Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC([N:6]([CH2:13][CH:14]([CH3:24])[CH2:15][P:16](=[O:23])([O:20]CC)[O:17]CC)[O:7]C(OCC)=O)=O)C.[ClH:25].C(OCC)(=O)C.N>CO.O>[ClH:25].[OH:7][NH:6][CH2:13][CH:14]([CH3:24])[CH2:15][P:16](=[O:17])([OH:23])[OH:20]
Reactant: CCOC(=O)ON(CC(C)CP(=O)(OCC)OCC)C(=O)OCC
Agent: Cl
Agent: N
Solvent: CCOC(C)=O
Solvent: O
Solvent: CO
Product: CC(CNO)CP(=O)(O)O

Procedure:
A mixture of diethyl 3-(N-ethoxycarbonyl-N-ethoxycarbonyloxyamino)-2-methylpropylphosphonate (28.3 g.). and conc. hydrochloric acid (280 ml.) was refluxed for 18 hours and then concentrated under reduced pressure to give an oily residue. To the residue was added a mixture of water (100 ml.) and ethyl acetate (100 ml.). From the resultant mixture, the aqueous layer was separated, treated with activated charcoal and concentrated under reduced pressure to give an oily residue. The residue was dissolved in a mixture of methanol (30 ml.) and water (15 ml.). The solution was adjusted to pH 4.0 with aqueous ammonia under ice-cooling and concentrated under reduced pressure to give a residue, which was passed through a column of anion exchange resin, Amberlite IRA-400 (OH- form). The column was washed with water and then the object compound was eluted with 1 N hydrochloric acid. The eluate was concentrated under reduced pressure to give oily hydrochloric acid salt of 3-(N-hydroxyamino)-2-methylpropylphosphonic acid (9.6 g.).
Reaction SMILES: Cl[CH2:2][C:3]([C:5]1[CH:9]=[C:8]([C:10](=[O:18])[C:11]2[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][CH:12]=2)[N:7]([CH3:19])[CH:6]=1)=[O:4].[CH:20]([N-:22][CH:23]=[O:24])=[O:21].[Na+]>C(#N)C>[CH:20]([N:22]([CH:23]=[O:24])[CH2:2][C:3]([C:5]1[CH:9]=[C:8]([C:10](=[O:18])[C:11]2[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][CH:12]=2)[N:7]([CH3:19])[CH:6]=1)=[O:4])=[O:21]
Reactant: Cn1cc(C(=O)CCl)cc1C(=O)c1ccc(Cl)cc1
Reactant: O=C[N-]C=O
Agent: [Na+]
Solvent: CC#N
Product: Cn1cc(C(=O)CN(C=O)C=O)cc1C(=O)c1ccc(Cl)cc1
Reaction time: 1.5 h
Yield: 54.6 %

Procedure:
A solution of 10 g (0.034 mole) of 2-chloro-1-[5-(4-chlorobenzoyl)-1-methyl-1H-pyrrol-3-yl]-ethanone and 3.8 g (0.041 mole) sodium diformylamide in 80 mL acetonitrile was heated under reflux overnight under argon. An additional 2.0 g portion of sodium diformylamide was added and reflux was continued for 1.5 hrs. After evaporation of the solvent in vacuo the residue was passed through a flash column (silica gel, 3:1 hexane:acetone the 2:1 hexane:acetone) to give 6.18 g of a solid. mp 279°-282° C. 260° C. decomp. mass spectrum (Cl--CH4) m/z=333 (M+1). NMR 300 MHz (CDCl3) d 9.0 (s, 2H); 7.8 (d, 2H); 7.55 (s, 1H); 7.45 (d, 2H); 7.1 (s, 1H); 4.85 (s, 2H); 4.1 (s, 3H).
Reaction SMILES: [C:1]([C:3]1[CH:10]=[CH:9][C:6]([CH:7]=O)=[CH:5][CH:4]=1)#[N:2].[NH2:11][C:12]1[CH:13]=[C:14]([CH:18]=[CH:19][CH:20]=1)[C:15]([OH:17])=[O:16].C([BH3-])#N.[Na+].C(O)(=O)C>CN(C)C=O>[C:1]([C:3]1[CH:10]=[CH:9][C:6]([CH2:7][NH:11][C:12]2[CH:13]=[C:14]([CH:18]=[CH:19][CH:20]=2)[C:15]([OH:17])=[O:16])=[CH:5][CH:4]=1)#[N:2]
Reactant: N#Cc1ccc(C=O)cc1
Reactant: Nc1cccc(C(=O)O)c1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CN(C)C=O
Product: N#Cc1ccc(CNc2cccc(C(=O)O)c2)cc1
Yield: 75.3 %

