Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12](CC3C=C(C=CC=3)C(O)=O)[C:11]3[CH:23]=[C:24]([F:28])[C:25]([F:27])=[CH:26][C:10]=3[N:9]=2)=[C:4](OCC2CCCC2)[CH:3]=1.FC1C=C(N)C(N)=CC=1F.[Br:46]C1C=C(Cl)C=CC=1C(O)=O>>[Br:46][C:4]1[CH:3]=[C:2]([Cl:1])[CH:7]=[CH:6][C:5]=1[C:8]1[NH:12][C:11]2[CH:23]=[C:24]([F:28])[C:25]([F:27])=[CH:26][C:10]=2[N:9]=1
Reactant: O=C(O)c1ccc(Cl)cc1Br
Reactant: O=C(O)c1cccc(Cn2c(-c3ccc(Cl)cc3OCC3CCCC3)nc3cc(F)c(F)cc32)c1
Agent: Nc1cc(F)c(F)cc1N
Product: Fc1cc2nc(-c3ccc(Cl)cc3Br)[nH]c2cc1F

Procedure:
The title compound was prepared in analogy to Example 19, intermediate c, from 4,5-difluoro-benzene-1,2-diamine (CAS Reg. No. 76179-40-3) and 2-bromo-4-chloro-benzoic acid (CAS Reg. No. 936-08-3). Colorless solid (54%). MS (Turbo Spray): m/z=344.1 (M+H).
Reaction SMILES: [Cl:1][C:2]1[C:7](I)=[C:6]([CH3:9])[N:5]=[C:4]([CH3:10])[N:3]=1.[CH2:11]([O:13][C:14]([Sn](CCCC)(CCCC)CCCC)=[CH2:15])[CH3:12].[Cl-].[Li+].[F-].[K+]>CCOC(C)=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.O1CCOCC1>[Cl:1][C:2]1[C:7]([C:11]([O:13][CH2:14][CH3:15])=[CH2:12])=[C:6]([CH3:9])[N:5]=[C:4]([CH3:10])[N:3]=1
Reactant: C=C(OCC)[Sn](CCCC)(CCCC)CCCC
Reactant: Cc1nc(C)c(I)c(Cl)n1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cl-]
Agent: [F-]
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: C=C(OCC)c1c(C)nc(C)nc1Cl
Reaction time: 25 h
Yield: 60.6 %

Procedure:
A mixture of 4-chloro-2,6-dimethyl-5-iodopyrimidine (13.5 g, 0.050 mol), (1ethoxyvinyl)tributyltin (20.0 g, 0.055 mol), lithium chloride (6.4 g, 0.150 mol), tetrakis(triphenylphosphine)palladium(0) (1.7 g, 0.0015 mol), and dioxane (100 mL) was heated under reflux for 23 h. Additional tetrakis(triphenylphosphine)palladium(0) (1.1 g, 0.0010 mol) was added and heating was continued for 25 h. The mixture was cooled, diluted with EtOAc, and ! N KF (100 mL) was added. The solids were removed by filtration through Celite and the layers were separated. The organic phase was washed with pH 7 phosphate buffer (100 mL), brine (100 mL), dried MgSO4), and concentrated. Purification by flash chromatography (twice; 5-10% EtOAc/hexane) gave 6.44 g (61%) of product as a colorless oil.
Reaction SMILES: [NH2:1][C@@H:2]1[CH2:7][CH2:6][C@H:5]([N:8]([CH3:30])[C:9]2[C:10]([CH3:29])=[C:11]([CH:25]=[C:26]([Br:28])[CH:27]=2)[C:12]([NH:14][CH2:15][C:16]2[C:17](=[O:24])[NH:18][C:19]([CH3:23])=[CH:20][C:21]=2[CH3:22])=[O:13])[CH2:4][CH2:3]1.CCN=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1.C(N(CC)CC)C.[C:60](O)(=[O:62])[CH3:61]>CN(C=O)C.O>[C:60]([NH:1][C@@H:2]1[CH2:3][CH2:4][C@H:5]([N:8]([CH3:30])[C:9]2[C:10]([CH3:29])=[C:11]([CH:25]=[C:26]([Br:28])[CH:27]=2)[C:12]([NH:14][CH2:15][C:16]2[C:17](=[O:24])[NH:18][C:19]([CH3:23])=[CH:20][C:21]=2[CH3:22])=[O:13])[CH2:6][CH2:7]1)(=[O:62])[CH3:61]
Reactant: Cc1cc(C)c(CNC(=O)c2cc(Br)cc(N(C)[C@H]3CC[C@@H](N)CC3)c2C)c(=O)[nH]1
Reactant: CC(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC(=O)N[C@H]1CC[C@@H](N(C)c2cc(Br)cc(C(=O)NCc3c(C)cc(C)[nH]c3=O)c2C)CC1
Reaction time: 18 h
Yield: 69.3 %

