Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:4][N:5]=[C:6]([C:37]1[N:38]=[C:39]([NH:42]C(=O)C(F)(F)F)[S:40][CH:41]=1)[C:7]([NH:9][CH:10]1[C:35](=[O:36])[N:12]2[C:13]([C:32]([OH:34])=[O:33])=[C:14]([CH2:17][S:18][C:19]3[N:23]([CH2:24][C:25]([C:29]([OH:31])=[O:30])=[N:26][O:27][CH3:28])[N:22]=[N:21][N:20]=3)[CH2:15][S:16][C@H:11]12)=[O:8])[C:2]#[CH:3].C([O-])(=O)C.[Na+].Cl>O>[CH2:1]([O:4][N:5]=[C:6]([C:37]1[N:38]=[C:39]([NH2:42])[S:40][CH:41]=1)[C:7]([NH:9][CH:10]1[C:35](=[O:36])[N:12]2[C:13]([C:32]([OH:34])=[O:33])=[C:14]([CH2:17][S:18][C:19]3[N:23]([CH2:24][C:25]([C:29]([OH:31])=[O:30])=[N:26][O:27][CH3:28])[N:22]=[N:21][N:20]=3)[CH2:15][S:16][C@H:11]12)=[O:8])[C:2]#[CH:3]
Reactant: C#CCON=C(C(=O)NC1C(=O)N2C(C(=O)O)=C(CSc3nnnn3CC(=NOC)C(=O)O)CS[C@H]12)c1csc(NC(=O)C(F)(F)F)n1
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Product: C#CCON=C(C(=O)NC1C(=O)N2C(C(=O)O)=C(CSc3nnnn3CC(=NOC)C(=O)O)CS[C@H]12)c1csc(N)n1

Procedure:
A mixture of 7-[2-(2-propynyloxyimino)-2-{2-(2,2,2-trifluoroacetamido)thiazol-4-yl}acetamido]-3-[1-(2-carboxy-2-methoxyiminoethyl)-1H-tetrazol-5yl]thiomethyl-3-cephem-4-carboxylic acid (syn isomer: in the 7-position) (2.0 g) and sodium acetate.trihydrate (3.71 g) in water (15 ml) was stirred overnight at room temperature. The solution was adjusted to pH 2.5 with 10% hydrochloric acid under ice-cooling and the resultant precipitates were filtered and washed with water to give 7-[2-(2-propynyloxyimino)-2-(2-aminothiazol-4-yl)acetamido]-3-[1-(2-carboxy-2-methoxyiminoethyl)-1H-tetrazol-5-yl]thiomethyl-3-cephem-4-carboxylic acid (syn isomer: in the 7-position). (1.12 g).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]([O:13][CH3:14])[CH:10]=[C:9](/[CH:15]=[CH:16]/[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:4]=1[C:5]([O:7][CH3:8])=[O:6].[Br:23]Br>C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:12]=[C:11]([O:13][CH3:14])[C:10]([Br:23])=[C:9](/[CH:15]=[CH:16]/[C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)[C:4]=1[C:5]([O:7][CH3:8])=[O:6]
Reactant: BrBr
Reactant: COC(=O)c1c(/C=C/c2ccccc2)cc(OC)cc1OC
Solvent: ClCCl
Product: COC(=O)c1c(OC)cc(OC)c(Br)c1/C=C/c1ccccc1
Yield: 87 %

Procedure:
Dissolve compound 6 (13.0 g, 0.046 mol) CH2Cl2 (150 ml), add bromine (8.1 g, 0.050 mol) dropwise at room temperature, react at room temperature for 1 h, after completion of the reaction, wash the organic layer successively with water, saturated NaHCO3 solution and brine, dry the organic solution over anhydrous MgSO4. Filter the solution and evaporate the solvent, redissolve the residue, feed the solution to a silica gel column, evaporate the solvent in the eluent to obtain a white solid (15.1 g, 87%). 1H NMR (400 MHz, CDCl3): 3.80 (s, 3H), 3.86 (s, 3H), 3.93 (s, 3H), 639 (d, J=15.6 Hz, 1H), 6.50 (s, 1H), 70 (d, J=15.6 Hz, 1H), 7.29 (t, J=7.6 Hz, 1H), 7.37 (t, J=7.6 Hz, 2H), 7.49 (d, J=7.6 Hz, 2H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4](B(O)O)[CH:5]=[CH:6][C:7]=1[S:8][CH3:9].[CH2:13]([N:20]1[C:25](=[O:26])[C:24]([O:27][CH3:28])=[C:23](Br)[CH:22]=[N:21]1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>>[CH2:13]([N:20]1[C:25](=[O:26])[C:24]([O:27][CH3:28])=[C:23]([C:4]2[CH:5]=[CH:6][C:7]([S:8][CH3:9])=[C:2]([F:1])[CH:3]=2)[CH:22]=[N:21]1)[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: COc1c(Br)cnn(Cc2ccccc2)c1=O
Reactant: CSc1ccc(B(O)O)cc1F
Product: COc1c(-c2ccc(SC)c(F)c2)cnn(Cc2ccccc2)c1=O
Yield: 91 %

