Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(O)(=O)C.[CH2:5]([N:12]1[CH2:18][C:16](=[O:17])[NH:15][C:13]1=[O:14])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.BrBr.[CH2:21]([OH:24])[CH2:22][OH:23]>O>[CH2:5]([N:12]1[CH:18]([O:23][CH2:22][CH2:21][OH:24])[C:16](=[O:17])[NH:15][C:13]1=[O:14])[C:6]1[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=1
Reactant: O=C1CN(Cc2ccccc2)C(=O)N1
Reactant: OCCO
Agent: BrBr
Solvent: O
Solvent: CC(=O)O
Product: O=C1NC(=O)N(Cc2ccccc2)C1OCCO
Temperature: 80 °C
Yield: 69.3 %

Procedure:
500 ml of acetic acid was added to 57 g of 1-benzylhydantoin and, while maintaining at 80° C. with stirring, 50.3 g of bromine was dropwise added thereto. After completion of the dropwise addition, the solution was further stirred for 2 hours. The reaction solution was then cooled and, while cooling with ice, 56 g of ethylene glycol was added thereto. After stirring for 30 minutes, the solution was further stirred for 3 hours at room temperature. One liter of water was added to the reaction solution, followed by extraction with 500 ml of ethyl acetate. The extract was further washed twice with 500 ml of water. The thus obtained ethyl acetate solution was dried with sodium sulfate, concentrated, and purified by silica gel chromatography to obtain 52 g of 1-benzyl-5-(2-hydroxyethoxy)hydantoin. (Yield: 74%)
Reaction SMILES: [CH3:1][O:2][C:3]1[C:11]([CH3:12])=[C:10]2[C:6]([CH:7]=[C:8]([C:13]([OH:15])=O)[NH:9]2)=[CH:5][CH:4]=1.C([C:18]1[C:19]([N:24]2[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]2)=[N:20][CH:21]=[CH:22][CH:23]=1)C.C(N1C=CN=C1)([N:32]1[CH:36]=[CH:35]N=C1)=O>C1COCC1>[CH3:35][CH2:36][NH:32][C:18]1[CH:23]=[CH:22][CH:21]=[N:20][C:19]=1[N:24]1[CH2:25][CH2:26][N:27]([C:13]([C:8]2[NH:9][C:10]3[C:11]([CH3:12])=[C:3]([O:2][CH3:1])[CH:4]=[CH:5][C:6]=3[CH:7]=2)=[O:15])[CH2:28][CH2:29]1
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: COc1ccc2cc(C(=O)O)[nH]c2c1C
Reactant: CCc1cccnc1N1CCNCC1
Solvent: C1CCOC1
Product: CCNc1cccnc1N1CCN(C(=O)c2cc3ccc(OC)c(C)c3[nH]2)CC1

Procedure:
Following the general procedure of EXAMPLE 16 and making non-critical variations but starting with 6-methoxy-7-methylindole-2-carboxylic acid (0.23 g), 1-(3-ethyl-2-pyridinyl) piperazine (0.24 g), 1,1'-carbonyldiimidazole (0.19 g) and THF (3 ml), the title compound is obtained, mp 162°-163°.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][N:3]=1.Cl.[NH2:13][C@H:14]1[CH2:18][CH2:17][CH2:16][C@@H:15]1[NH:19][C:20](=[O:31])[C:21]1[C:26]([O:27][CH3:28])=[CH:25][CH:24]=[CH:23][C:22]=1[O:29][CH3:30].CCN(C(C)C)C(C)C>CS(C)=O>[CH3:30][O:29][C:22]1[CH:23]=[CH:24][CH:25]=[C:26]([O:27][CH3:28])[C:21]=1[C:20]([NH:19][C@H:15]1[CH2:16][CH2:17][CH2:18][C@@H:14]1[NH:13][C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][N:3]=1)=[O:31]
Reactant: FC(F)(F)c1ccc(Cl)nc1
Reactant: COc1cccc(OC)c1C(=O)N[C@H]1CCC[C@@H]1N
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CS(C)=O
Product: COc1cccc(OC)c1C(=O)N[C@H]1CCC[C@@H]1Nc1ccc(C(F)(F)F)cn1