Procedure:
To a stirred solution of compound cis-3-((4-aminocyclohexyl)(methyl)amino)-5-bromo-N-((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-2-methylbenzamide (free base) (0.225, 0.474 mmol) in DMF (3 mL), EDCI.HCl (0.138 g, 0.718 mmol), HOBt (0.064 g, 0.47 mmol), triethyl amine (0.1 g, 0.99 mmol) and acetic acid (0.057 g, 0.949 mmol) were added at room temperature and stirred at same temperature for 18 h. On completion, water was added and extracted with 10% MeOH/DCM. Combined organic layers were dried, concentrated giving crude material; which then purified by column chromatography to afford the desired compound (0.17 g, 72%). LCMS: 517.25 (M+1)+; HPLC % 95.83 (@ 254 nm) (Rt; 4.894; Method: Column: YMC ODS-A 150 mm×4.6 mm×5μ; Mobile Phase: A; 0.05% TFA in water/B; 0.05% TFA in acetonitrile; Inj. Vol: 10 μL, Col. Temp.: 30° C.; Flow rate: 1.4 mL/min.; Gradient: 5% B to 95% B in 8 min, Hold for 1.5 min, 9.51-12 min 5% B); 1H NMR (DMSO-d6, 400 MHz) δ 11.46 (s, 1H), 8.22 (t, 1H), 7.76 (d, 1H, J=7.2 Hz), 7.23 (s, 1H), 7.03 (s, 1H), 5.85 (s, 1H), 4.23 (d, 2H, J=3.6 Hz), 3.71 (bs, 1H), 2.89 (m, 1H), 2.53 (s, 3H), 2.18 (s, 3H), 2.16 (s, 3H), 2.10 (s, 3H), 1.81 (s, 3H), 1.74-1.76 (m, 2H), 1.53 (m, 2H), 1.39 (m, 4H).
Reaction SMILES: CC1(C)O[C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[C:13]2[CH:18]=[CH:17][C:16]([CH3:19])=[C:15]([F:20])[CH:14]=2)=[N:4]C1.N1C=CC=CC=1.P(Cl)(Cl)(Cl)=O.Cl>CCOCC>[F:20][C:15]1[CH:14]=[C:13]([C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[C:5]#[N:4])[CH:18]=[CH:17][C:16]=1[CH3:19]
Reactant: Cc1ccc(-c2ccccc2C2=NCC(C)(C)O2)cc1F
Agent: Cl
Solvent: CCOCC
Solvent: c1ccncc1
Solvent: O=P(Cl)(Cl)Cl
Product: Cc1ccc(-c2ccccc2C#N)cc1F
Temperature: 25 °C

Procedure:
97.0 g (343 mmol) of the compound from Example III are initially introduced into 500 ml of pyridine, and 31.3 ml (343 mmol) of phosphorus oxychloride are added at 0° C., while stirring. The mixture is heated slowly, and is finally boiled under reflux for 1 hour. After cooling to room temperature, ether and an amount of 1M hydrochloric acid such that the pH of the aqueous phase is 1.5 are added. The organic phase is washed three more times with 1M sulphuric acid, dried with sodium sulphate and evaporated on a rotary evaporator and the residue is freed from the residual solvent under a high vacuum.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[F:11][C:12]([F:21])([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[CH2:13][OH:14].C(N(CC)CC)C>C(Cl)Cl.O>[F:11][C:12]([F:21])([C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1)[CH:13]=[O:14]
Reactant: OCC(F)(F)c1ccccc1
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: O
Solvent: CCN(CC)CC
Product: O=CC(F)(F)c1ccccc1
Reaction time: 0.5 h
Yield: 29.5 %