Procedure:
4-cyanobenzaldehyde (0.65 g; 5 mmoles), 3-aminobenzoic acid (0.68 g; 5 mmoles) and sodiumcyanoborohydride (0.35 g; 5 mmols) were stirred in N,N-dimethylformamide (25 ml) containing 1% acetic acid at room temperature for 2 hrs. The product was precipitated out by addition of water. The solid was filtered and dried in vacuo to give 0.95 g white solid. FAB-MS: MH+ =253.
Reaction SMILES: [C:1]([O:5][C:6]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1B1OC(C)(C)C(C)(C)O1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C1(C)C=CC=CC=1.[CH2:30]([O:32][C:33](=[O:55])[C@H:34]([OH:54])[C@H:35]([NH:43][C:44](=[O:53])[C:45]1[CH:50]=[CH:49][C:48]([F:51])=[C:47](Br)[CH:46]=1)[CH2:36][C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1)[CH3:31].C([O-])([O-])=O.[K+].[K+]>O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CCO>[C:1]([O:5][C:6]([C:8]1[C:9]([C:47]2[CH:46]=[C:45]([C:44](=[O:53])[NH:43][C@H:35]([CH2:36][C:37]3[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=3)[C@H:34]([C:33]([O:32][CH2:30][CH3:31])=[O:55])[OH:54])[CH:50]=[CH:49][C:48]=2[F:51])=[CH:10][CH:11]=[CH:12][CH:13]=1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CCOC(=O)[C@H](O)[C@@H](Cc1ccccc1)NC(=O)c1ccc(F)c(Br)c1
Reactant: CC(C)(C)OC(=O)c1ccccc1B1OC(C)(C)C(C)(C)O1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: Cc1ccccc1
Solvent: CCO
Product: CCOC(=O)[C@H](O)[C@@H](Cc1ccccc1)NC(=O)c1ccc(F)c(-c2ccccc2C(=O)OC(C)(C)C)c1
Temperature: 100 °C

Procedure:
2-t-Butoxycarbonylphenylboronic acid pinacol ester (173 mg, 568 μmol, 1.2 eq.) and toluene (661 μL) were added to (2R,3R)-3-(3-bromo-4-fluoro-benzoylamino)-2-hydroxy-4-phenyl-butyric acid ethyl ester (201 mg, 474 μmol, 1.0 eq.), followed by EtOH (361 μL) then K2CO3 (131 mg, 947 μmol, 2.0 eq.) predissolved in water (124 μL). The mixture was stirred to aid in dissolution. The reaction vessel was purged with nitrogen then Pd(PPh3)4 (54.7 mg, 47.4 μmol) was added quickly. The reaction vessel was capped and heated to 100° C. for 30 minutes. The organics were removed and evaporated under vacuum to yield 5′-((1R,2R)-1-benzyl-2-ethoxycarbonyl-2-hydroxy-ethylcarbamoyl)-2′-fluoro-biphenyl-2-carboxylic acid t-butyl ester.
Reaction SMILES: [Cl:1][C:2]1[C:10]([Cl:11])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.[Cl:12][C:13]1[CH:18]=[CH:17][C:16]([CH:19]([CH:22]2[CH2:27][CH2:26][O:25][CH2:24][CH2:23]2)[CH2:20][NH2:21])=[CH:15][CH:14]=1>>[Cl:1][C:2]1[C:10]([Cl:11])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([NH:21][CH2:20][CH:19]([C:16]1[CH:15]=[CH:14][C:13]([Cl:12])=[CH:18][CH:17]=1)[CH:22]1[CH2:23][CH2:24][O:25][CH2:26][CH2:27]1)=[O:6]
Reactant: O=C(O)c1cccc(Cl)c1Cl
Reactant: NCC(c1ccc(Cl)cc1)C1CCOCC1
Product: O=C(NCC(c1ccc(Cl)cc1)C1CCOCC1)c1cccc(Cl)c1Cl