Procedure:
A mixture of 2-chloro-5-(trifluoromethyl)pyridine (CAS number 52334-81-3; 266 mg, 1.46 mmol), N-[(1S,2S)-2-aminocyclopentyl]-2,6-dimethoxybenzamide hydrochloride (Intermediate 5; 400 mg, 1.33 mmol), DIPEA (0.70 ml, 3.99 mmol) and DMSO (4.8 ml) was subjected to microwave irradiation at 140° C. for 2 hours. Upon cooling, the resulting mixture was partitioned between ethyl acetate (10 ml) and water (10 ml) and the combined organics were washed with brine (10 ml), dried over magnesium sulfate, filtered and concentrated in vacuo. The crude product was further purified by trituration with di-isopropylether to afford the title compound.
Reaction SMILES: Br[C:2]([CH3:11])([CH3:10])[C:3]([NH:5][C:6]([NH:8][CH3:9])=[O:7])=[O:4].[Na+].[C:13]([O:16][CH2:17][C:18]1[CH2:19][S:20][C@@H:21]2[C@H:28]([NH:29][C:30](=[O:39])/[C:31](/[C:34]3[O:35][CH:36]=[CH:37][CH:38]=3)=[N:32]\[OH:33])[C:27](=[O:40])[N:22]2[C:23]=1[C:24]([O-:26])=[O:25])(=[O:15])[CH3:14].CCO>CS(C)=O>[C:13]([O:16][CH2:17][C:18]1[CH2:19][S:20][C@@H:21]2[C@H:28]([NH:29][C:30](=[O:39])/[C:31](/[C:34]3[O:35][CH:36]=[CH:37][CH:38]=3)=[N:32]\[O:33][C:2]([C:3]([NH:5][C:6]([NH:8][CH3:9])=[O:7])=[O:4])([CH3:11])[CH3:10])[C:27](=[O:40])[N:22]2[C:23]=1[C:24]([OH:26])=[O:25])(=[O:15])[CH3:14]
Reactant: CNC(=O)NC(=O)C(C)(C)Br
Reactant: CC(=O)OCC1=C(C(=O)[O-])N2C(=O)[C@@H](NC(=O)/C(=N\O)c3ccco3)[C@H]2SC1
Agent: [Na+]
Solvent: CS(C)=O
Solvent: CCO
Product: CNC(=O)NC(=O)C(C)(C)O/N=C(\C(=O)N[C@@H]1C(=O)N2C(C(=O)O)=C(COC(C)=O)CS[C@H]12)c1ccco1
Yield: 76 %

Procedure:
This compound was prepared from 1-(2-bromo-2-methylpropionyl)-3-methylurea and (6R,7R)-3-acetoxymethyl-7-[Z-2-(fur-2-yl)-2-hydroxyiminoacetamido]-ceph-3-em-4-carboxylic acid sodium salt by the method described in Example 1. [α]D22 +84.6° (c 0.65, DMSO), λmax (EtOH) 274 nm (ε 16,900), νmax (Nujol) 3340 (NH), 3700-2100 (bonded OH), 1790 (β-lactam), 1740 (OCOCH3), 1700 (CO2H), 1690, 1540 cm-1 (--CONH--, --CONHCONH--), τ (DMSO d6) 2.25, 3.2, 3.35 (fur-2-yl), 8.51, 8.52 (C(Me)2), 0.5 (--CONHCO), 1.75 (CONHMe), 7.28 (CONHMe), 4.1 (7 H), 4.75 (6 H), 6.28, 6.50 (2 CH2), 4.97, 5.29 (3 CH2), 7.9 (OCOCH3). Yield: 76%.
Reaction SMILES: COC1C=CC=C[C:4]=1[OH:9].BrC1C([N+]([O-])=O)=CC=CN=1.[CH3:20][O:21][C:22]1[CH:35]=[CH:34][CH:33]=[CH:32][C:23]=1[O:24][C:25]1[C:30]([NH2:31])=[CH:29][CH:28]=[CH:27][N:26]=1.[NH2:36][C:37]1[S:38][CH:39]=[CH:40][N:41]=1>>[CH3:20][O:21][C:22]1[CH:35]=[CH:34][CH:33]=[CH:32][C:23]=1[O:24][C:25]1[C:30]([NH:31][C:4]([NH:36][C:37]2[S:38][CH:39]=[CH:40][N:41]=2)=[O:9])=[CH:29][CH:28]=[CH:27][N:26]=1
Reactant: Nc1nccs1
Reactant: COc1ccccc1O
Reactant: COc1ccccc1Oc1ncccc1N
Agent: O=[N+]([O-])c1cccnc1Br
Product: COc1ccccc1Oc1ncccc1NC(=O)Nc1nccs1
Yield: 61336.7 %

