[CH2:6]1)(=O)C.C(O)(=O)C.NN.C1(P(O[C:39]2[C@H:40]([CH3:63])[C@H:41]3[C@@H:58]([C@H:59]([OH:61])[CH3:60])[C:57](=[O:62])[N:42]3[C:43]=2[C:44]([O:46][CH2:47][C:48]2[CH:53]=[CH:52][C:51]([N+:54]([O-:56])=[O:55])=[CH:50][CH:49]=2)=[O:45])(C2C=CC=CC=2)=O)C=CC=CC=1.C(N(C(C)C)CC)(C)C.C(=O)([O-])O.[Na+]>CN(C)C=O.C(#N)C.C(OCC)(=O)C>[C:15]([C:13]1[N:14]=[C:10]([N:7]2[CH2:8][CH2:9][C@H:5]([S:4][C:39]3[C@H:40]([CH3:63])[C@@H:41]4[C@@H:58]([C@H:59]([OH:61])[CH3:60])[C:57](=[O:62])[N:42]4[C:43]=3[C:44]([O:46][CH2:47][C:48]3[CH:49]=[CH:50][C:51]([N+:54]([O-:56])=[O:55])=[CH:52][CH:53]=3)=[O:45])[CH2:6]2)[S:11][CH:12]=1)(=[O:17])[NH2:16]
Reactant: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(OP(=O)(c3ccccc3)c3ccccc3)[C@H](C)[C@@H]12
Reactant: CC(=O)S[C@H]1CCN(c2nc(C(N)=O)cs2)C1
Agent: NN
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CC#N
Solvent: CN(C)C=O
Product: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(S[C@H]3CCN(c4nc(C(N)=O)cs4)C3)[C@H](C)[C@H]12
Temperature: 25 °C
Reaction time: 1 h
Yield: 99.6 %

Procedure:
To a solution of (3S)-3-acetylthio-1-(4-carbamoyl-1,3-thiazol-2-yl)pyrrolidine (210 mg, 0.721 mmol) (obtained as described in Reference Example 18) in dimethylformamide (10 ml) was added hydrazine acetate (80 mg, 0.865 mmol) at room temperature under an atmosphere of nitrogen and the mixture was stirred for 1 hour. After checking the completion of the reaction, a solution of p-nitrobenzyl (1R,5S,6S)-2-diphenylphosphoryloxy-6-[(R)-1-hydroxyethyl]-1-methylcarbapen-2-em-3-carboxylate (429 mg, 0.721 mmol) in acetonitrile (20 ml) was added dropwise to the resulting mixture in an ice bath under an atmosphere of nitrogen, followed by the addition of diisopropylethylamine (0.502 ml, 2.88 mmol). The mixture was stirred overnight while gradually raising the temperature to room temperature. After checking the completion of the reaction, ethyl acetate and saturated aqueous sodium hydrogencarbonate solution were added to the reaction mixture. The resulting mixture was shaken in a separatory funnel and the ethyl acetate layer was separated, washed with 0.5 M hydrochloric acid, saturated aqueous sodium hydrogencarbonate solution and saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by chromatography on a silica gel column using methylene chloride—10% methanol and methylene chloride as the eluant to afford p-nitrobenzyl (1R,5S,6S)-2-[(3S)-1-(4-carbamoyl-1,3-thiazol-2-yl)pyrrolidin-3-yl]thio-6-[(R)-1-hydroxyethyl]-1-methylcarbapen-2-em-3-carboxylate as a pale yellow solid (412 mg, yield 100%).
Reaction SMILES: [NH2:1][S:2]([C:5]1[CH:6]=[C:7]([CH:11]=[CH:12][CH:13]=1)[C:8](O)=[O:9])(=[O:4])=[O:3].Cl>CO>[OH:9][CH2:8][C:7]1[CH:6]=[C:5]([S:2]([NH2:1])(=[O:3])=[O:4])[CH:13]=[CH:12][CH:11]=1
Reactant: NS(=O)(=O)c1cccc(C(=O)O)c1
Agent: Cl
Solvent: CO
Product: NS(=O)(=O)c1cccc(CO)c1
Temperature: 0 °C
Reaction time: 8 h
Yield: 78.6 %

Procedure:
3-(Aminosulfonyl)benzoic acid (2.18 g) was stirred with ice-water cooling and under nitrogen while borane-THF complex (32.5 ml) was added dropwise over 15 min. After 2 h at 22° further borane-THF complex (16 ml) was added. After a further 2 h the mixture was cooled with ice-water and methanol (40 ml) was added dropwise. After 15 min 2M hydrochloric acid (90 ml) was added and the mixture was left to stand at 21° overnight. The solution was extracted 3 times with ethyl acetate and the organic layers were combined and washed twice with brine, dried (MgSO4) and concentrated. This solution was loaded onto a column of silica gel (200 g) and the column was run with ethyl acetate and then 10% methanol in ethyl acetate to give the title compound (1.595 g), LCMS RT=0.83 min.
Reaction SMILES: [Cl:1][C:2]1[C:3]2[C:10](I)=[CH:9][N:8]([CH2:12][O:13][CH2:14][CH2:15][Si:16]([CH3:19])([CH3:18])[CH3:17])[C:4]=2[N:5]=[CH:6][N:7]=1.[CH3:20][N:21]1[CH:25]=[C:24](B2OC(C)(C)C(C)(C)O2)[CH:23]=[N:22]1.C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[Cl:1][C:2]1[C:3]2[C:10]([C:24]3[CH:23]=[N:22][N:21]([CH3:20])[CH:25]=3)=[CH:9][N:8]([CH2:12][O:13][CH2:14][CH2:15][Si:16]([CH3:19])([CH3:18])[CH3:17])[C:4]=2[N:5]=[CH:6][N:7]=1
Reactant: Cn1cc(B2OC(C)(C)C(C)(C)O2)cn1
Reactant: C[Si](C)(C)CCOCn1cc(I)c2c(Cl)ncnc21
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Product: Cn1cc(-c2cn(COCC[Si](C)(C)C)c3ncnc(Cl)c23)cn1
Temperature: 25 °C