Procedure:
From 2,3-dichlorobenzoic acid and 2-(4-chlorophenyl)-2-(tetrahydro-2H-pyran-4-yl)ethanamine. LCMS (MH+): m/z=412.1, tR (minutes, Method G)=2.49
Reaction SMILES: [NH2:1][C@H:2]1[CH2:7][CH2:6][CH2:5][CH2:4][C@H:3]1[NH:8][C:9]1[N:14]=[C:13](NC2C=CC(C3ON=CC=3)=CC=2)[C:12]([C:27]([NH2:29])=[O:28])=[CH:11][N:10]=1.[CH3:30][C:31]1[CH:35]=[C:34]([CH3:36])[N:33]([C:37]2[CH:43]=[CH:42][C:40]([NH2:41])=[CH:39][CH:38]=2)[N:32]=1>>[NH2:1][C@H:2]1[CH2:7][CH2:6][CH2:5][CH2:4][C@H:3]1[NH:8][C:9]1[N:14]=[C:13]([NH:41][C:40]2[CH:42]=[CH:43][C:37]([N:33]3[C:34]([CH3:36])=[CH:35][C:31]([CH3:30])=[N:32]3)=[CH:38][CH:39]=2)[C:12]([C:27]([NH2:29])=[O:28])=[CH:11][N:10]=1
Reactant: NC(=O)c1cnc(N[C@@H]2CCCC[C@@H]2N)nc1Nc1ccc(-c2ccno2)cc1
Reactant: Cc1cc(C)n(-c2ccc(N)cc2)n1
Product: Cc1cc(C)n(-c2ccc(Nc3nc(N[C@@H]4CCCC[C@@H]4N)ncc3C(N)=O)cc2)n1

Procedure:
This compound was synthesised using the synthetic scheme described for the synthesis of compound 122, and using 4-(3,5-dimethyl-1H-pyrazol-1-yl)aniline in step 1. MS: 421.5 (M+H).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:63])[C@@H:4]([CH2:59][CH:60]([CH3:62])[CH3:61])[NH:5][C:6](=[O:58])[C@H:7]([CH2:43][C:44]1[CH:49]=[CH:48][C:47]([O:50][CH2:51][C:52]2[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=2)=[CH:46][CH:45]=1)[NH:8][C:9](=[O:42])[C@H:10]([CH2:33][O:34][CH2:35][C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)[NH:11][C:12](=[O:32])[C@H:13]([CH2:22][C:23]1[C:31]2[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=2)[NH:25][CH:24]=1)[NH:14][C:15]([O:17]C(C)(C)C)=O.FC(F)(F)C(O)=O.[CH:71]1(C(O)=O)[CH2:76][CH2:75][CH2:74][CH2:73][CH2:72]1.ON1C2C=CC=CC=2N=N1.C1(N=C=NC2CCCCC2)CCCCC1>C(N(CC)CC)C>[CH3:1][O:2][C:3](=[O:63])[C@@H:4]([CH2:59][CH:60]([CH3:62])[CH3:61])[NH:5][C:6](=[O:58])[C@H:7]([CH2:43][C:44]1[CH:49]=[CH:48][C:47]([O:50][CH2:51][C:52]2[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=2)=[CH:46][CH:45]=1)[NH:8][C:9](=[O:42])[C@H:10]([CH2:33][O:34][CH2:35][C:36]1[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=1)[NH:11][C:12](=[O:32])[C@H:13]([CH2:22][C:23]1[C:31]2[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=2)[NH:25][CH:24]=1)[NH:14][C:15]([CH:71]1[CH2:76][CH2:75][CH2:74][CH2:73][CH2:72]1)=[O:17]
Reactant: COC(=O)[C@@H](CC(C)C)NC(=O)[C@H](Cc1ccc(OCc2ccccc2)cc1)NC(=O)[C@H](COCc1ccccc1)NC(=O)[C@H](Cc1c[nH]c2ccccc12)NC(=O)OC(C)(C)C
Reactant: O=C(O)C1CCCCC1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: On1nnc2ccccc21
Solvent: O=C(O)C(F)(F)F
Solvent: CCN(CC)CC
Product: COC(=O)[C@@H](CC(C)C)NC(=O)[C@H](Cc1ccc(OCc2ccccc2)cc1)NC(=O)[C@H](COCc1ccccc1)NC(=O)[C@H](Cc1c[nH]c2ccccc12)NC(=O)C1CCCCC1