Procedure:
2-(2-Methoxy)phenoxy-3-nitropyridine (0.86 g, 70%) was prepared from 2-methoxyphenol (0.68 g, 5.5 mmol) and 2-bromo-3-nitropyridine (1.05 g, 5.0 mmol) following the general procedure A. This compound was reduced to 2-(2-methoxyphenoxy)-3-aminopyridine (0.49 g, 65%) following general procedure B. N-[2-(2-Methoxyphenoxy)pyridin-3-yl]-N′-(thiazol-2-yl)urea (126 g, 74%) was prepared from 2-(2-methoxyphenoxy)-3-aminopyridine (108 mg, 0.5 mmol) and 2-aminothiazole (60 mg, 0.6 mmol) following the general procedure D.
Reaction SMILES: [ClH:1].[NH2:2][C:3]1[C:8]([CH2:9][Cl:10])=[CH:7][N:6]=[C:5]([CH2:11]C)[N:4]=1.[F:13][CH2:14][CH2:15][C:16]1[S:20][CH:19]=[N:18][C:17]=1[CH3:21].CS(C)=O>C(O)(C)C>[ClH:10].[Cl-:1].[NH2:2][C:3]1[C:8]([CH2:9][N:18]2[C:17]([CH3:21])=[C:16]([CH2:15][CH2:14][F:13])[S:20][CH2:19]2)=[CH:7][N:6]=[C:5]([CH3:11])[N:4]=1
Reactant: Cc1ncsc1CCF
Reactant: CCc1ncc(CCl)c(N)n1
Agent: Cl
Solvent: CS(C)=O
Solvent: CC(C)O
Product: CC1=C(CCF)SCN1Cc1cnc(C)nc1N
Product: [Cl-]
Temperature: 100 °C
Reaction time: 0.33 h
Yield: 71.7 %

Procedure:
To 25 ml flask 1.7 g (8.2 mmol) of 4-amino-5-chloromethyl 2-ethylpyrimidine hydrochloride and 1.3 g (9.0 mmol) of 5-(2-fluoroethyl)-4-methylthiazole were charged, followed by 1 ml of DMSO. The reaction mixture was stirred at 100° C. for 20 minutes. Then it was cooled to room temperature and 10 ml of isopropanol was added. After standing for 2 h, a precipitate was formed and filtered. 2 g of 3-[(4-amino-2-methylpyrimidin-5-yl)methyl]-5-(2-fluoroethyl)-4-methylthiazol chloride hydrochloride was obtained as white solid (yield 70%).
Reaction SMILES: [CH:1]1([C:6](=[O:19])[CH2:7][CH2:8][NH:9][C:10](=[O:18])[CH2:11][CH2:12][C:13]2[O:14][CH:15]=[CH:16][CH:17]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.C1(C(=O)CCC#CC2C=C(C)C(O)=CC=2C)CCCC1.[Cl:40][CH:41]([C:46]([CH3:48])=[O:47])[C:42](OC)=[O:43]>>[Cl:40][CH:41]1[C:42](=[O:43])[O:19][C:6]([CH2:7][CH2:8][NH:9][C:10](=[O:18])[CH2:11][CH2:12][C:13]2[O:14][CH:15]=[CH:16][CH:17]=2)([CH:1]2[CH2:2][CH2:3][CH2:4][CH2:5]2)[CH2:48][C:46]1=[O:47]
Reactant: COC(=O)C(Cl)C(C)=O
Reactant: O=C(CCc1ccco1)NCCC(=O)C1CCCC1
Agent: Cc1cc(C#CCCC(=O)C2CCCC2)c(C)cc1O
Product: O=C(CCc1ccco1)NCCC1(C2CCCC2)CC(=O)C(Cl)C(=O)O1

