Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CC(C)([O-])C.[K+].[CH2:7]([O:9][C:10](=[O:17])[CH2:11][N:12]1[N:16]=[CH:15][CH:14]=[N:13]1)[CH3:8].Br[CH2:19][C:20]#[C:21][CH2:22][CH2:23][CH2:24][C:25]1[N:26]=[C:27]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[O:28][C:29]=1[CH3:30].Cl>C1COCC1.CCOC(C)=O>[CH2:7]([O:9][C:10](=[O:17])[CH:11]([N:12]1[N:13]=[CH:14][CH:15]=[N:16]1)[CH2:19][C:20]#[C:21][CH2:22][CH2:23][CH2:24][C:25]1[N:26]=[C:27]([C:31]2[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=2)[O:28][C:29]=1[CH3:30])[CH3:8]
Reactant: CCOC(=O)Cn1nccn1
Reactant: Cc1oc(-c2ccccc2)nc1CCCC#CCBr
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCOC(=O)C(CC#CCCCc1nc(-c2ccccc2)oc1C)n1nccn1
Reaction time: 1 h
Yield: 60.9 %

Procedure:
Potassium t-butoxide (2.6 mL, 2.6 mmol) was added to a to a solution of [1,2,3]triazol-2-yl-acetic acid ethyl ester (355 mg, 2.3 mmol) in THF (30 mL) at −78° C. under N2 atmosphere and stirred for 1 hour. A solution of bromide 1-9 (1.5 g, 4.5 mmol) in THF (30 mL) was then added and the solution allowed to equilibrate to 0° C. for 1 hour. Reaction was then poured into dilute aqueous HCl and diluted with EtOAc. The organic layer was washed with water, brine, and dried over MgSO4. Chromatography with 20% EtOAc/Hex gave 550 mg of a mixture of mono-1-4 and bis-alkylated products. The mixture was not separated, and was taken on to hydrolysis step.
Reaction SMILES: [CH3:1][C:2]1[N:7]=[CH:6][C:5]([CH:8]=O)=[CH:4][N:3]=1.Cl.[NH2:11][OH:12].C(=O)([O-])[O-].[Na+].[Na+]>CO>[CH3:1][C:2]1[N:7]=[CH:6][C:5]([CH:8]=[N:11][OH:12])=[CH:4][N:3]=1
Reactant: NO
Reactant: Cc1ncc(C=O)cn1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CO
Product: Cc1ncc(C=NO)cn1
Temperature: 30 °C
Reaction time: 0.5 h

Procedure:
To a mixture of 2-methyl-5-formyl-pyrimidine (180 gm) and hydroxylamine hydrochloride (128 gm) in 50% v/v aqueous methanol (3600 ml) was added sodium carbonate (94 gm). The reaction mixture was stirred at 30° C. for 0.5 h. The resulting suspension was cooled and filtered at −10° C. to provide single isomer of title compound in 113.5 gm quantity (56%) as a solid.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([OH:8])[CH:5]=[CH:6][CH:7]=1.[CH:9]1(Br)[CH2:11][CH2:10]1.[I-].[Na+].C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C.CCOC(C)=O>[CH:9]1([O:8][C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([Br:1])[CH:3]=2)[CH2:11][CH2:10]1
Reactant: BrC1CC1
Reactant: Oc1cccc(Br)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Agent: [I-]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: Brc1cccc(OC2CC2)c1
Temperature: 150 °C
Reaction time: 19 h
Yield: 20.5 %