Procedure:
Nα-t-Butoxycarbonyl-L-tryptophyl-O-benzyl-L-seryl-O-benzyl-L-tyrosyl-D-leucine methyl ester (Example 17), 1 g., 1.16 mmol, is reacted according to the appropriate part of Example 1 with 20 ml. of trifluoroacetic acid, neutralized with triethylamine and coupled with 150 mg., 1.17 mmol, of cyclohexane carboxylic acid using 180 mg., 1.17 mmol, of 1-hydroxybenzotriazole and 240 mg., 1.17 mmol, of dicyclohexylcarbodiimide. The solution is evaporated and the residue triturated with ether. The product is precipitated from isopropanol on cooling as a cream solid; 1 g.; m.p. 158°-160° C.
Reaction SMILES: N1C(Cl)=NC(Cl)=NC=1Cl.C(N(CC)CC)C.[F:17][CH:18]([F:35])[O:19][C:20]1[CH:21]=[CH:22][C:23]([C:32]([OH:34])=O)=[C:24]2[C:28]=1[O:27][C:26]([CH2:29][O:30][CH3:31])=[CH:25]2.[CH3:36][C:37]1[C:41]([NH2:42])=[C:40]([CH3:43])[O:39][N:38]=1>ClCCl>[CH3:36][C:37]1[C:41]([NH:42][C:32]([C:23]2[CH:22]=[CH:21][C:20]([O:19][CH:18]([F:17])[F:35])=[C:28]3[O:27][C:26]([CH2:29][O:30][CH3:31])=[CH:25][C:24]=23)=[O:34])=[C:40]([CH3:43])[O:39][N:38]=1
Reactant: COCc1cc2c(C(=O)O)ccc(OC(F)F)c2o1
Reactant: Cc1noc(C)c1N
Agent: Clc1nc(Cl)nc(Cl)n1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COCc1cc2c(C(=O)Nc3c(C)noc3C)ccc(OC(F)F)c2o1
Reaction time: 8 h
Yield: 28.8 %

Procedure:
Cyanuric chloride (19 mg) and triethylamine (0.05 ml) were added to a stirred solution of 7-difluoromethoxy-2-methoxymethylbenzofuran-4-carboxylic acid (85 mg) in dry dichloromethane at room temperature under a dry nitrogen atmosphere. After stirring for 20 minutes 3,5-dimethylisoxazol-4-ylamine (42 mg) was added and the reaction left overnight. The reaction was mixture was preadsorbed onto silica. Purification by column chromatography on silica eluting with 30% ethyl acetate in hexane gave the title compound as a cream solid (33 mg)
Reaction SMILES: Br[C:2]1[C:3]([N:24]2[CH2:29][CH2:28][CH2:27][C@@H:26]([NH:30][C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[CH2:25]2)=[C:4]2[C:10]([NH:11][C:12]([CH:14]3[CH2:16][CH2:15]3)=[O:13])=[CH:9][N:8]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[C:5]2=[N:6][CH:7]=1.[C:38](=O)([O-])[O-].[K+].[K+].CB1OB(C)OB(C)O1.CC#N.O>O1CCOCC1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:34]([O:33][C:31]([NH:30][C@@H:26]1[CH2:27][CH2:28][CH2:29][N:24]([C:3]2[C:2]([CH3:38])=[CH:7][N:6]=[C:5]3[N:8]([C:17]([O:19][C:20]([CH3:22])([CH3:21])[CH3:23])=[O:18])[CH:9]=[C:10]([NH:11][C:12]([CH:14]4[CH2:16][CH2:15]4)=[O:13])[C:4]=23)[CH2:25]1)=[O:32])([CH3:36])([CH3:37])[CH3:35]
Reactant: O=C([O-])[O-]
Reactant: CC(C)(C)OC(=O)N[C@@H]1CCCN(c2c(Br)cnc3c2c(NC(=O)C2CC2)cn3C(=O)OC(C)(C)C)C1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: CB1OB(C)OB(C)O1
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Solvent: CC#N
Product: Cc1cnc2c(c(NC(=O)C3CC3)cn2C(=O)OC(C)(C)C)c1N1CCC[C@@H](NC(=O)OC(C)(C)C)C1
Yield: 55.3 %