Procedure:
The desired product was prepared analogously to example F(1), Step 2, substituting N-(3-cyclopentyl-3-oxo-propyl)-3-furan-2-yl-propionamide (300 mg, 1.1 mmol) from Step 2 above in place of 1-cyclopentyl-5-(4-hydroxy-2,5-dimethyl-phenyl)-pent-4-yn-1-one and methyl 2-chloroacetoacetate (0.7 mL, 5.7 mmol) in place of methyl acetoacetate. Yield: 103 mg, 14%.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][N:5]=[C:4]([NH:12][C:13]2[CH:32]=[CH:31][C:16]([CH2:17][N:18]3[CH2:23][CH2:22][N:21]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:20][CH2:19]3)=[CH:15][CH:14]=2)[N:3]=1.[C:33]([C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][C:36]=1[CH2:41][C:42]([O:44][CH3:45])=[O:43])#[CH:34].C(N(CC)CC)C>CN(C=O)C.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.[Cu]I>[CH3:45][O:44][C:42](=[O:43])[CH2:41][C:36]1[CH:37]=[CH:38][CH:39]=[CH:40][C:35]=1[C:33]#[C:34][C:2]1[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][N:5]=[C:4]([NH:12][C:13]2[CH:32]=[CH:31][C:16]([CH2:17][N:18]3[CH2:23][CH2:22][N:21]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:20][CH2:19]3)=[CH:15][CH:14]=2)[N:3]=1
Reactant: C#Cc1ccccc1CC(=O)OC
Reactant: CC(C)(C)OC(=O)N1CCN(Cc2ccc(Nc3ncc(C(F)(F)F)c(Cl)n3)cc2)CC1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COC(=O)Cc1ccccc1C#Cc1nc(Nc2ccc(CN3CCN(C(=O)OC(C)(C)C)CC3)cc2)ncc1C(F)(F)F
Temperature: 100 °C
Yield: 30 %

Procedure:
tert-Butyl 4-(4-((4-chloro-5-(trifluoromethyl)pyrimidin-2-yl)amino)benzyl)piperazine-1-carboxylate (I94) (0.500 g, 1.06 mmol) and methyl 2-(2-ethynylphenyl)acetate (I4) (0.203 g, 1.17 mmol) were dissolved in DMF (10 mL) and bis(triphenylphosphine)palladium(II) chloride (37 mg, 5 mol %) was added. The mixture was degassed with nitrogen for ten minutes, then copper(I) iodide (10 mg, 5 mol %) and triethylamine (0.738 mL, 5.30 mmol) were added. The mixture was heated under microwave irradiation (100° C./20 minutes) then concentrated. Chromatography of the residue (12 g silica cartridge, 0-100% ethyl acetate/petroleum benzine 40-60° C.) gave the title compound (I95) (192 mg, 30% yield) as a brown oil;
Reaction SMILES: O=[C:2]1[C:10]2([CH2:19][CH2:18][C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[CH2:11]2)[CH2:9][C:8]2[C:3]1=[CH:4][C:5]([C:20]1[CH:21]=[C:22]([CH:25]=[CH:26][CH:27]=1)[C:23]#[N:24])=[CH:6][CH:7]=2.[C:28](=[N:34][Si](C)(C)C)=[N:29][Si](C)(C)C>C(Cl)Cl.Cl[Ti](Cl)(Cl)Cl>[C:23]([C:22]1[CH:21]=[C:20]([C:5]2[CH:4]=[C:3]3[C:8](=[CH:7][CH:6]=2)[CH2:9][C:10]2([CH2:19][CH2:18][C:17]4[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=4)[CH2:11]2)/[C:2]/3=[N:34]/[C:28]#[N:29])[CH:27]=[CH:26][CH:25]=1)#[N:24]
Reactant: C[Si](C)(C)N=C=N[Si](C)(C)C
Reactant: N#Cc1cccc(-c2ccc3c(c2)C(=O)C2(CCc4ccccc4C2)C3)c1
Agent: Cl[Ti](Cl)(Cl)Cl
Solvent: ClCCl
Product: N#C/N=C1\c2cc(-c3cccc(C#N)c3)ccc2CC12CCc1ccccc1C2
Temperature: 50 °C
Reaction time: 0.08 h
Yield: 133.9 %