Procedure:
3-Fluoro-4-(methylthio)benzeneboronic acid and 2-benzyl-4-methoxy-5-bromo-3(2H)-pyridazinone were coupled according to the method of Example 83C to provide 2-benzyl-4-methoxy-5-[3-fluoro-4-(methylthio)phenyl]-3(2H)-pyridazinone as a yellow solid (yield: 4.98 g, 91%). 1H NMR (300 MHz, CDCl3) ? 7.76 (s, 1H), 7.47 (m, 2H), 7.39-7.21 (m, 7H), 5.34 (s, 2H), 4.13 (s, 3H), 2.51 (s, 3H). MS (DCI/NH3) m/z 357 (M+H)+, m/z 374 (M+NH4)+.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[O:7][C:8]([CH3:34])=[C:9]([CH2:11][O:12][C:13]2[CH:33]=[CH:32][C:16]([CH2:17][O:18][C:19]3[C:23]([CH:24]=O)=[CH:22][N:21]([C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=4)[N:20]=3)=[CH:15][CH:14]=2)[N:10]=1.C(OP([CH2:43][C:44]([O:46][CH2:47][CH3:48])=[O:45])(OCC)=O)C.CN(C)C=O.[H-].[Na+]>O>[O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[O:7][C:8]([CH3:34])=[C:9]([CH2:11][O:12][C:13]2[CH:14]=[CH:15][C:16]([CH2:17][O:18][C:19]3[C:23](/[CH:24]=[CH:43]/[C:44]([O:46][CH2:47][CH3:48])=[O:45])=[CH:22][N:21]([C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=4)[N:20]=3)=[CH:32][CH:33]=2)[N:10]=1
Reactant: Cc1oc(-c2ccco2)nc1COc1ccc(COc2nn(-c3ccccc3)cc2C=O)cc1
Reactant: CCOC(=O)CP(=O)(OCC)OCC
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)/C=C/c1cn(-c2ccccc2)nc1OCc1ccc(OCc2nc(-c3ccco3)oc2C)cc1
Temperature: 25 °C
Reaction time: 15 h
Yield: 83.2 %

Procedure:
To a mixture of 3-[(4-{[2-(2-furyl)-5-methyl-1,3-oxazol-4-yl]methoxy}benzyl)oxy]-1-phenyl-1H-pyrazole-4-carbaldehyde (0.50 g), ethyl diethylphosphonoacetate (0.25 g) and N,N-dimethylformamide (20 mL) was added sodium hydride (60% in oil, 0.050 g) under ice-cooling. The mixture was stirred at room temperature for 15 hrs. Water was added to the reaction mixture and the precipitated crystals were collected by filtration to give ethyl (2E)-3-(3-[(4-{[2-(2-furyl)-5-methyl-1,3-oxazol-4-yl]methoxy}benzyl)oxy]-1-phenyl-1H-pyrazol-4-yl}-2-propenoate as colorless crystals (0.48 g, yield 83%). Recrystallization from ethyl acetate-hexane gave colorless prism crystals. melting point: 142-143° C.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][NH:7][C:8]2=[O:11])=[CH:4][CH:3]=1.Br[CH2:13][CH2:14][CH2:15][CH2:16]Br>>[N:1]1([C:2]2[CH:10]=[C:9]3[C:5]([CH2:6][NH:7][C:8]3=[O:11])=[CH:4][CH:3]=2)[CH2:16][CH2:15][CH2:14][CH2:13]1
Reactant: BrCCCCBr
Reactant: Nc1ccc2c(c1)C(=O)NC2
Product: O=C1NCc2ccc(N3CCCC3)cc21