Procedure:
To a solution of 3-bromophenol (0.57 g, 3.29 mmol) (commercially available from Aldrich) in dry DMF (5.0 mL) was added cyclopropyl bromide (0.53 mL, 6.62 mmol) (commercially available from Aldrich), sodium iodide (50.1 mg, 0.334 mmol), and cesium carbonate (3.2 g, 9.86 mmol). The reaction mixture was heated in a pressure tube to 150° C. After 19 hours, the reaction was cooled to room temperature then diluted with EtOAc, washed with water, and extracted three times with EtOAc. The combined organic layers were dried over sodium sulfate, filtered, and concentrated. The residue was purified by silica gel flash chromatography (0-5% EtOAc/hexane) to afford T24.1 as a colorless oil (144 mg, 21% yield). 1H NMR (400 MHz, CDCl3) δ ppm 7.29 (1H, m), 7.19 (2H, m), 6.99 (1H, d, J=7.8 Hz), 3.74 (1H, ddd, J=8.9, 5.8, 3.3 Hz), 0.81 (4H, ddd, J=11.2, 9.0, 8.8 Hz.).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]2[C@H:12]([NH:13][CH3:14])[CH2:11][N:10]([C:15]([CH:17]3[CH2:22][CH2:21][N:20]([C:23]4[CH:28]=[CH:27][C:26]([C:29]#[N:30])=[CH:25][N:24]=4)[CH2:19][CH2:18]3)=[O:16])[CH2:9]2)=[CH:4][CH:3]=1.Cl[C:32]([O:34][CH2:35][CH2:36][CH3:37])=[O:33]>>[CH2:35]([O:34][C:32](=[O:33])[N:13]([C@H:12]1[C@H:8]([C:5]2[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=2)[CH2:9][N:10]([C:15]([CH:17]2[CH2:22][CH2:21][N:20]([C:23]3[CH:28]=[CH:27][C:26]([C:29]#[N:30])=[CH:25][N:24]=3)[CH2:19][CH2:18]2)=[O:16])[CH2:11]1)[CH3:14])[CH2:36][CH3:37]
Reactant: CCCOC(=O)Cl
Reactant: CN[C@@H]1CN(C(=O)C2CCN(c3ccc(C#N)cn3)CC2)C[C@H]1c1ccc(Cl)cc1
Product: CCCOC(=O)N(C)[C@@H]1CN(C(=O)C2CCN(c3ccc(C#N)cn3)CC2)C[C@H]1c1ccc(Cl)cc1

Procedure:
In analogy to the procedure described for the synthesis of example 136, the title compound [(3S,4R)-4-(4-chloro-phenyl)-1-(5′-cyano-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-4-carbonyl)-pyrrolidin-3-yl]-methyl-carbamic acid propyl ester was prepared from 4-[(3R,4S)-3-(4-chloro-phenyl)-4-methylamino-pyrrolidine-1-carbonyl]-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-5′-carbonitrile using propyl chloroformate instead of ethyl chloroformate and was obtained as a colorless foam. MS m/e: 510.4 [M]+.
Reaction SMILES: [CH2:1]([NH:8][C:9]([C:11]1[S:15][C:14]([C:16]2[CH:21]=[N:20][CH:19]=[C:18](/[CH:22]=[CH:23]/[C:24]3[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=3)[N:17]=2)=[N:13][C:12]=1[CH3:31])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>C(OCC)(=O)C.C(O)C.[OH-].[OH-].[Pd+2]>[CH2:1]([NH:8][C:9]([C:11]1[S:15][C:14]([C:16]2[CH:21]=[N:20][CH:19]=[C:18]([CH2:22][CH2:23][C:24]3[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=3)[N:17]=2)=[N:13][C:12]=1[CH3:31])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cc1nc(-c2cncc(/C=C/c3ccc(F)cc3)n2)sc1C(=O)NCc1ccccc1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CCO
Solvent: CCOC(C)=O
Product: Cc1nc(-c2cncc(CCc3ccc(F)cc3)n2)sc1C(=O)NCc1ccccc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 61.7 %