Procedure:
To a solution of 3-(1-oxo-1,3,3′,4′-tetrahydro-1′H-spiro[indene-2,2′-naphthalene]-6-yl)benzonitrile (35 mg, 0.1 mmol) in DCM (5 mL) was added TiCl4 (76 mg, 0.4 mmol) dropwise, the mixture was stirred at 50° C. at Ar2 under microwave for 5 minutes, N,N′-methanediylidenebis(1,1,1-trimethylsilanamine) (74 mg, 0.4 mmol) was added dropwise. The mixture was stirred at 60° C. at Ar2 under microwave for 10 minutes and poured into ice-water (10 mL). The aqueous layer was extracted with CH2Cl2, which was combined with the organic layer. The organic layer was dried and concentrated to give crude (Z)—N-(5-(3-cyanophenyl)-3′,4′-dihydro-1′H-spiro[indene-2,2′-naphthalene]-3(1H)-ylidene)cyanamide (50 mg, 93%).
Reaction SMILES: [NH2:1][C@@H:2]([C:15]([NH:17][C@@H:18]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:19][C:20](=[O:23])[O:21][CH3:22])=[O:16])[CH2:3][C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[NH:6][C:5]=1[C:13]#[N:14].[N:31]1([C:56]([O:58][C:59]([CH3:62])([CH3:61])[CH3:60])=[O:57])[CH2:55][CH2:54][CH2:53][C@H:32]1[C:33]([NH:35][C@@H:36]([C:42]([NH:44][C@H:45]([C:50](O)=[O:51])[CH2:46][CH:47]([CH3:49])[CH3:48])=[O:43])[C:37]([S:40][CH3:41])([CH3:39])[CH3:38])=[O:34].C1C=CC2N(O)N=NC=2C=1.O.CCN=C=NCCCN(C)C.Cl>CN(C=O)C.C(OCC)(=O)C>[N:31]1([C:56]([O:58][C:59]([CH3:60])([CH3:61])[CH3:62])=[O:57])[CH2:55][CH2:54][CH2:53][C@H:32]1[C:33]([NH:35][C@@H:36]([C:42]([NH:44][C@H:45]([C:50]([NH:1][C@@H:2]([C:15]([NH:17][C@@H:18]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:19][C:20](=[O:23])[O:21][CH3:22])=[O:16])[CH2:3][C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[NH:6][C:5]=1[C:13]#[N:14])=[O:51])[CH2:46][CH:47]([CH3:49])[CH3:48])=[O:43])[C:37]([S:40][CH3:41])([CH3:39])[CH3:38])=[O:34]
Reactant: CSC(C)(C)[C@@H](NC(=O)[C@@H]1CCCN1C(=O)OC(C)(C)C)C(=O)N[C@@H](CC(C)C)C(=O)O
Reactant: COC(=O)C[C@@H](NC(=O)[C@H](N)Cc1c(C#N)[nH]c2ccccc12)C(=O)OC(C)(C)C
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)C[C@@H](NC(=O)[C@@H](Cc1c(C#N)[nH]c2ccccc12)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](NC(=O)[C@@H]1CCCN1C(=O)OC(C)(C)C)C(C)(C)SC)C(=O)OC(C)(C)C
Temperature: 25 °C
Yield: 76.9 %

Procedure:
To a mixture of H-DTrp(2-CN)-DAsp(OMe)-OtBu (26 mg, prepared in Example (9-b)) and Boc-Pro-DPen(Me)-Leu-OH (33 mg, prepared in Example (9-f)) in DMF (3 mL) were added HOBT·H2O (12 mg) and EDCI·HCl (15 mg) under ice-cooling. The mixture was stirred under ice-cooling for 1 h and at room temperature for 1.5 h. The mixture was diluted with ethyl acetate (30 mL), washed with sat. aq. NaHCO3 (15 mL), 10% aq. citric acid (15 mL) and brine (15 mL) successively, dried over MgSO4 and evaporated under reduced pressure. The residue was purified by preparative TLC (Merck, Kieselgel 60 F254) with chloroform/methanol=30/1 for development to give the product (42 mg).
Reaction SMILES: C=[C:2]1[CH2:7][C:6]2([CH2:12][CH2:11][N:10]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:9][CH2:8]2)[O:5][CH2:4][CH2:3]1.I([O-])(=O)(=O)=[O:21].[Na+].O>O1CCOCC1.O.[Os](=O)(=O)(=O)=O.O>[O:21]=[C:2]1[CH2:7][C:6]2([CH2:12][CH2:11][N:10]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:9][CH2:8]2)[O:5][CH2:4][CH2:3]1
Reactant: [O-][I+3]([O-])([O-])[O-]
Reactant: C=C1CCOC2(CCN(C(=O)OC(C)(C)C)CC2)C1
Agent: O=[Os](=O)(=O)=O
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)N1CCC2(CC1)CC(=O)CCO2
Temperature: 25 °C
Reaction time: 2 h
Yield: 59.5 %