Procedure:
A solution of (R)-tert-butyl 5-bromo-4-(3-(tert-butoxycarbonylamino) piperidin-1-yl)-3-(cyclopropanecarboxamido)-1H-pyrrolo[2,3-b]pyridine-1-carboxylate (175 mg, 0.303 mmol) in dioxane (5 mL) at room temperature was treated with potassium carbonate (107 mg, 0.771 mmol), Pd(PPh3)4 (31.5 mg, 0.0272 mmol), and 2,4,6-trimethyl-1,3,5,2,4,6-trioxatriborinane (34.2 mg, 0.272 mmol). N2 was bubbled through the mixture for 5 minutes, and the mixture was heated at reflux for 24 hours under N2 atmosphere. The mixture was then diluted with EtOAc (20 mL) and washed with water (1×5 mL). The organic layer was separated, dried (MgSO4), filtered, and concentrated in vacuo. The residue obtained was purified by reverse phase chromatography (Biotage SP4, C-18 25M+, 40-95% CH3CN/water, 24 CV) to provide (R)-tert-butyl 4-(3-(tert-butoxycarbonylamino)piperidin-1-yl)-3-(cyclopropanecarboxamido)-5-methyl-1H-pyrrolo[2,3-b]pyridine-1-carboxylate (86 mg, 55% yield) as a solid. LCMS (APCI+) m/z 514.1 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:19]=[C:18]([N+:20]([O-])=O)[CH:17]=[CH:16][C:4]=1[O:5][CH2:6][CH2:7][N:8]1[CH2:13][CH:12]([CH3:14])[CH2:11][CH:10]([CH3:15])[CH2:9]1>ClCCl.CO>[CH3:14][CH:12]1[CH2:11][CH:10]([CH3:15])[CH2:9][N:8]([CH2:7][CH2:6][O:5][C:4]2[CH:16]=[CH:17][C:18]([NH2:20])=[CH:19][C:3]=2[O:2][CH3:1])[CH2:13]1
Reactant: COc1cc([N+](=O)[O-])ccc1OCCN1CC(C)CC(C)C1
Solvent: CO
Solvent: ClCCl
Product: COc1cc(N)ccc1OCCN1CC(C)CC(C)C1

Procedure:
Prepared analogously to Example 3.1.b. from 1-[2-(2-methoxy-4-nitrophenoxy)ethyl]-3,5-dimethylpiperidine. Yield: 0.35 g (96.9% of theory); C15H24N2O2 (M=264.37); calc.: molecular ion peak (M+H)+: 279; found: molecular ion peak (M+H)+: 279; Rf value: 0.3 (silica gel, dichloromethane/methanol (9:1)).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][C:7]([NH:9][C@@H:10]1[C:32](=[O:33])[N:12]2[C:13]([C:29]([OH:31])=[O:30])=[C:14]([CH2:17]OC(=O)C(C3C=CC=CC=3)O)[CH2:15][S:16][C@H:11]12)=[O:8].[SH:34][C:35]1[N:39]([CH3:40])[N:38]=[N:37][N:36]=1.C(=O)([O-])O.[Na+]>O>[S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][C:7]([NH:9][C@@H:10]1[C:32](=[O:33])[N:12]2[C:13]([C:29]([OH:31])=[O:30])=[C:14]([CH2:17][S:34][C:35]3[N:39]([CH3:40])[N:38]=[N:37][N:36]=3)[CH2:15][S:16][C@H:11]12)=[O:8]
Reactant: Cn1nnnc1S
Reactant: O=C(Cc1cccs1)N[C@@H]1C(=O)N2C(C(=O)O)=C(COC(=O)C(O)c3ccccc3)CS[C@H]12
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Product: Cn1nnnc1SCC1=C(C(=O)O)N2C(=O)[C@@H](NC(=O)Cc3cccs3)[C@H]2SC1
Temperature: 60 °C
Reaction time: 0.5 h
Yield: 88.1 %

Procedure:
In water (4 ml) was dissolved 7β-(2-thienylacetamido)-3-mandelyloxymethyl-3-cephem-4-carboxylic acid (0.49 g) together with 5-mercapto-1-methyl-1H-tetrazole (0.12 g) and sodium hydrogen carbonate (0.17 g). The solution was stirred at 60° C. for 30 minutes. After the reaction had been completed, the reaction mixture was treated by a procedure similar to that described in Example 85. The procedure provided 7β-(2-thienylacetamido)-3-(1-methyl-1H-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylic acid (0.40 g).
Reaction SMILES: [CH3:1][C:2]1([C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH2:7][CH2:6][CH2:5][CH2:4][C:3]1=[O:8].[BH4-].[Na+]>C(O)C>[OH:8][CH:3]1[CH2:4][CH2:5][CH2:6][CH2:7][C:2]1([CH3:1])[C:9]([O:11][CH2:12][CH3:13])=[O:10]
Reactant: CCOC(=O)C1(C)CCCCC1=O
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: CCOC(=O)C1(C)CCCCC1O