Procedure:
The starting material 6-pyrrolidin-1-yl-2,3-dihydro-isoindol-1-one was prepared from 6-amino-2,3-dihydro-isoindol-1-one (CAS 675109-45-2) and 1,4-dibromobutane in analogy to the precedure described in example 56.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[C:5]#[N:6].[Cl-].[NH4+].[N-:12]=[N+:13]=[N-:14].[Na+]>CN(C=O)C>[Br:1][C:2]1[CH:3]=[C:4]([C:5]2[NH:14][N:13]=[N:12][N:6]=2)[CH:7]=[CH:8][CH:9]=1
Reactant: N#Cc1cccc(Br)c1
Reactant: [N-]=[N+]=[N-]
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Brc1cccc(-c2nnn[nH]2)c1
Temperature: 100 °C
Reaction time: 1 h
Yield: 102.2 %

Procedure:
3-Bromo-benzonitrile 8a (18.2 g, 0.1 mol) and ammonium chloride (5.9 g, 0.11 mol) were dissolved in 80 mL of N,N′-dimethylformamide followed by addition of sodium azide (7.16 g, 0.11 mol) under argon atmosphere. The reaction mixture was heated to 100° C. and reacted overnight. Then the mixture was cooled to 60° C. and concentrated under reduced pressure to remove N,N′-dimethylformamide. The residue was diluted with 100 mL of water and 4 mL of concentrated hydrochloric acid and stirred for 1 hour. The mixture was filtered and dried to obtain the title compound 5-(3-bromo-phenyl)-1H-tetrazole 8b (23 g) as a white solid.
Reaction SMILES: [CH2:1]=[N:2][CH2:3][CH2:4][OH:5].[Cl:6][C:7]1[CH:8]=[C:9]([CH:24]=[CH:25][C:26]=1[Cl:27])[CH2:10][N:11]([CH3:23])[C:12](=[O:22])[CH:13]=[C:14]1[C:18](=[O:19])OC(C)(C)[O:15]1>CO>[Cl:6][C:7]1[CH:8]=[C:9]([CH:24]=[CH:25][C:26]=1[Cl:27])[CH2:10][N:11]([CH3:23])[C:12]([C:13]1[CH2:1][N:2]([CH2:3][CH2:4][OH:5])[C:18](=[O:19])[C:14]=1[OH:15])=[O:22]
Reactant: CN(Cc1ccc(Cl)c(Cl)c1)C(=O)C=C1OC(C)(C)OC1=O
Reactant: C=NCCO
Solvent: CO
Product: CN(Cc1ccc(Cl)c(Cl)c1)C(=O)C1=C(O)C(=O)N(CCO)C1
Temperature: 55 °C
Reaction time: 1 h

Procedure:
To a solution of 2-methyleneamino-ethanol (1 mL, 0.1 mmol) in MeOH (1 mL) was added N-(3,4-dichloro-benzyl)-2-(2,2-dimethyl-5-oxo-[1,3]dioxolan-4-ylidene)-N-methyl-acetamide (0.036 g, 0.1 mmol). The mixture was stirred at 55° C. for 1 h, cooled and purified by preparative HPLC (YMC Combiprep ODS-A, 30 mm×50 mm, MeOH/H2O/0.1% TFA). The title compound was isolated as a white foam (0.018 g, 49% yield). HRMS (M−H) calcd for C15H15N2Cl2O4: 357.04089. found: 357.0396.
Reaction SMILES: O=[C:2]([CH3:25])[C:3](=[CH:15][C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([N+:22]([O-:24])=[O:23])[CH:17]=1)[C:4]([NH:6][CH2:7][C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])=[O:5].[CH3:26]/[C:27](/[NH2:31])=[CH:28]\[C:29]#[N:30]>C1(C)C=CC=CC=1>[C:29]([C:28]1[CH:15]([C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([N+:22]([O-:24])=[O:23])[CH:17]=2)[C:3]([C:4]([NH:6][CH2:7][C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])=[O:5])=[C:2]([CH3:25])[NH:31][C:27]=1[CH3:26])#[N:30]
Reactant: CC(=O)C(=Cc1cccc([N+](=O)[O-])c1)C(=O)NCC(=O)OC(C)(C)C
Reactant: C/C(N)=C\C#N
Solvent: Cc1ccccc1
Product: CC1=C(C#N)C(c2cccc([N+](=O)[O-])c2)C(C(=O)NCC(=O)OC(C)(C)C)=C(C)N1
Yield: 98.7 %