Procedure:
To a solution of oxalyl chloride (2.66 g, 21.0 mmol) in DCM (300 mL) was added DMSO (2.5 mL, 35.0 mmol) at 60° C. The mixture was stirred for 30 min. Then 2,2-difluoro-2-phenyl-ethanol (28.1 g, 18.0 mmol) was added at the same temperature. The mixture was stirred for another 30 min. Triethylamine (11.1 mL, 80.0 mmol) was added and then the mixture was stirred for 2 h at room temperature. Water was added and the organic layer was dried over anhydrous sodium sulfate and concentrated to obtain the crude product difluoro-phenyl-acetaldehyde (828 mg, 30%), which was used to the next step without further purification.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:37])[CH:4]=[CH:5][CH2:6][C@@H:7]1[C@H:12]2[C@H:13]3[C@H:22]([CH2:23][CH2:24][C@:10]2([CH3:11])[C:9](=[O:36])[CH2:8]1)[C:21]1[CH:20]=[C:19]([O:25][CH2:26][CH3:27])[C:18]([O:28]CC2C=CC=CC=2)=[CH:17][C:16]=1[CH2:15][CH2:14]3>C1COCC1.CO.[Pd]>[CH3:1][O:2][C:3](=[O:37])[CH2:4][CH2:5][CH2:6][C@@H:7]1[C@H:12]2[C@H:13]3[C@H:22]([CH2:23][CH2:24][C@:10]2([CH3:11])[C:9](=[O:36])[CH2:8]1)[C:21]1[CH:20]=[C:19]([O:25][CH2:26][CH3:27])[C:18]([OH:28])=[CH:17][C:16]=1[CH2:15][CH2:14]3
Reactant: CCOc1cc2c(cc1OCc1ccccc1)CC[C@H]1[C@@H]3[C@@H](CC=CC(=O)OC)CC(=O)[C@@]3(C)CC[C@H]21
Agent: [Pd]
Solvent: CO
Solvent: C1CCOC1
Product: CCOc1cc2c(cc1O)CC[C@H]1[C@@H]3[C@@H](CCCC(=O)OC)CC(=O)[C@@]3(C)CC[C@H]21
Temperature: 25 °C
Reaction time: 48 h
Yield: 106.7 %

Procedure:
4-(3-Benzyloxy-2-ethoxy-17-oxo-estra-1,3,5(10)-trien-15α-yl)but-2-enoic acid methyl ester (3.17 g, 6.30 mmol) was dissolved in THF (80 ml) and MeOH (80 ml). Pd/C 10% (50% in water, 0.3 g) was added. The mixture was stirred at 1 atm H2 (balloon) at RT for 48 h. The mixture was filtered over Celite. The filter cake was rinsed with MeOH (200 ml) and the filtrate was concentrated in vacuo to provide 2.8 g (6.72 mmol, >100%) of a greenish solid.
Reaction SMILES: C(OC(=O)[NH:7][CH2:8][CH2:9][N:10]([CH2:29][C:30]1[CH:35]=[CH:34][C:33]([Cl:36])=[CH:32][CH:31]=1)[C:11]([CH:13]1[CH2:18][CH2:17][N:16]([C:19]2[C:28]3[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=3)[N:22]=[CH:21][N:20]=2)[CH2:15][CH2:14]1)=[O:12])(C)(C)C.[ClH:38]>C(Cl)Cl.CCOCC.ClCCCl>[ClH:36].[ClH:38].[NH2:7][CH2:8][CH2:9][N:10]([CH2:29][C:30]1[CH:35]=[CH:34][C:33]([Cl:36])=[CH:32][CH:31]=1)[C:11]([CH:13]1[CH2:14][CH2:15][N:16]([C:19]2[C:28]3[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=3)[N:22]=[CH:21][N:20]=2)[CH2:17][CH2:18]1)=[O:12]
Reactant: CC(C)(C)OC(=O)NCCN(Cc1ccc(Cl)cc1)C(=O)C1CCN(c2ncnc3ccccc23)CC1
Agent: Cl
Solvent: CCOCC
Solvent: ClCCCl
Solvent: ClCCl
Product: NCCN(Cc1ccc(Cl)cc1)C(=O)C1CCN(c2ncnc3ccccc23)CC1
Reaction time: 12 h