Procedure:
To a solution of Compound 29a (1.6 g, 5.99 mmol) in a mixture of dioxane-water (32.9 mL and 11 mL respectively) under stirring at r.t. was added a 4% sol. of osmium tetroxide in water (0.762 μL, 0.125 mmol). After 2 h, was added portionwise milled sodium metaperiodate (2.56 g, 12 mmol) affording a suspension that tended to become clear gray from brownish. After 4 h H2O was added, extracting with EtOAc, washing with H2O, drying over Na2SO4, evaporating the solvent to dryness. The residual tawny semi-solid was purified by means of automated flash chromatography (SP1®TM-Biotage; Petroleum Ether-EtOAc 7:3) to give 0.96 g of the title compound as a grey solid. Yield: 59.5%
Reaction SMILES: [BH4-].[Na+].[C:3]([C:5]1[O:9][C:8]([CH:10]=[O:11])=[CH:7][CH:6]=1)#[N:4].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>C(O)C.O>[OH:11][CH2:10][C:8]1[O:9][C:5]([C:3]#[N:4])=[CH:6][CH:7]=1
Reactant: N#Cc1ccc(C=O)o1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: N#Cc1ccc(CO)o1
Temperature: -30 °C
Reaction time: 2 h
Yield: 8800 %

Procedure:
2.34 g (62 mmol) of sodium borohydride were added in portions to a solution of 30 g (0.25 mol) of 5-cyanofuran-2-carbaldehyde in 500 ml of absolute ethanol at -30° C. The solution was stirred at -30° C. for 2 hours and, while cooling, was adjusted to pH 7 with a 5% strength citric acid solution in water. The reaction mixture was concentrated under water pump vacuum, saturated sodium chloride solution was added to the residue, the mixture was extracted several times with 150 ml of diethyl ether each time, the combined organic phases were dried over magnesium sulfate, the desiccant was filtered off, and the solvent was distilled off under water pump vacuum at room temperature. This resulted in 27 g (22 mol, 88%) of the title compound as a dark red oil, which was employed without further purification in the following reactions. 1H-NMR (250 MHz, d6 -DMSO): δ=4.4 (m, 2H), 5.6 (bs, 1H), 6.6 (d, 1H), 7.5 (d, 1H).
Reaction SMILES: [Cl:1][C:2]1[C:21]([Cl:22])=[CH:20][C:5]2[N:6]=[C:7]([C:9]3[CH:14]=[CH:13][C:12]([C:15]([OH:17])=O)=[CH:11][C:10]=3[O:18]C)[NH:8][C:4]=2[CH:3]=1.ClC1C(Cl)=CC2N=C(C3C=CC(C(O)=O)=CC=3O)NC=2C=1.Cl.CN(C)CCCN=C=NCC.[CH3:56][N:57]1[C:62]([CH3:64])([CH3:63])[CH2:61][CH:60]([NH2:65])[CH2:59][C:58]1([CH3:67])[CH3:66]>C1COCC1>[Cl:22][C:21]1[C:2]([Cl:1])=[CH:3][C:4]2[N:8]=[C:7]([C:9]3[CH:14]=[CH:13][C:12]([C:15]([NH:65][CH:60]4[CH2:59][C:58]([CH3:66])([CH3:67])[N:57]([CH3:56])[C:62]([CH3:64])([CH3:63])[CH2:61]4)=[O:17])=[CH:11][C:10]=3[OH:18])[NH:6][C:5]=2[CH:20]=1
Reactant: COc1cc(C(=O)O)ccc1-c1nc2cc(Cl)c(Cl)cc2[nH]1
Reactant: CN1C(C)(C)CC(N)CC1(C)C
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: O=C(O)c1ccc(-c2nc3cc(Cl)c(Cl)cc3[nH]2)c(O)c1
Solvent: C1CCOC1
Product: CN1C(C)(C)CC(NC(=O)c2ccc(-c3nc4cc(Cl)c(Cl)cc4[nH]3)c(O)c2)CC1(C)C
Temperature: 25 °C