Procedure:
A toluene solution containing 348 mg (1 mmol) of t-butyl 2-[N-[3-oxo-2-(3-nitrobenzylidene)butanoyl]amino]acetate and 123 mg (1.5 mmol) of 3-aminocrotonitrile was refluxed for 4 hours. The reaction mixture was chromatographed on a silica gel column for purification, whereby 407 mg (98.7%) of t-butyl 2-[N-(5-cyano-1,4-dihydro-2,6-dimethyl-4-(3-nitro-phenyl)pyridine-3-carbonyl)amino]acetate was obtained.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH2:15][CH2:16][CH2:17][N:18]3[CH2:23][CH2:22][O:21][CH2:20][CH2:19]3)=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][N:3]=1.[NH2:24][C:25]1[CH:26]=[C:27]([NH:31][C:32](=[O:41])[C:33]2[CH:38]=[CH:37][C:36]([C:39]#[N:40])=[CH:35][CH:34]=2)[CH:28]=[CH:29][CH:30]=1>>[C:39]([C:36]1[CH:35]=[CH:34][C:33]([C:32]([NH:31][C:27]2[CH:28]=[CH:29][CH:30]=[C:25]([CH:26]=2)[NH:24][C:2]2[C:11]3[C:6](=[CH:7][C:8]([O:14][CH2:15][CH2:16][CH2:17][N:18]4[CH2:23][CH2:22][O:21][CH2:20][CH2:19]4)=[C:9]([O:12][CH3:13])[CH:10]=3)[N:5]=[CH:4][N:3]=2)=[O:41])=[CH:38][CH:37]=1)#[N:40]
Reactant: COc1cc2c(Cl)ncnc2cc1OCCCN1CCOCC1
Reactant: N#Cc1ccc(C(=O)Nc2cccc(N)c2)cc1
Product: COc1cc2c(Nc3cccc(NC(=O)c4ccc(C#N)cc4)c3)ncnc2cc1OCCCN1CCOCC1
Yield: 48 %

Procedure:
Using an analogous procedure to that described in Example 26, 4-chloro-6-methoxy-7-(3-morpholinopropoxy)quinazoline was reacted with N-(3-aminophenyl)-4-cyanobenzamide. The material so obtained was purified by column chromatography eluting with 85:10:5 methylene chloride/methanol/isopropylamine. The material so obtained was triturated under diethyl ether to give the title compound in 48% yield; NMR: 2.1 (m, 2H), 3.35-3.45 (m, 4H), 3.7-3.8 (m, 8H), 3.98 (s, 3H), 4.22 (m, 2H), 7.2 (s, 1 H), 7.38 (m, 1H), 7.51 (m, 1H), 7.58 (m, 1H), 7.93 (s, 1H), 8.04 (d, 2H), 8.13 (d, 2H), 8.31 (s, 1H), 8.46 (s, 1H), 9.59 (s, 1H); Mass: M+H+ 539.
Reaction SMILES: [F:1][C:2]1[C:10]([CH2:11][S:12][CH3:13])=[C:9]2[C:5]([C:6]([CH:14]([C:19]3[CH:24]=[CH:23][C:22]([C:25]([F:28])([F:27])[F:26])=[CH:21][CH:20]=3)[CH2:15][CH2:16][C:17]#[N:18])=[CH:7][NH:8]2)=[CH:4][CH:3]=1.ClC1C=CC(C(C2C3C(=C(CS(C)=[O:53])C(F)=CC=3)NC=2)CCC#N)=CC=1>>[F:1][C:2]1[C:10]([CH2:11][S:12]([CH3:13])=[O:53])=[C:9]2[C:5]([C:6]([CH:14]([C:19]3[CH:20]=[CH:21][C:22]([C:25]([F:28])([F:26])[F:27])=[CH:23][CH:24]=3)[CH2:15][CH2:16][C:17]#[N:18])=[CH:7][NH:8]2)=[CH:4][CH:3]=1
Reactant: CS(=O)Cc1c(F)ccc2c(C(CCC#N)c3ccc(Cl)cc3)c[nH]c12
Reactant: CSCc1c(F)ccc2c(C(CCC#N)c3ccc(C(F)(F)F)cc3)c[nH]c12
Product: CS(=O)Cc1c(F)ccc2c(C(CCC#N)c3ccc(C(F)(F)F)cc3)c[nH]c12