Procedure:
To a solution of 2-{6-[(E)-2-(4-fluoro-phenyl)-vinyl]-pyrazin-2-yl}-4-methyl-thiazole-5-carboxylic acid benzylamide (40 mg, 0.09 mmol, 1.0 equiv) in ethyl acetate/ethanol (1:1) was added Pd(OH)2 (10 mg, 20%). The flask was first purged with nitrogen, then with hydrogen. The reaction mixture was stirred at ambient temperature for 3 hr and monitored by LCMS. Upon completion, the reaction mixture was diluted with ethyl acetate, filtered through Celite and concentrated in vacuo. The crude product was purified by preparative HPLC (acetonitrile/water, 0.1% trifluoroacetic acid) to afford {6-[2-(4-fluoro-phenyl)-ethyl]-pyrazin-2-yl}-4-methyl-thiazole-5-carboxylic acid benzylamide (24 mg, 60%). 1H NMR (400 MHz, CD2Cl2) δ 9.15 (s, 1H), 8.36 (s, 1H), 7.28-7.37 (m, 5H), 7.13-7.17 (m, 2H), 6.92-6.96 (m, 2H), 6.25 (bs, 1H), 4.60 (d, J=4.0 Hz, 2H), 3.07-3.16 (m, 4H), 2.73 (s, 3H); HRMS (M+H)+=433.15.
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][CH2:15][OH:16])[CH2:10][CH2:9]1)(OC(C)(C)C)=O.[H-].[Na+].[CH3:19]I.[ClH:21]>C1COCC1.CCO>[ClH:21].[CH3:19][O:16][CH2:15][CH2:14][CH:11]1[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]1
Reactant: CC(C)(C)OC(=O)N1CCC(CCO)CC1
Reactant: CI
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CCO
Solvent: C1CCOC1
Product: COCCC1CCNCC1
Temperature: 0 °C
Reaction time: 1 h
Yield: 89 %

Procedure:
N-Boc-4-(2-hydroxy-ethyl)-piperidine (5 g, 21.8 mmol) in THF (25 ml) was added to a suspension of NaH (1.47 g, 43.7 mmol) in THF (75 ml) at 0° C. under N2. The reaction was stirred for 1 hour at 0° C. and MeI (2.72 ml, 43.7 mmol) added slowly. The reaction was allowed to warm to room temperature and stirred overnight. The reaction was quenched with water (100 ml) and extracted with DCM (3×100 ml). The combined DCM layers were dried over MgSO4, filtered, washed with DCM and concentrated in vacuo. The crude reaction (7.5 g) was treated with 3M HCl solution in EtOH (150 ml) for 12 hours. The reaction was concentrated in vacuo and azeotroped with toluene (2×150 ml) to give 4-(2-methoxy-ethyl)-piperidine hydrochloride (3.5 g, 89%) as a pale yellow solid.
Reaction SMILES: N[C:2]1[CH:11]=[C:10](Cl)[CH:9]=[CH:8][C:3]=1[C:4]([NH:6][CH3:7])=[O:5].[ClH:13]>N1C=CC=CC=1>[Cl:13][C:9]1[CH:10]=[CH:11][CH:2]=[C:3]([CH:8]=1)[C:4]([NH:6][CH3:7])=[O:5]
Reactant: CNC(=O)c1ccc(Cl)cc1N
Reactant: Cl
Solvent: c1ccncc1
Product: CNC(=O)c1cccc(Cl)c1
Temperature: 0 °C
Reaction time: 1 h
Yield: 51 %