Procedure:
To a solution of 4-chloro-5-iodo-7-{[2-(trimethylsilyl)ethoxy]methyl}-7H-pyrrolo[2,3-d]pyrimidine (C1) (4.1 g, 10 mmol), 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (2.1 g, 10 mmol) and potassium carbonate (2.8 g, 20 mmol) in aqueous 1,4-dioxane was added dichlorobis(triphenylphosphine)palladium(II) (350 mg, 0.50 mmol). The reaction mixture was degassed and purged with nitrogen; this procedure was carried out a total of three times. After heating at reflux for 18 hours, the reaction mixture was cooled to room temperature, diluted with water (200 mL) and extracted with ethyl acetate (3×200 mL). The combined organic layers were washed with saturated aqueous sodium chloride solution (500 mL), dried over sodium sulfate, filtered, and concentrated in vacuo. Purification by chromatography on silica gel (Gradient: 0% to 10% ethyl acetate in petroleum ether) afforded the product as a white solid. Yield: 2.0 g, 5.5 mmol, 55%. 1H NMR (400 MHz, CDCl3) δ 8.66 (s, 1H), 7.68 (d, J=0.5 Hz, 1H), 7.62 (br s, 1H), 7.36 (s, 1H), 5.68 (s, 2H), 3.99 (s, 3H), 3.54-3.59 (m, 2H), 0.91-0.97 (m, 2H), −0.03 (s, 9H).
Reaction SMILES: [Na].[Cl:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([CH3:9])[C:4]=1[NH:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[C:17](=O)[C:18]([OH:20])=[O:19].O.NN.C[O-].[Na+]>C(O)C>[Cl:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([CH3:9])[C:4]=1[NH:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[CH2:17][C:18]([OH:20])=[O:19]
Reactant: Cc1cccc(Cl)c1Nc1ccccc1C(=O)C(=O)O
Agent: C[O-]
Agent: NN
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: Cc1cccc(Cl)c1Nc1ccccc1CC(=O)O

Procedure:
To a solution of 35.5 g of sodium salt of [o-(3-chloro-o-toluidino)-phenyl]-glyoxylic acid in 455 ml of abs. ethanol are added at 50° 28.5 g of hydrazine hydrate, and 5 minutes afterwards 66.2 g of sodium methylate. The solution is thereupon heated in an oil bath with a bath temperature of 150°, whereby the ethanol slowly distills off. To the solution are simultaneously added dropwise 455 ml of ethylene glycol monoethyl ether. The internal temperature thereby increases to 130°. After the dropwise addition is completed, the solution is stirred for a further hour at 150°; it is then cooled and diluted with 3,000 ml of water. The solution is extracted twice with 300 ml of ether each time, and then acidified with concentrated hydrochloric acid. The precipitated yellow oil is extracted with 200 ml of ethyl acetate; the ethyl acetate solution is washed with 200 ml of water, dried over sodium sulphate, and concentrated at 30° under 11 Torr, whereby [ o-(3-chloro-o-toluidino)-phenyl]-acetic acid crystallises out, M.P. 124°-125°.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][N:11]=[C:10]([CH3:13])[C:9]=2[CH:14]=[CH:15][CH2:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[CH:4][CH:3]=1.[CH2:24]([O:26][C:27]([C@@H:29]1[CH2:31][C@H:30]1[C:32]1[CH:37]=[CH:36][C:35](B2OC(C)(C)C(C)(C)O2)=[CH:34][CH:33]=1)=[O:28])[CH3:25]>>[CH2:24]([O:26][C:27]([C@@H:29]1[CH2:31][C@H:30]1[C:32]1[CH:37]=[CH:36][C:35]([C:2]2[CH:7]=[CH:6][C:5]([C:8]3[O:12][N:11]=[C:10]([CH3:13])[C:9]=3[CH:14]=[CH:15][CH2:16][CH2:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[CH:4][CH:3]=2)=[CH:34][CH:33]=1)=[O:28])[CH3:25]
Reactant: CCOC(=O)[C@@H]1C[C@H]1c1ccc(B2OC(C)(C)C(C)(C)O2)cc1
Reactant: Cc1noc(-c2ccc(Br)cc2)c1C=CCCc1ccccc1
Product: CCOC(=O)[C@@H]1C[C@H]1c1ccc(-c2ccc(-c3onc(C)c3C=CCCc3ccccc3)cc2)cc1

Procedure:
Prepared according to the procedure described in Example 3, Step 5, using 5-(4-bromo-phenyl)-3-methyl-4-(4-phenyl-but-1-enyl)-isoxazole and (trans)-2-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-cyclopropanecarboxylic acid ethyl ester.