Procedure:
Step 5: 1 {2-[(4-Chlorobenzyl)-(1-quinazolin-4-yl-piperidine-4-carbonyl)-amino]-ethyl}-carbamic acid tert-butyl ester (190 mg, 0.36 mmol) was dissolved in DCM (5 mL) followed by the addition of 2.0 M HCl in Et2O (2 mL). After being stirred for 12 hours, the mixture was diluted with DCE and concentrated in vacuo. The resulting white solid was then suspended in MeCN and concentrated in vacuo (repeated twice) to give 1-quinazolin-4-yl-piperidine-4-carboxylic acid (2-amino-ethyl)-(4-chlorobenzyl)-amide dihydrochloride as a white powder (120 mg). 1H NMR (DMSO-d6, 400 MHz) δ 8.83 (m, 1H), 8.51 (bs, 2H), 8.20 (m, 2H), 8.01 (m, 2H), 7.71 (m, 1H), 7.48 (d, J=8.3 Hz, 1H), 7.39 (d, J=8.3 Hz, 1H), 7.31 (d, J=8.3 Hz, 1H), 7.25 (d, J=8.3 Hz, 1H), 4.79 (m, 2H), 4.55 (s, 1H), 3.59 (m, 7H), 3.03 (m, 1H), 2.90 (m, 1H), 1.92 (m, 4H). LCMS (APCI+) m/z 424, 426 [M+H]+.
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:7]=[N:8][N:9]([CH3:30])[C:10]=1[N:11]([CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[S:12]([C:15]1[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=1)(=[O:14])=[O:13])=[O:5])C.[OH-].[Na+]>CO.C1COCC1>[CH2:23]([N:11]([S:12]([C:15]1[CH:16]=[CH:17][C:18]([O:21][CH3:22])=[CH:19][CH:20]=1)(=[O:14])=[O:13])[C:10]1[N:9]([CH3:30])[N:8]=[CH:7][C:6]=1[C:4]([OH:5])=[O:3])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: CCOC(=O)c1cnn(C)c1N(Cc1ccccc1)S(=O)(=O)c1ccc(OC)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: COc1ccc(S(=O)(=O)N(Cc2ccccc2)c2c(C(=O)O)cnn2C)cc1
Temperature: 25 °C
Yield: 93.2 %

Procedure:
To a solution of 0.799 g (1.862 mmol) of the product of Example 7 in 20 mL of methanol/THF (1:1) was added 9.3 mL of 1N sodium hydroxide solution and the resulting mixture was heated to reflux for 18 h. The reaction was then cooled to room temperature and the organics were removed in vacuo. The resulting mixture was acidified with 10% HCl and extracted with ethyl acetate. The combined organics were washed with water and brine, dried over MgSO4, filtered and concentrated in vacuo. The resulting residue was triturated with ether and filtered to provide 0.697 g (93%) of the desired carboxylic acid as a white solid. Electrospray Mass Spec: 402 (M+H).
Reaction SMILES: CS(O[CH2:6][C:7]#[C:8][C:9]1[CH:21]=[CH:20][C:12]2[N:13]([CH2:16][CH:17]3[CH2:19][CH2:18]3)[N:14]=[N:15][C:11]=2[C:10]=1[Cl:22])(=O)=O.[CH3:23][N:24]1[C:28](=[O:29])[CH2:27][NH:26][C:25]1=[O:30].C(=O)([O-])[O-].[K+].[K+]>C(#N)C.C(OCC)(=O)C>[Cl:22][C:10]1[C:11]2[N:15]=[N:14][N:13]([CH2:16][CH:17]3[CH2:19][CH2:18]3)[C:12]=2[CH:20]=[CH:21][C:9]=1[C:8]#[C:7][CH2:6][N:26]1[CH2:27][C:28](=[O:29])[N:24]([CH3:23])[C:25]1=[O:30]
Reactant: CS(=O)(=O)OCC#Cc1ccc2c(nnn2CC2CC2)c1Cl
Reactant: CN1C(=O)CNC1=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: CCOC(C)=O
Product: CN1C(=O)CN(CC#Cc2ccc3c(nnn3CC3CC3)c2Cl)C1=O
Temperature: 50 °C