Procedure:
A suspension of (E)-3,4-bis(difluoromethoxy)phenyl-2-propenoic acid (0.10 g, 0.42 mmol) in CH2Cl2 (5 mL) was treated with oxalyl chloride (0.14 mL, 1.7 mmol) and catalytic DMF (1 drop). The solution was stirred at rt for 1 h and the solvent was removed under reduced pressure to give the acid chloride as a yellow solid. A solution of the acid chloride (0.42 mmol) in pyridine (2.0 mL) was added to a cooled solution of 2-amino-4-chloro-N-methylbenzamide (0.12 g, 0.63 mmol) in pyridine (2.0 mL) at 0° C. The suspension was stirred at 0° C. for 1 h, warmed to rt and stirred for 16 h and then acidified with 1 M HCl. The precipitate was collected by filtration and recrystallised from EtOH/water providing (E)-2-[[3,4-bis(difluoromethoxy)phenyl)-1-oxo-2-propenyl]amino]-5-chloro-N-methylbenzamide (95 mg, 51%) as a pale brown crystalline solid; mp 191.5-195.5° C.; δH (500 MHz, DMSO-d6) 2.82 (d, J=4.5 Hz, 3H, NHCH3), 6.94 (d, J=15.6 Hz, 1H, CH═CHCO), 7.27 (t, J=73 Hz, 1H, OCHF2), 7.28 (t, J=73 Hz, 1H, OCHF2), 7.26 (dd, J5,6=8.0, J3,5=1.6 Hz, 1H, H5), 7.39 (d, J5′,6′=8.0 Hz, 1H, H5′), 7.59 (d, J=15.6 Hz, 1H, CH═CHCO), 7.69 (dd, J5′,6′=8.5, J2′,6′=2.5 Hz, 1H, H6′), 7.77 (d, J5,6=2.5 Hz, 1H, H6), 7.80 (d, J2′,6′=2.5 Hz, 1H, H2′), 8.67 (d, J3,5=2.5 Hz, 1H, H3), 8.84 (m, 1H, NHCH3), 11.82 (s, 1H, NH); δC (125 MHz, DMSO-d6) 26.3, 116.3 (t, J=259 Hz), 116.5 (t, J=259 Hz), 119.2, 119.9, 119.9, 120.7, 122.6, 123.4, 126.8, 129.6, 132.7, 136.2, 139.7, 140.2, 141.9, 142.8, 163.5, 167.8; HRMS (ESI+) calculated for C19H15ClF4N2O4 [M+Na]+ 469.0549, found 469.0546; νmax 1038, 1113, 1260, 1505, 1578, 1626, 3025, 3382 cm−1.
Reaction SMILES: [CH2:1]([O:8][CH2:9][CH2:10][CH:11]([C:20]1[NH:21][C:22]([C:32]2[CH:41]=[CH:40][CH:39]=[C:38]3[C:33]=2[N:34]=[C:35]([NH:43][C:44]([CH3:47])([CH3:46])[CH3:45])[C:36]([CH3:42])=[N:37]3)=[CH:23][C:24]=1C(OC(C)(C)C)=O)[NH:12][C:13]([O:15]C(C)(C)C)=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(O)(C(F)(F)F)=O.CCN(C(C)C)C(C)C.F[P-](F)(F)(F)(F)F.N1(O[P+](N2CCCC2)(N2CCCC2)N2CCCC2)C2C=CC=CC=2N=N1>C(Cl)Cl>[CH2:1]([O:8][CH2:9][CH2:10][CH:11]1[C:20]2[NH:21][C:22]([C:32]3[CH:41]=[CH:40][CH:39]=[C:38]4[C:33]=3[N:34]=[C:35]([NH:43][C:44]([CH3:47])([CH3:46])[CH3:45])[C:36]([CH3:42])=[N:37]4)=[CH:23][C:24]=2[C:13](=[O:15])[NH:12]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cc1nc2cccc(-c3cc(C(=O)OC(C)(C)C)c(C(CCOCc4ccccc4)NC(=O)OC(C)(C)C)[nH]3)c2nc1NC(C)(C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: CCN(C(C)C)C(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1nc2cccc(-c3cc4c([nH]3)C(CCOCc3ccccc3)NC4=O)c2nc1NC(C)(C)C
Temperature: 40 °C
Reaction time: 0.25 h
Yield: 69.7 %