Procedure:
The title compound was prepared starting from 557 mg (1.37 mmol) of the compound from Example 51 in analogy to the synthesis of the compound from Example 88. 412 mg (71% of theory) of the target compound were obtained as mixture of diastereomers.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C@:15]3([CH2:19][S:18][C:17]([NH2:20])=[N:16]3)[C:14]3[C:9](=[CH:10][CH:11]=[C:12]([I:21])[CH:13]=3)[O:8][C:5]2=[N:6][CH:7]=1.[C:22](=[O:25])(O)[O-:23].[Na+]>O1CCOCC1.CCOC(C)=O>[Br:1][C:2]1[CH:3]=[C:4]2[C@:15]3([CH2:19][S:18][C:17]([NH:20][C:22](=[O:25])[O:23][C:4]([CH3:15])([CH3:5])[CH3:3])=[N:16]3)[C:14]3[C:9](=[CH:10][CH:11]=[C:12]([I:21])[CH:13]=3)[O:8][C:5]2=[N:6][CH:7]=1
Reactant: NC1=N[C@@]2(CS1)c1cc(I)ccc1Oc1ncc(Br)cc12
Reactant: O=C([O-])O
Agent: [Na+]
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)NC1=N[C@@]2(CS1)c1cc(I)ccc1Oc1ncc(Br)cc12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
(S)-3-Bromo-7-iodo-5′H-spiro[chromeno[2,3-b]pyridine-5,4′-thiazol]-2′-amine (2.31 g, 4.87 mmol, prepared as described in Method BB26) was dissolved in dioxane (24.36 mL). 25 mL of saturated sodium bicarbonate solution was added, followed by boc-anhydride (11.31 mL, 48.7 mmol). The reaction was stirred overnight at RT. The reaction was diluted with EtOAc and washed with water. The aqueous layer was extracted with EtOAc, and the combined organic layers were dried with sodium sulfate, filtered, and concentrated. The material was purified via column chromatography on silica gel (0-25% EtOAc:Hex) to afford (S)-tert-butyl 3-bromo-7-iodo-5′H-spiro[chromeno[2,3-b]pyridine-5,4′-thiazole]-2′-ylcarbamate (2.614 g, 4.55 mmol) as a yellow solid. MS m/z=597.9 [M+H]+. Calculated for C19H17BrIN3O3S: 574.23.
Reaction SMILES: [CH:1]([CH:14]1[CH2:19][CH2:18][N:17]([CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][NH2:26])[CH2:16][CH2:15]1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:27]1(=[O:34])[O:33][C:31](=[O:32])[CH2:30][O:29][CH2:28]1>O.ClCCl>[CH:1]([CH:14]1[CH2:15][CH2:16][N:17]([CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][NH:26][C:31](=[O:32])[CH2:30][O:29][CH2:28][C:27]([OH:34])=[O:33])[CH2:18][CH2:19]1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C1COCC(=O)O1
Reactant: NCCCCCCN1CCC(C(c2ccccc2)c2ccccc2)CC1
Solvent: O
Solvent: ClCCl
Product: O=C(O)COCC(=O)NCCCCCCN1CCC(C(c2ccccc2)c2ccccc2)CC1
Reaction time: 2 h