Procedure:
3-[4-Chloro-1-(cyclopropylmethyl)-1H-benzotriazol-5-yl]prop-2-yn-1-yl methanesulfonate (30 mg, 0.088 mmol), 3-methylimidazolidine-2,4-dione (20.15 mg, 0.177 mmol), and potassium carbonate (36.6 mg, 0.265 mmol) were combined in acetonitrile (1 ml) and heated at 50° C. for 24 hours. The mixture was cooled to ambient temperature, diluted with ethyl acetate and washed with saturated aqueous ammonium chloride and brine. The organic extract was dried with sodium sulfate, filtered, concentrated in vacuo. The residue was purified by silica gel gradient chromatography (0-5% acetone/dichloromethane) to provide the titled compound: 1H NMR (500 MHz, d6-DMSO) δ 7.97 (d, J=8.6 Hz, 1H), 7.73 (d, J=8.6 Hz, 1H), 4.64 (d, J=7.3 Hz, 2H), 4.53 (s, 2H), 4.13 (s, 2H), 2.88 (s, 3H), 1.42-1.34 (m, 1H), 0.56 (m, 2H), 0.47 (m, 2H) ppm. LRMS m/z (M+H) 358.0 [calculated for C17H17ClN5O2: 358.8].
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:4]=1[CH2:5][CH2:6][CH2:7][C:8]2=O.[I-].[CH3:15][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.CC(C)([O-])C.[K+]>C1COCC1>[CH3:1][O:2][C:3]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:4]=1[CH2:5][CH2:6][CH2:7][C:8]2=[CH2:15]
Reactant: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: COc1cccc2c1CCCC2=O
Agent: CC(C)(C)[O-]
Agent: [I-]
Agent: [K+]
Solvent: C1CCOC1
Product: C=C1CCCc2c(OC)cccc21
Reaction time: 1 h
Yield: 99 %

Procedure:
To a slurry of 5-Methoxy-3,4-dihydro-2H-naphthalen-1-one (25 g, 0.14 mol) and methyltriphenylphosphonium iodide (1.13 eq) in THF (250 mL) at RT was added potassium t-butoxide (1.6 eq) at such a rate as to maintain a temperature no higher than warm to the touch. The reaction was stirred for one hour and concentrated. The reaction was then azeotroped with three volumes of hexane to remove excess t-butanol. Fresh hexane was added the solution was let to stand overnight to effect trituration. The red-brown solid was removed by filtration and the filtratewas washed twice with water and was concentrated. Purification by chromatography on ISCO (330 g SiO2 cartridge: stepwise hexane and then DCM) affords the title compound as a pale yellow oil (24 g, 99%). 1H-NMR (400 MHz, CDCl3) 7.29 (d, J=8.0 Hz, 1H), 7.15 (t, J=8.0 Hz, 1H), 6.76 (d, J=8.0 Hz, 1H), 5.49 (s, 1H), 4.98 (s, 1H), 3.85 (s, 3H), 2.77 (t, J=6.4 Hz, 2H), 2.53-2.50 (m, 2H), 1.93-1.87 (m, 2H).
Reaction SMILES: [C:1]1([CH3:11])[CH:6]=[CH:5][C:4]([S:7](Cl)(=[O:9])=[O:8])=[CH:3][CH:2]=1.[NH2:12][CH2:13][CH2:14][CH2:15][NH:16][CH2:17][CH2:18][CH2:19][NH2:20]>N1C=CC=CC=1>[C:1]1([CH3:11])[CH:6]=[CH:5][C:4]([S:7]([NH:12][CH2:13][CH2:14][CH2:15][N:16]([S:7]([C:4]2[CH:5]=[CH:6][C:1]([CH3:11])=[CH:2][CH:3]=2)(=[O:9])=[O:8])[CH2:17][CH2:18][CH2:19][NH:20][S:7]([C:4]2[CH:5]=[CH:6][C:1]([CH3:11])=[CH:2][CH:3]=2)(=[O:9])=[O:8])(=[O:9])=[O:8])=[CH:3][CH:2]=1
Reactant: NCCCNCCCN
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: c1ccncc1
Product: Cc1ccc(S(=O)(=O)NCCCN(CCCNS(=O)(=O)c2ccc(C)cc2)S(=O)(=O)c2ccc(C)cc2)cc1
Yield: 58.8 %