Procedure:
To a solution of tert-butyl 2-(3-(benzyloxy)-1-((tert-butoxycarbonyl)amino)propyl)-5-(3-(tert-butylamino)-2-methylquinoxalin-5-yl)-1H-pyrrole-3-carboxylate (1.28 g, 1.98 mmol) in 20 mL of DCM at RT was added TFA (5 mL) and the dark red solution was heated in an oil bath at 40° C. for 4 h. It was concentrated under reduced pressure. 5 mL of toluene was added to the residue and concentrated to dryness again. The brown amorphous solid was stirred in 15 mL of hexanes and the liquid was decanted. The brown residue was treated with 5 mL of DMF and 30 mL of DCM, cooled at 0° C., and added DIPEA (2.06 mL, 11.88 mmol) followed by (benzotriazol-1-yloxy)tripyrrolidinophosphonium hexafluorophosphate (1.28 g, 2.47 mmol). It was stirred at 0° C. for 10 min followed by RT for 15 min, then diluted with 50 mL of DCM. The mixture was washed sequentially with 5 mL of water, 5 mL of 0.5 N NaOH, and 5 mL of brine. The DCM solution was concentrated. The residue was purified on a silica gel column (50-100% EtOAc in DCM followed by 5% MeOH in DCM) to give 6-(2-(benzyloxy)ethyl)-2-(3-(tert-butylamino)-2-methylquinoxalin-5-yl)-5,6-dihydropyrrolo[3,4-b]pyrrol-4(1H)-one (0.65 g, 1.38 mmol, 70% yield) as a brown crystalline solid. m/z (ESI, +ve) 470.0 (M+H)+.
Reaction SMILES: [NH:1]([CH2:5][CH2:6][OH:7])[CH2:2][CH2:3][OH:4].C(N(CC)CC)C.[CH2:15]([O:17][P:18](Cl)([O:20][CH2:21][CH3:22])=[O:19])[CH3:16]>ClCCl.CCOCC>[CH2:15]([O:17][P:18]([N:1]([CH2:5][CH2:6][OH:7])[CH2:2][CH2:3][OH:4])([O:20][CH2:21][CH3:22])=[O:19])[CH3:16]
Reactant: CCOP(=O)(Cl)OCC
Reactant: OCCNCCO
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: CCOCC
Product: CCOP(=O)(OCC)N(CCO)CCO
Yield: 53.5 %

Procedure:
To a solution of diethanolamine (5.0 g, 48 mmol) and triethylamine (8.0 ml) in dichloromethane (75 ml) was added dropwise with stirring under Argon, a solution of diethylchlorophosphate (8.2 g, 48 mmol) in dichloromethane (25 ml) over approximately 15 minutes and then allowed to stir at room temperature overnight. The mixture was washed with brine (50 ml) then dried (Na2SO4) and evaporated in vacuo to give the crude product as a viscous oil. The oil was dissolved in ether (100 ml) and the white solid which precipitated was filtered off (triethylamine hydrochloride). The ether solution was evaporated in vacuo giving N-diethoxyphosphoryldiethanolamine (6.2 g, 54%) as a colourless oil.
Reaction SMILES: [NH:1]([C:35]([O:37]C(C)(C)C)=O)[C@H:2]([C:12]([NH:14][C@H:15]([C:25]([O:27]N1C(=O)CCC1=O)=[O:26])[CH2:16][CH2:17][C:18](=[O:24])[O:19]C(C)(C)C)=[O:13])[CH2:3][CH2:4][C:5](=[O:11])[O:6]C(C)(C)C.[NH2:42][C@H:43](C(O)=O)[CH2:44][CH2:45][C:46](=[O:48])[OH:47].[CH3:52][N:53]1[C@@H:70]2[CH2:71][C:58]3[CH:59]=[CH:60][C:61]([O:72][CH3:73])=[C:62]4[O:63][C@H:64]5[C:65]([CH2:67][CH2:68][C@@H:69]2[C@:56]5([C:57]=34)[CH2:55][CH2:54]1)=[O:66]>>[NH2:42][C@H:43]([C:35]([NH:1][C@H:2]([C:12]([NH:14][C@H:15]([C:25]([OH:27])=[O:26])[CH2:16][CH2:17][C:18](=[O:24])[OH:19])=[O:13])[CH2:3][CH2:4][C:5](=[O:11])[OH:6])=[O:37])[CH2:44][CH2:45][C:46](=[O:47])[OH:48].[CH3:52][N:53]1[C@@H:70]2[CH2:71][C:58]3[CH:59]=[CH:60][C:61]([O:72][CH3:73])=[C:62]4[O:63][C@H:64]5[C:65]([CH2:67][CH2:68][C@@H:69]2[C@:56]5([C:57]=34)[CH2:55][CH2:54]1)=[O:66]
Reactant: N[C@@H](CCC(=O)O)C(=O)O
Reactant: CC(C)(C)OC(=O)CC[C@H](NC(=O)OC(C)(C)C)C(=O)N[C@@H](CCC(=O)OC(C)(C)C)C(=O)ON1C(=O)CCC1=O
Agent: COc1ccc2c3c1O[C@H]1C(=O)CC[C@H]4[C@@H](C2)N(C)CC[C@]314
Product: N[C@@H](CCC(=O)O)C(=O)N[C@@H](CCC(=O)O)C(=O)N[C@@H](CCC(=O)O)C(=O)O