Procedure:
A 1.02 gram (2.10 millimoles) sample of sodium {2-[6-(4-benzhydrylpiperidino)hexyl]amino-2-oxoethoxy}acetate (prepared as described in Example XIII) and 7.3 milliliters of 5 N aqueous NaOH is heated under reflux temperature for 1.5 hours to obtain 6-(4-benzhydrylpiperidino)hexanamine and diglycolate in the reaction mixture; the mixture is then diluted with 25 milliliters of water and extracted with ether. The ether solution is washed with aqueous NaCl, dried with Na2SO4, and concentrated to obtain as residue, 6-(4-benzhydrylpiperidino)hexanamine. To a solution of 0.685 gram (1.96 millimoles) of the thus prepared 6-(4-benzhydrylpiperidino)hexanamine in 14 milliliters of dichloromethane is added drop by drop during about 10 minutes, a warm solution of 0.227 gram (1.95 millimole) of diglycolic anhydride in 26 milliliters of dichloromethane. After the addition, the mixture is stirred at a temperature range of 25°-30° C. for two hours to obtain the desired {2-[ 6-(4-benzhydrylpiperidino)hexyl]amino-2-oxoethoxy}acetic acid; the latter is isolated by volatilization of the solvent.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][N:5]1[CH2:10][C:9](=[O:11])[C:8]2[N:12]([CH3:15])[CH:13]=[CH:14][C:7]=2[S:6]1(=[O:17])=[O:16].[F:18][C:19]1[CH:24]=[CH:23][C:22]([N:25]2[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]2)=[CH:21][CH:20]=1.C(=O)([O-])O.[Na+]>O1CCOCC1>[F:18][C:19]1[CH:20]=[CH:21][C:22]([N:25]2[CH2:30][CH2:29][N:28]([CH2:2][CH2:3][CH2:4][N:5]3[CH2:10][C:9](=[O:11])[C:8]4[N:12]([CH3:15])[CH:13]=[CH:14][C:7]=4[S:6]3(=[O:17])=[O:16])[CH2:27][CH2:26]2)=[CH:23][CH:24]=1
Reactant: Fc1ccc(N2CCNCC2)cc1
Reactant: Cn1ccc2c1C(=O)CN(CCCBr)S2(=O)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1COCCO1
Product: Cn1ccc2c1C(=O)CN(CCCN1CCN(c3ccc(F)cc3)CC1)S2(=O)=O
Yield: 93.7 %

Procedure:
A suspension of 54 mg (0.17 mmol) of Compound 17, 46 mg (0.25 mmol) of 1-(4-fluorophenyl)piperazine and 57 mg (0.68 mmol) of sodium hydrogencarbonate in 3.4 ml of dioxane was refluxed for 7 hours. Post treatment and purification were conducted as in Example 9, whereby 67 mg of the title compound were obtained (yield: 94%).
Reaction SMILES: [C:1]([C:3]1[N:7]2[CH:8]=[C:9]([C:16]3[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][CH:17]=3)[CH:10]=[C:11]([C:12]([F:15])([F:14])[F:13])[C:6]2=[N:5][CH:4]=1)#[CH:2].Br[C:27]1[CH:35]=[CH:34][C:30]([CH:31]([OH:33])[CH3:32])=[CH:29][CH:28]=1>>[F:15][C:12]([F:14])([F:13])[C:11]1[C:6]2[N:7]([C:3]([C:1]#[C:2][C:27]3[CH:35]=[CH:34][C:30]([CH:31]([OH:33])[CH3:32])=[CH:29][CH:28]=3)=[CH:4][N:5]=2)[CH:8]=[C:9]([C:16]2[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][CH:17]=2)[CH:10]=1
Reactant: C#Cc1cnc2c(C(F)(F)F)cc(-c3ccc(C(F)(F)F)cc3)cn12
Reactant: CC(O)c1ccc(Br)cc1
Product: CC(O)c1ccc(C#Cc2cnc3c(C(F)(F)F)cc(-c4ccc(C(F)(F)F)cc4)cn23)cc1

Procedure:
The title compound was prepared from 3-ethynyl-8-trifluoromethyl-6-(4-trifluoromethyl-phenyl)-imidazo[1,2-a]pyridine (example C.18) (360 mg, 1 mmol) and commercially available 4-bromo-methylbenzyl alcohol (184 mg, 1 mmol) according to general procedure II. Obtained as an off-white solid (65 mg, 13%). MS (ISP) 475.2 [(M+H)+]; mp 157-158° C.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][C@H:10]([C@H:13]([OH:23])[CH2:14][O:15]CC2C=CC=CC=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].F[C:25]1[CH:30]=[CH:29][C:28]([C:31]([F:34])([F:33])[F:32])=[CH:27][CH:26]=1.CN(C=O)C.[H-].[Na+]>[Pd]>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][C@H:10]([C@H:13]([O:23][C:25]2[CH:30]=[CH:29][C:28]([C:31]([F:34])([F:33])[F:32])=[CH:27][CH:26]=2)[CH2:14][OH:15])[CH2:9]1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)N1CC[C@H]([C@H](O)COCc2ccccc2)C1
Reactant: Fc1ccc(C(F)(F)F)cc1
Agent: [Pd]
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CC[C@H]([C@@H](CO)Oc2ccc(C(F)(F)F)cc2)C1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 62.8 %