Procedure:
To a stirred solution of p-toluenesulfonyl chloride (240 g, 1.26 mole) in pyridine (600 ml) at 0° C. was added a solution of 1,5,9-triazanonane (50.0 g, 0.381 mole) in pyridine (100 ml) under a dry nitrogen atmosphere, maintaining the temperature ≤60° C. The addition required 15 minutes. The solvent was removed in vacuo and the resulting yellow oil was dissolved in ethyl acetate (1 l) and H2O (500 ml). The ethyl acetate layer was separated, washed with 0.1N HCl, H2O and saturated NaCl solution and dried (MgSO4). The solution was decolorized with silica gel and the solvent was removed in vacuo to give 133 g (59% yield) of the crude product as a glassy solid: 1H NMR (CDCl3) δ1.71 (quint, J=6.6 Hz, 4 H), 2.42 (s, 6 H), 2.43 (s, 3 H), 2.96 (quart, J=6.4 Hz, 4 H), 3.11 (t, J=6.8 Hz, 4 H), 5.12 (t, J=6.6 Hz, 2 H), 7.30 (m, 6 H), 7.63 (m, 2 H), 7.73 (m, 4 H).
Reaction SMILES: [OH:1][CH2:2][C:3]1([CH3:15])[CH2:7][CH2:6][N:5](C(OC(C)(C)C)=O)[CH2:4]1.CO.[ClH:18]>>[ClH:18].[CH3:15][C:3]1([CH2:2][OH:1])[CH2:7][CH2:6][NH:5][CH2:4]1
Reactant: CC1(CO)CCN(C(=O)OC(C)(C)C)C1
Agent: Cl
Solvent: CO
Product: CC1(CO)CCNC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
tert-butyl 3-(hydroxymethyl)-3-methylpyrrolidine-1-carboxylate (0.31 g, 1.44 mmol, see WO 2009132986) was dissolved in HCl in methanol (1.25M, 3.5 mL, 4.32 mmol). The reaction mixture was stirred at RT overnight and then the mixture was evaporated. Ethanol was added and the mixture was again evaporated to afford 243 mg. The crude product was used in the next step without further purification.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][O:4][C:5]1[CH:14]=[CH:13][C:8]([C:9]([O:11][CH3:12])=[O:10])=[CH:7][CH:6]=1.[F:15][C:16]1[CH:24]=[CH:23][C:19]([C:20](O)=[O:21])=[CH:18][CH:17]=1.C1(N=C=NC2CCCCC2)CCCCC1>CN(C)C=O>[F:15][C:16]1[CH:24]=[CH:23][C:19]([C:20]([NH:1][CH2:2][CH2:3][O:4][C:5]2[CH:14]=[CH:13][C:8]([C:9]([O:11][CH3:12])=[O:10])=[CH:7][CH:6]=2)=[O:21])=[CH:18][CH:17]=1
Reactant: O=C(O)c1ccc(F)cc1
Reactant: COC(=O)c1ccc(OCCN)cc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(OCCNC(=O)c2ccc(F)cc2)cc1
Temperature: 25 °C
Yield: 67.2 %