Procedure:
For the synthesis of the protected acid side-chain 1-methyl-2-(tetrahydropyran-2′-yloxy)-cyclohexane carboxylic acid, ethyl 2-oxocyclohexane carboxylate (8.5 g, 50 mmol) was dissolved in dry THF at ambient temperature under N2. Potassium tert-butoxide (75 mmol) was added slowly and the reaction was stirred for 5 minutes. Iodomethane (100 mmol) was then added and the reaction was stirred at ambient temperature for 1 hour. The reaction solvent was removed under reduced pressure and the residue was partitioned between water and hexane. The organic layer was dried over sodium sulfate and reduced under reduced pressure to give racemic ethyl 1-methyl-2-oxo-cyclohexanecarboxylate as a colourless oil (8.11 g 88%); δH (400 MHz, CDCl3) 4.25-4.12 (2H, m, OCH2CH3), 2.55-2.40 (3H, m, CH2CO and one other cyclohexane peak), 2.05-1.95 (1H, m, cyclohexane), 1.77-1.57 (3H, m, cyclohexane), 1.50-1.40 (1H, m, cyclohexane), 1.28 (3H, s, CCH3) and 1.25 (1H, t, J 7, CH2CH3). Ethyl 1-methyl-2-oxo-cyclohexanecarboxylate (5.52 g, 30 mmol) was dissolved in ethanol (100 ml) at ambient temperature and sodium borohydride (1.14 g, 30 mmol) was added slowly. After 1 hour the reaction solvent was removed in vacuo and the residue was partitioned between water and dichloromethane. The organic extracts were dried over sodium sulphate and reduced to give ethyl 2-hydroxy-1-methylcyclohexanecarboxylate as a mixture of diastereoisomers (5.37 g 96%). This material was then protected and the ester hydrolysed as follows: Ethyl 2-hydroxy-1-methylcyclohexanecarboxylate (16.7 mmol) was dissolved in dichloromethane along with 3,4-dihydro-2H-pyran (17 mmol) and para-toluene-sulphonic acid (5 mg), and the reaction was stirred at ambient temperature for 16 hours. The solvent was removed under reduced pressure to give a residue to which was added ethanol (40 ml), water (10 ml) and potassium hydroxide (20 mmol). The mixture was heated at reflux overnight and allowed to cool. The reaction solvent was removed under reduced pressure and the residue was partioned between water and diethyl ether. The aqueous layer was acidified to pH 2 and then extracted with diethyl ether. This ether layer was dried over sodium sulphate and reduced in vacuo to give crude 1-methyl-2-(tetrahydropyran-2′-yloxy)-cyclohexane carboxylic acid (2.52 g) as a mixture of diastereoisomers. This material was used in the synthesis of (S)-3-(2′-hydroxy-1′-methylcyclohexanecarbonyl)amino-caprolactam above
Reaction SMILES: CC1(C)[O:6][C@H:5]([C@@H:7]([NH:11][CH2:12][C:13]2[C:17]3[N:18]=[CH:19][NH:20][C:21](=[O:22])[C:16]=3[NH:15][CH:14]=2)[CH2:8][S:9][CH3:10])[CH2:4][O:3]1.Cl>CO>[OH:6][C@@H:5]([CH2:4][OH:3])[C@@H:7]([NH:11][CH2:12][C:13]1[C:17]2[N:18]=[CH:19][NH:20][C:21](=[O:22])[C:16]=2[NH:15][CH:14]=1)[CH2:8][S:9][CH3:10]
Reactant: CSC[C@H](NCc1c[nH]c2c(=O)[nH]cnc12)[C@@H]1COC(C)(C)O1
Agent: Cl
Solvent: CO
Product: CSC[C@H](NCc1c[nH]c2c(=O)[nH]cnc12)[C@@H](O)CO
Yield: 80.4 %