Procedure:
A solution of 5,6-dichloro-2-(4-carboxy-2-methoxyphenyl)benzimidazole and 5,6-dichloro-2-(4-carboxy-2-hydroxyphenyl)benzimidazole (0.5 g, 1.48 mmol), prepared as described in Preparation 3,1-hydroxybenzotriazole (0.21 g, 1.56 mmol) and N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (0.35 g, 1.82 mmol) in THF (20 ml) was refluxed for 5 h. A solution of 1,2,2,6,6-pentamethyl-4-aminopiperidine (0.25 g, 1.5 mmol) in THF (3 ml) was added dropwise and refluxed for 3 h. After cooling to room temperature the solvent was evaporated under vacuum and the crude residue was purified by column chromatography eluting with CH2Cl2/MeOH/NH4OH 86:10:0.6 to give 10 mg of the title compound, mp>250° C.
Reaction SMILES: [OH:1][CH2:2][CH2:3][O:4][C@H:5]([CH2:9][O:10][C:11]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[CH2:6][CH2:7][OH:8].C(N(CC)CC)C.[CH3:37][S:38](Cl)(=[O:40])=[O:39]>C(Cl)Cl>[CH3:37][S:38]([O:8][CH2:7][CH2:6][C@H:5]([O:4][CH2:3][CH2:2][O:1][S:38]([CH3:37])(=[O:40])=[O:39])[CH2:9][O:10][C:11]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)([C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1)[C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1)(=[O:40])=[O:39]
Reactant: CS(=O)(=O)Cl
Reactant: OCCO[C@@H](CCO)COC(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)OCCO[C@@H](CCOS(C)(=O)=O)COC(c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 88.3 %

Procedure:
(S)-3-(2-hydroxyethoxy)-4-(tripenylmethoxy)-1-butanol (500 g, 1.27 mole) was dissolved in 4.8 L of CH2Cl2, was cooled to 0° C. under N2, and triethylamine (386.4 g, 532 mL, 3.81 mole, 3.0 eq.) was added. Methanesulfonyl chloride (396.3 g, 268 mL, 3.46 mole, 2.7 eq.) was then added dropwise over 30 minutes at <5° C. The resultant reaction mixture was stirred at 0° to 5° C. for 1-2 hours and was monitored by HPLC. The reaction mixture was diluted with additional CH2Cl2 and was washed twice with 2 L of water and 2 L of an aqueous saturated solution of ammonium chloride. The aqueous layers were back-extracted with 1 L of CH2Cl2 and the combined organic layer was dried (MgSO4) and evaporated in vacuo to give a crude solid that was recrystallized from 1/1 heptane/ethyl acetate to give 615 g (88%) of (S)-3-[2-[(methylsulfonyl)oxy]ethoxy]-4-(triphenylmethoxy)-1-butanol methane sulfonate in three crops as a solid. NMR. MS.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][CH:6]=[N:5]2.[BH4-].[Na+]>CO.O.O.O.O.O.O.[Ni](Cl)Cl>[CH3:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH2:7][CH2:6][NH:5]2
Reactant: Cc1ccc2nccnc2c1
Agent: Cl[Ni]Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: Cc1ccc2c(c1)NCCN2
Temperature: 0 °C
Reaction time: 4 h
Yield: 42.8 %

Procedure:
To a solution of 6-methylquinoxaline (2 g, 13.87 mmol) and nickel (II) chloride hexahydrate (6.6 g, 27.74 mmol) in anhydrous methanol (70 mL) was added in portions, sodium borohydride (10.5 g, 277.43 mmol) while maintaining the temperature between 0° C. and 5° C. The reaction mixture was stirred at 0° C. for 20 minutes and at room temperature for 4 hours. Removal of the solvent under reduced pressure was ensued by acidification of the residue with 2N HCl (600 mL). The mixture was stirred at room temperature for 16 hours and filtered. The green filtrate was made basic (pH 10-11) using concentrated NH4OH (150 mL) and extracted with diethylether (3×200 mL). The ethereal extracts were successively washed with water (2×300 mL), a saturated aqueous solution of NaCl (150 mL), dried over MgSO4 and filtered. Removal of the solvent under reduced pressure gave 6-methyl-1,2,3,4-tetrahydroquinoxaline as a solid (880 mg, 43%).
Reaction SMILES: [C:1]([C:3]1[C:4](F)=[C:5]([F:22])[CH:6]=[C:7]2[C:12]=1[N:11]([CH:13]1[CH2:15][CH2:14]1)[CH:10]=[C:9]([C:16]([O:18][CH2:19][CH3:20])=[O:17])[C:8]2=[O:21])#[N:2].[C@@H:24]12[CH2:32][NH:31][CH2:30][C@@H:29]1[CH2:28][CH2:27][CH2:26][NH:25]2.C(N(CC)CC)C>C(#N)C>[C:1]([C:3]1[C:4]([N:31]2[CH2:32][C@@H:24]3[C@@H:29]([CH2:28][CH2:27][CH2:26][NH:25]3)[CH2:30]2)=[C:5]([F:22])[CH:6]=[C:7]2[C:12]=1[N:11]([CH:13]1[CH2:15][CH2:14]1)[CH:10]=[C:9]([C:16]([O:18][CH2:19][CH3:20])=[O:17])[C:8]2=[O:21])#[N:2]
Reactant: C1CN[C@@H]2CNC[C@@H]2C1
Reactant: CCOC(=O)c1cn(C2CC2)c2c(C#N)c(F)c(F)cc2c1=O
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CCOC(=O)c1cn(C2CC2)c2c(C#N)c(N3C[C@@H]4CCCN[C@@H]4C3)c(F)cc2c1=O
Yield: 81.7 %