Procedure:
Methyl 4-(2-aminoethoxy)benzoate (19.5 g) and 14 g of p-fluorobenzoic acid were dissolved in 300 ml of N,N-dimethylformamide and 20.6 g of N,N'-dicyclohexylcarbodiimide was added thereto little by little with stirring at room temperature. The mixture was stirred for 8 hours, the resulting N,N'-dicyclohexylurea was removed by filtration, the filtrate was poured into ice water, and the mixture was extracted with ethyl acetate. The organic layer was washed with 10% hydrochloric acid, saturated potassium carbonate solution, and water. This was dried with anhydrous magnesium sulphate, concentrated in vacuo, the residue was crystallised with n-hexane, and the resulting 25.4 g of crystals were recrystallised from ethyl acetate/n-hexane to give 21.3 g (yield: 67%) of crystalline product. M.p. 105°-107° C.
Reaction SMILES: N[C@H](C=O)CCSC.[CH2:9]([O:16][CH2:17][CH2:18][O:19][CH2:20][CH2:21][O:22][CH2:23][CH2:24][O:25][CH2:26][CH2:27][O:28][CH2:29][CH2:30][OH:31])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.Cl[CH2:33][C:34]([OH:36])=[O:35]>O>[CH2:9]([O:16][CH2:17][CH2:18][O:19][CH2:20][CH2:21][O:22][CH2:23][CH2:24][O:25][CH2:26][CH2:27][O:28][CH2:29][CH2:30][O:31][CH2:33][C:34]([OH:36])=[O:35])[C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1
Reactant: OCCOCCOCCOCCOCCOCc1ccccc1
Reactant: O=C(O)CCl
Agent: CSCC[C@H](N)C=O
Solvent: O
Product: O=C(O)COCCOCCOCCOCCOCCOCc1ccccc1
Temperature: 90 °C
Reaction time: 3 h
Yield: 201.8 %

Procedure:
Metal sodium (115 mg, 5.0 mmol) was added to pentaethylene glycol monobenzyl ether (328 mg, 1.0 mmol), and the mixture was stirred at 90° C. for three hours. Chloroacetic acid (47 mg, 0.5 mmol) was added to the mixture which was then stirred at 90° C. for 16 hours. Water was added to the mixture which was then washed with ethyl acetate. Next, the aqueous layer was made acidic by 1 N hydrochloric acid, followed by extraction with ethyl acetate. The extract was dried over anhydrous sodium sulfate, and then the solvent was evaporated under reduced pressure to obtain 390 mg of crude [2-(2-{2-[2-(2-benzyloxyethoxy)ethoxy]ethoxy}ethoxy)ethoxy]acetic acid in the form of a reddish brown substance.
Reaction SMILES: [Na+].[Cl-].C([OH:5])C.[C:6]1(=[O:25])[N:10]([N:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]2[S:17][S:18][CH2:19][CH2:20][C:21]([O-:23])=[O:22])[C:9](=[O:24])[CH2:8][CH2:7]1>P([O-])([O-])([O-])=O.[Na+].[Na+].[Na+]>[C:9]1(=[O:24])[N:10]([N:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]2[S:17][S:18][CH2:19][CH2:20][C:21]([O-:23])=[O:22])[C:6](=[O:25])[CH2:7][CH2:8]1.[OH:5][N:10]1[C:9](=[O:24])[CH2:8][CH2:7][C:6]1=[O:25]
Reactant: CCO
Agent: O=C([O-])CCSSC1C=CC=CN1N1C(=O)CCC1=O
Agent: O=P([O-])([O-])[O-]
Agent: [Cl-]
Product: O=C1CCC(=O)N1O