Procedure:
The product from Example 27.6 (0.049 g, 0.15 mmol) was stirred in a 1% hydrogen chloride solution in methanol (10 ml) for 3 h at ambient temperature. The reaction mixture was neutralised with Amberlyst A-21 ion exchange resin. The resin was filtered and the reaction solution concentrated. The residue was chromatographed (methanol [3,5N ammonia solution]-DCM, 1:4) giving a white solid (0.036 g, 83%). 1H NMR revealed this compound to be identical to the enantiomer from Example 26.7. +ESMS Found 299.1180 (M+H)+ C12H19N4O3S requires 299.1178.
Reaction SMILES: [CH2:1]1[CH2:33][O:32][C:3]([CH2:27][CH2:28][CH2:29][CH2:30][CH3:31])([CH2:4][CH2:5][C@H:6]2[C@H:10]([O:11][CH:12]3[CH2:17][CH2:16][CH2:15][CH2:14][O:13]3)[CH2:9][C@H:8]([O:18][SiH2:19][C:20]([CH3:23])([CH3:22])[CH3:21])[C@H:7]2[CH2:24][CH:25]=[O:26])[O:2]1.Br[C:35]([F:49])([F:48])[C:36]#[C:37][CH2:38][CH2:39][O:40][Si:41]([C:44]([CH3:47])([CH3:46])[CH3:45])([CH3:43])[CH3:42]>C1COCC1.[Zn].[Hg]Cl>[O:13]1[CH2:14][CH2:15][CH2:16][CH2:17][CH:12]1[O:11][C@@H:10]1[CH2:9][C@H:8]([O:18][SiH2:19][C:20]([CH3:21])([CH3:23])[CH3:22])[C@H:7]([CH2:24][CH:25]([OH:26])[C:35]([F:49])([F:48])[C:36]#[C:37][CH2:38][CH2:39][O:40][Si:41]([C:44]([CH3:45])([CH3:46])[CH3:47])([CH3:43])[CH3:42])[C@H:6]1[CH2:5][CH2:4][C:3]1([O:2][CH2:1][CH2:33][O:32]1)[CH2:27][CH2:28][CH2:29][CH2:30][CH3:31]
Reactant: CC(C)(C)[Si](C)(C)OCCC#CC(F)(F)Br
Reactant: CCCCCC1(CC[C@@H]2[C@H](CC=O)[C@@H](O[SiH2]C(C)(C)C)C[C@H]2OC2CCCCO2)OCCO1
Agent: Cl[Hg]
Agent: [Zn]
Solvent: C1CCOC1
Product: CCCCCC1(CC[C@@H]2[C@@H](CC(O)C(F)(F)C#CCCO[Si](C)(C)C(C)(C)C)[C@@H](O[SiH2]C(C)(C)C)C[C@H]2OC2CCCCO2)OCCO1

Procedure:
To a solution of 2-[(1S,2R,3R,5S)-2-(3,3-ethylenedioxyoctyl)-3-(tetrahydropyranyloxy)-5-(t-butylsiloxy)cyclopentyl]acetaldehyde (64) (1.00 g) in THF (25 ml) was added activated zinc powder (2.54 g), and while cooling on ice, the solution of 1-bromo-1,1-difluoro-5-(t-butyl-dimethylsilyloxy)-2-pentyne (i) (0.92 g) in THF (5 ml) was added dropwise the resultant mixture. To the resultant solution was added mercury chloride (0.11 g) and the resultant mixture was stirred under ultrasonic irradiation. The reaction mixture was treated in the conventional manner and the obtained crude product was subjected to silica gel column chromatography to give the title compound (65).
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([C:6]2[N:11]3[CH:12]=[CH:13][N:14]=[C:10]3[CH:9]=[C:8]([C:15]3[CH:20]=[CH:19][C:18]([N:21]4[CH2:26][CH2:25][O:24][CH2:23][CH2:22]4)=[CH:17][CH:16]=3)[N:7]=2)[CH:3]=[N:2]1.[CH:27]1([CH:32]=[CH:33][C:34]#[N:35])[CH2:31][CH2:30][CH2:29][CH2:28]1.N1CCCN2CCCCCC=12>CN(C=O)C>[CH:27]1([CH:32]([N:1]2[CH:5]=[C:4]([C:6]3[N:11]4[CH:12]=[CH:13][N:14]=[C:10]4[CH:9]=[C:8]([C:15]4[CH:20]=[CH:19][C:18]([N:21]5[CH2:26][CH2:25][O:24][CH2:23][CH2:22]5)=[CH:17][CH:16]=4)[N:7]=3)[CH:3]=[N:2]2)[CH2:33][C:34]#[N:35])[CH2:31][CH2:30][CH2:29][CH2:28]1
Reactant: N#CC=CC1CCCC1
Reactant: c1cn2c(-c3cn[nH]c3)nc(-c3ccc(N4CCOCC4)cc3)cc2n1
Solvent: CN(C)C=O
Solvent: C1CCC2=NCCCN2CC1
Product: N#CCC(C1CCCC1)n1cc(-c2nc(-c3ccc(N4CCOCC4)cc3)cc3nccn23)cn1
Temperature: 25 °C
Yield: 46.9 %