Procedure:
(S)-3-((S)-2-Benzyloxy-1-hydroxyethyl)-pyrrolidine-1-carboxylic acid t-butyl ester (4.6 g, 14 mmol, 10. eq.) was combined with 4-fluorobenzotrifluoride (5.5 mL, 42.9 mmol, 3.0 eq.) in DMF (30 mL, 400 mmol). The mixture was degassed under nitrogen, and NaH (481 mg, 20.0 mmol) was added in small portions. The resulting mixture was stirred for 10 minutes at room temperature, followed by stirring at 90° C. for 3 hours. The mixture was then cooled to room temperature, extracted with hexanes (50 mL), and washed with water (50 mL) then 2M aqueous NaCl (50 mL). The organic layer was collected, stirred in activated carbon (460 mg) for 5 minutes, dried over Na2SO4, filtered, and concentrated. The resulting crude oil was dissolved in MeOH (50 mL), and 10% Pd/C (0.1:0.9, Palladium:carbon black, 670 mg, 630 μmol) was added under nitrogen. The mixture was stirred under hydrogen (1 atm) overnight. The mixture was filtered and the filtrate was concentrated. The resulting crude oil was dissolved in hexanes (˜30 mL) and EtOAc (˜15 ml), then concentrated until precipitate formed. Additional hexanes was added and the precipitate was stirred for 15 minutes. The precipitate was filtered and dried to give the title compound as a white solid (3.3 g).
Reaction SMILES: CON(C)[C:4]([CH:6]1[CH2:12][CH:11]2[N:13]([C:14]([O:16]C(C)(C)C)=[O:15])[CH:8]([CH2:9][CH2:10]2)[CH2:7]1)=[O:5].[Br-].O.Cl>O1CCCC1>[C:6]([C@@:11]12[N:13]([C:14]([OH:16])=[O:15])[C@@H:8]([CH2:9][CH2:10]1)[CH2:7][CH:6]([C:4](=[O:5])[CH2:11][CH2:10][CH:9]=[CH2:8])[CH2:12]2)([CH3:12])([CH3:7])[CH3:4]
Reactant: CON(C)C(=O)C1CC2CCC(C1)N2C(=O)OC(C)(C)C
Agent: Cl
Agent: [Br-]
Solvent: O
Solvent: C1CCOC1
Product: C=CCCC(=O)C1C[C@@H]2CC[C@](C(C)(C)C)(C1)N2C(=O)O
Temperature: 0 °C
Reaction time: 1 h
Yield: 173.4 %

Procedure:
While under a nitrogen atmosphere, a solution of tert-butyl 3-(methoxy(methyl)carbamoyl)-8-azabicyclo[3.2.1]octane-8-carboxylate (1.7 g, 5.7 mmol), in tetrahydrofuran (25 mL) was cooled to 0° C. and treated with 3-butenylmagnesiun bromide (0.5 M in THF, 28.5 mL, 14.3 mmol) in a drop wise manner. The solution was stirred for 1 hour at 0° C. then allowed to warm to room temperature overnight. The resulting solution was poured into water, acidified to pH 3-4 with 1 N hydrochloric acid, and extracted with ethyl acetate (3×). The combined organic phase was washed with saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo. Purification by flash column chromatography (silica gel, 0-25% ethyl acetate in heptane) gave (1R,5S)-tert-Butyl-3-pent-4-enoyl-8-azabicyclo[3.2.1]-octane-8-carboxylic acid as a colorless oil (1.45 g, 87%); 1H NMR (CDCl3, 400 MHz) δ 5.81 (m, 1H), 5.01 (m, 2H), 4.29 (br s, 2H), 2.83 (m, 1H), 2.53 (t, J=7.5 Hz, 1H), 2.32 (q, J=7 Hz, 2H), 2.03 (m, 2H), 1.83 (t, J=12.5 Hz, 2H), 1.60-1.71 (m, 5H) and 1.48 (s, 9H); m/z for C17H27NO3 expected 293.2. found 316.3 (M+Na)+, 294.3 (M+H)+.
Reaction SMILES: Cl.[OH:2][C@H:3]1[C@@H:7]([OH:8])[CH2:6][NH:5][CH2:4]1.[Cl:9][C:10]1[CH:11]=[C:12]2[C:16](=[CH:17][CH:18]=1)[NH:15][C:14]([C:19]([NH:21][CH2:22][C:23](O)=[O:24])=[O:20])=[CH:13]2>C(Cl)Cl.CN(C=O)C>[OH:2][C@H:3]1[C@@H:7]([OH:8])[CH2:6][N:5]([C:23](=[O:24])[CH2:22][NH:21][C:19]([C:14]2[NH:15][C:16]3[C:12]([CH:13]=2)=[CH:11][C:10]([Cl:9])=[CH:18][CH:17]=3)=[O:20])[CH2:4]1
Reactant: O=C(O)CNC(=O)c1cc2cc(Cl)ccc2[nH]1
Reactant: O[C@@H]1CNC[C@@H]1O
Agent: Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: O=C(NCC(=O)N1C[C@@H](O)[C@@H](O)C1)c1cc2cc(Cl)ccc2[nH]1
Reaction time: 1 h