Procedure:
Rabbit IgG (10 mg) was dissolved in 2 mL of 0.1M sodium phosphate buffer containing 0.1M NaCl (pH 7.5) and treated with an ethanol solution of N-succinimidyl-3-(2-pyridyl-dithio)propionate (SPDP) (2-5 equiv. of 9.6 mM solution). The SPDP solution was added in aliquots over a period of 30 minutes. The unreacted SPDP and N-hydroxy-succinimide formed were removed by gel filtration on Sephadex G-25 column (1×14 cm) that was equilibrated with 0.1M sodium phosphate buffer/0.1M NaCl (pH 7.5) and the SPDP-coupled protein eluted with same buffer.
Reaction SMILES: [H-].[Na+].[S:3]1[CH2:8][CH2:7][CH:6]([OH:9])[CH2:5][CH2:4]1.[Br:10][C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([CH2:17]Br)[N:12]=1>O1CCCC1.C(OCC)(=O)C>[Br:10][C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([CH2:17][O:9][CH:6]2[CH2:7][CH2:8][S:3][CH2:4][CH2:5]2)[N:12]=1
Reactant: OC1CCSCC1
Reactant: BrCc1cccc(Br)n1
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: Brc1cccc(COC2CCSCC2)n1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
Sodium hydride (0.24 g, 5.98 mmol) was suspended in tetrahydrofuran (19.9 mL) and cooled to 0° C. Tetrahydro-2H-thiopyran-4-ol (0.24 g, 1.99 mmol) was added and the reaction was stirred for 30 minutes. 2-Bromo-6-(bromomethyl)pyridine (Example 190, Step 1) (0.5 g, 1.99 mmol) was added and the reaction was warmed to and maintained at ambient temperature overnight. The reaction was diluted with ethyl acetate, quenched slowly with water, the layers were separated, and the aqueous layer was extracted with ethyl acetate. The combined organic layers were dried over magnesium sulfate, filtered and concentrated. The crude mixture was purified by silica gel chromatography to yield the title compound.
Reaction SMILES: [NH2:1][C:2]1[CH:12]=[CH:11][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:4][CH:3]=1.Cl[CH2:14][CH:15]=[CH:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.CN(C)P(N(C)C)(N(C)C)=O>O>[CH2:14]([NH:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:11][CH:12]=1)[CH:15]=[CH:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: ClCC=Cc1ccccc1
Reactant: CCOC(=O)c1ccc(N)cc1
Solvent: O
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: CCOC(=O)c1ccc(NCC=Cc2ccccc2)cc1

Procedure:
A mixture of 33 g. of ethyl p-aminobenzoate 15.3 g. of (3-chloropropenyl)benzene and 80 ml. of hexamethylphosphoramide is heated in an oil bath at 110° C. for 21 hours. The solution is chilled, diluted with 25 ml. of water, chilled, filtered and the solid washed with water to give cream crystals, m.p. 123°-131° C. Recrystallization from ethanol-benzene (9:1) gives pale yellow crystals, m.p. 135°-137° C. Recrystallization from benzene gives white crystals, m.p. 135°-137° C.
Reaction SMILES: Cl[C:2]1[N:3]=[N:4][C:5]([C:8]2[CH:9]=[C:10]([C:14]([F:17])([F:16])[F:15])[CH:11]=[CH:12][CH:13]=2)=[CH:6][CH:7]=1.[CH:18]([NH:20][NH2:21])=O>C(O)CCC>[F:15][C:14]([F:17])([F:16])[C:10]1[CH:11]=[CH:12][CH:13]=[C:8]([C:5]2[CH:6]=[CH:7][C:2]3[N:3]([CH:18]=[N:20][N:21]=3)[N:4]=2)[CH:9]=1
Reactant: NNC=O
Reactant: FC(F)(F)c1cccc(-c2ccc(Cl)nn2)c1
Solvent: CCCCO
Product: FC(F)(F)c1cccc(-c2ccc3nncn3n2)c1

Procedure:
A mixture of 6.0 g. of 3-chloro-6-(α,α,α-trifluoro-m-tolyl)pyridazine (prepared as in Example 10), 2.78 g. of formylhydrazine and 75 ml. of butyl alcohol is allowed to stir at reflux temperature for 48 hours. The reaction mixture is concentrated free of solvent and the residue is dissolved in ethyl alcohol, treated with activated charcoal and filtered. The filtrate is cooled in an ice bath and the cream colored solid is collected. The solid is heated with diethyl ether and the mixture is filtered. The solid is recrystallized from ethyl acetate to afford the product of the example as cream colored crystals, m.p. 140°-143° C.