Procedure:
14.32 g (45 mmol) of ethyl 8-cyano-1-cyclopropyl-6,7-difluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylate, 6.31 g (50 mmol) of (1S,6S)-2,8-diazabicyclo[4.3.0]nonane and 10.22 g (101 mmol) of triethylamine are boiled under reflux in 270 ml of acetonitrile for 4 hours. The reaction mixture is left to stand at room temperature for some hours and the solid which has crystallized out is filtered off with suction, rinsed with acetonitrile and dried. 15.6 g of a beige solid are obtained (82% of theory).
Reaction SMILES: [CH2:1]([N:3]([Si](C)(C)C)[CH2:4][CH3:5])[CH3:2].[CH2:10]([N:12]([S:15](F)(F)[F:16])[CH2:13][CH3:14])[CH3:11].[C:19]([F:22])([F:21])=[O:20]>C(#N)C>[F:21][C:19]([F:16])([F:22])[O-:20].[CH2:1]([N:3]([S+:15]([N:3]([CH2:4][CH3:5])[CH2:1][CH3:2])[N:12]([CH2:13][CH3:14])[CH2:10][CH3:11])[CH2:4][CH3:5])[CH3:2]
Reactant: CCN(CC)[Si](C)(C)C
Reactant: O=C(F)F
Reactant: CCN(CC)S(F)(F)F
Solvent: CC#N
Product: CCN(CC)[S+](N(CC)CC)N(CC)CC
Product: [O-]C(F)(F)F
Reaction time: 8 h
Yield: 91 %

Procedure:
Diethylaminotrimethylsilane (29.06 g, 0.2 mol) was added dropwise to a solution of 12.5 mL (0.1 mol) of diethylaminosulfur trifluoride in 75 mL of acetonitrile at 25°. The reaction mixture was stirred overnight, and then saturated with carbonyl fluoride. Evaporation of the solvent under reduced pressure gave 30.3 g (91%) of the trifluoromethoxide: mp 85°-95°; 1H NMR (CD3CN) δ1.21 ppm (t, J=7H, 9H), 3.29 ppm (q, J=7 Hz, 6H); F NMR (CD3CN) δ-20.8 ppm. Anal. Calcd. for C13H30F3N3OS: C, 46.83; H, 9.07; F, 17.07; N, 12.60. Found: C, 46.53; H, 9.17; F, 17.25; N, 12.55.
Reaction SMILES: [C:1]([NH:5][CH2:6][CH:7]([OH:26])[CH2:8][O:9][C:10]1[CH:15]=[C:14]([O:16][CH3:17])[CH:13]=[CH:12][C:11]=1[C:18]1[N:23]=[N:22][C:21]([O:24]C)=[CH:20][CH:19]=1)([CH3:4])([CH3:3])[CH3:2].Cl.C(=O)([O-])[O-].[K+].[K+]>>[C:1]([NH:5][CH2:6][CH:7]([OH:26])[CH2:8][O:9][C:10]1[CH:15]=[C:14]([O:16][CH3:17])[CH:13]=[CH:12][C:11]=1[C:18]1[CH:19]=[CH:20][C:21](=[O:24])[NH:22][N:23]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: COc1ccc(-c2ccc(OC)nn2)c(OCC(O)CNC(C)(C)C)c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Product: COc1ccc(-c2ccc(=O)[nH]n2)c(OCC(O)CNC(C)(C)C)c1

Procedure:
6-[2-(3-t-Butylamino-2-hydroxypropoxy)-4-methoxyphenyl]-3-methoxypyridazine was hydrolysed with hydrochloric acid in a manner similar to that described in Example 3 vi). Addition of an excess of potassium carbonate to the cooled solution afforded the title compound which was recrystallised from ethanol/ether, m.p. 159°-161° C.