Procedure:
4-(4-(5-(1H-Pyrazol-4-yl)imidazo[1,2-c]pyrimidin-7-yl)phenyl)morpholine (0.0300 g, 0.0866 mmol) and 3-cyclopentylaerylonitrile (Table 1, compound g; 0.0175 g, 0.144 mmol) were suspended in DMF (3 mL) and 2,3,4,6,7,8,9,10-octahydropyrimido[1,2-a]azepine (0.0324 mL, 0.217 mmol) added in one portion. The reaction mixture was stirred at ambient temperature over the weekend. The reaction mixture was partitioned between saturated aqueous 1 N NaOH and EtOAc. The solids were isolated by filtration. The organics were washed with brine, dried over MgSO4 and concentrated under reduced pressure to afford the crude material, which was purified by flash column chromatography (eluant: 0.5-3% (9:1, MeOH:NH4OH)/DCM) to provide 3-cyclopentyl-3-(4-(7-(4-morpholinophenyl)imidazo[1,2-c]pyrimidin-5-yl)-1H-pyrazol-1-yl)propanenitrile (0.0190 g, 0.04064 mmol, 46.9% yield). MS (apci) m/z=468.2 (M+H).
Reaction SMILES: Cl.Cl.[N:3]12[CH2:10][CH2:9][CH:6]([CH2:7][CH2:8]1)[CH:5]([NH:11][C:12]([C:14]1[S:15][C:16]3[CH:22]=[CH:21][C:20]([NH2:23])=[CH:19][C:17]=3[CH:18]=1)=[O:13])[CH2:4]2.C(N(CC)CC)C.[C:31]([Cl:34])(=[O:33])[CH3:32]>CN(C=O)C>[ClH:34].[N:3]12[CH2:8][CH2:7][CH:6]([CH2:9][CH2:10]1)[CH:5]([NH:11][C:12]([C:14]1[S:15][C:16]3[CH:22]=[CH:21][C:20]([NH:23][C:31](=[O:33])[CH3:32])=[CH:19][C:17]=3[CH:18]=1)=[O:13])[CH2:4]2
Reactant: Nc1ccc2sc(C(=O)NC3CN4CCC3CC4)cc2c1
Reactant: CC(=O)Cl
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC(=O)Nc1ccc2sc(C(=O)NC3CN4CCC3CC4)cc2c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
41.0 mg (0.12 mmol) of rac-N-(1-azabicyclo[2.2.2]oct-3-yl)-5-amino-1-benzothiophene-2-carboxamide dihydrochloride and 36.8 mg (0.36 mmol) of triethylamine are dissolved in 1.5 ml of DMF. At 0° C., 14.3 mg (0.18 mmol) of acetyl chloride are added, and the mixture is stirred at RT overnight. The reaction mixture is purified by preparative HPLC. 29 mg (63% of theory) of the title compound are isolated.
Reaction SMILES: [NH2:1][C:2]1[CH:24]=[CH:23][C:5]([CH2:6][C:7]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[N:9]([CH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18])[C:8]=2[CH3:22])=[CH:4][CH:3]=1.C(N(CC)CC)C.[Cl:32][C:33]1[CH:34]=[C:35]([CH:39]=[CH:40][C:41]=1[Cl:42])[C:36](Cl)=[O:37]>ClCCl>[Cl:32][C:33]1[CH:34]=[C:35]([CH:39]=[CH:40][C:41]=1[Cl:42])[C:36]([NH:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][C:7]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[N:9]([CH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18])[C:8]=2[CH3:22])=[CH:23][CH:24]=1)=[O:37]
Reactant: CCOC(=O)Cn1c(C)c(Cc2ccc(N)cc2)c2ccccc21
Reactant: O=C(Cl)c1ccc(Cl)c(Cl)c1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOC(=O)Cn1c(C)c(Cc2ccc(NC(=O)c3ccc(Cl)c(Cl)c3)cc2)c2ccccc21
Yield: 79.8 %

Procedure:
In a dry reaction vessel, ethyl 2-[3-(4-aminobenzyl)-2-methyl-1H-indol-1-yl]acetate (1.0 g, 3.11 mmol) was added, and dissolved in 15 mL dichloromethane. Triethylamine (1.3 mL, 9.3 mmol) was added, and in an ice bath a dichloromethane solution dissolving 3,4-dichlorobenzoyl chloride (0.652 g, 3.11 mmol) was added slowly. After completion of dropwise addition, it was reacted in an ice bath for 4 h, and filtered. An aqueous solution of sodium bicarbonate was added, extracted with dichloromethane, rotate evaporated to dryness, chromatographed on a column to obtain a white solid 1.23 g, at a yield of 79.7%.