Procedure:
(3R,4S)-3,4-Dihydroxypyrrolidine hydrochloride (the cis, or meso isomer, 1.79 mmol) and [(5-chloro-1H-indole-2-carbonyl)-amino]-acetic acid (0.85 mmol) were coupled according to procedure A (1:1 CH2Cl2/DMF reaction solvent) with the following workup: the reaction mixture was concentrated, the residue suspended in 10 ml EtOAc and 10 ml 2 N NaOH, the solids filtered and washed successively with aqueous 1 N NaOH, EtOAc, aqueous 1 N HCl, H2O, and ether. This washing sequence was repeated and the resulting solids were suspended in EtOAc, stirred for 1 hour, filtered and dried: Yield 252 mg, 88%; HPLC (60/40) 2.33 minutes (93%); TSPMS 338/340 (MH+, 100%);
Reaction SMILES: [F:1][C:2]1[CH:11]=[C:10]([N:12]([CH:16]2[C:20]3[CH:21]=[C:22]4[C:27](=[CH:28][C:19]=3[CH2:18][CH2:17]2)[N:26]=[C:25]([CH3:29])[N:24]([CH2:30][O:31][C:32](=[O:37])[C:33]([CH3:36])([CH3:35])[CH3:34])[C:23]4=[O:38])[CH2:13][C:14]#[CH:15])[CH:9]=[CH:8][C:3]=1[CH:4]=C(C)C.[O:39]=[O+][O-]>C(Cl)Cl.C(O)C>[F:1][C:2]1[CH:11]=[C:10]([N:12]([CH:16]2[C:20]3[CH:21]=[C:22]4[C:27](=[CH:28][C:19]=3[CH2:18][CH2:17]2)[N:26]=[C:25]([CH3:29])[N:24]([CH2:30][O:31][C:32](=[O:37])[C:33]([CH3:35])([CH3:36])[CH3:34])[C:23]4=[O:38])[CH2:13][C:14]#[CH:15])[CH:9]=[CH:8][C:3]=1[CH:4]=[O:39]
Reactant: C#CCN(c1ccc(C=C(C)C)c(F)c1)C1CCc2cc3nc(C)n(COC(=O)C(C)(C)C)c(=O)c3cc21
Reactant: O=[O+][O-]
Solvent: CCO
Solvent: ClCCl
Product: C#CCN(c1ccc(C=O)c(F)c1)C1CCc2cc3nc(C)n(COC(=O)C(C)(C)C)c(=O)c3cc21
Temperature: -70 °C

Procedure:
o-Fluoro-p-[N-((6RS)-2-methyl-4-oxo-3-pivaloyloxymethyl-3,4,7,8-tetrahydro-6H-cyclopenta[g]quinazolin-6-yl)-N-(prop-2-ynyl)amino]-β,β-dimethylstyrene (0.626 g) was dissolved in a mixture of methylene chloride (2 ml) and ethanol (250 ml). The mixture was cooled to -70° C. and ozone gas was passed into the solution for 7.5 minutes. Argon gas was bubbled into the solution for 5 minutes. Dimethyl sulphide (4 ml) was added and the mixture was allowed to warm to ambient temperature. The mixture was evaporated and the residue was purified by column chromatography using a 1:1 mixture of hexane and ethyl acetate as eluant. There was thus obtained o-fluoro-p-[N-((6RS)-2-methyl-4-oxo-3-pivaloyloxymethyl-3,4,7,8-tetrahydro-6H-cyclopenta[g]quinazolin-6-yl)-N-(prop-2-ynyl)amino]benzaldehyde (0.47 g);