Procedure:
Glu-Glu-Glu-Hydrocodone was prepared by a similar method to Example 41 except the amino acid starting material was Boc-Glu(OtBu)-Glu(OtBu)-OSu and the conjugate starting material was Glu-Hydrocodone.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:19]=[CH:18][CH:17]=[C:16]2[C:7]=1[N+:8]([O-:22])=[C:9]1[C:14](=[N+:15]2[O-:20])[C:13]([OH:21])=[CH:12][CH:11]=[CH:10]1.[CH3:23][NH:24][CH3:25]>C(=O)=O.CC(C)=O>[CH3:23][N:24]([CH3:25])[CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:19]=[CH:18][CH:17]=[C:16]2[C:7]=1[N+:8]([O-:22])=[C:9]1[C:14](=[N+:15]2[O-:20])[C:13]([OH:21])=[CH:12][CH:11]=[CH:10]1
Reactant: CNC
Reactant: [O-][n+]1c2cccc(OCCCCl)c2[n+]([O-])c2cccc(O)c21
Agent: O=C=O
Solvent: CC(C)=O
Product: CN(C)CCCOc1cccc2c1[n+]([O-])c1cccc(O)c1[n+]2[O-]
Temperature: 25 °C
Reaction time: 70 h

Procedure:
Into a sealed tube was placed 2.0 grams of 6-(3-chloropropoxy)-1-phenazinol 5,10-dioxide. The tube was cooled in dry-ice-acetone and 80 ml of dimethylamine was condensed into the tube. The tube was sealed and shaken at room temperature for 70 hours. The tube was then opened and excess dimethylamine allowed to evaporate at room temperature. The residue was dissolved in CHCl3 solution, was washed with water and was then extracted with 3 × 150ml 10 percent aqueous HCl. The combined acid extracts were made basic with sodium carbonate, extracted with CHCl 3 and the combined CHCl3 extracts were washed with water, dried over sodium sulfate and concentrated in vacuo. The residue was recrystallized from acetone/ether to yield 6-(3-dimethylaminopropoxy)-1-phenazinol 5,10-dioxide, mp. 103°C (dec.).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([CH3:8])[CH:3]=1.[Cl:9][C:10]1[CH:20]=[CH:19][C:13]([C:14](OCC)=[O:15])=[CH:12][CH:11]=1.C[Si](C)(C)N[Si](C)(C)C.[Li]>O1CCCC1.C(OCC)(=O)C.O.C1CCCCC1>[Br:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([CH2:8][C:14]([C:13]2[CH:19]=[CH:20][C:10]([Cl:9])=[CH:11][CH:12]=2)=[O:15])[CH:3]=1
Reactant: CCOC(=O)c1ccc(Cl)cc1
Reactant: Cc1cc(Br)ccn1
Agent: C[Si](C)(C)N[Si](C)(C)C
Agent: [Li]
Solvent: O
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: O=C(Cc1cc(Br)ccn1)c1ccc(Cl)cc1
Temperature: 5 °C
Reaction time: 2 h
Yield: 93 %

Procedure:
5 g (29.07 mmol) of 4-bromo-2-methylpyridine and 11.27 g (61.04 mmol) of ethyl 4-chlorobenzoate are placed under a stream of nitrogen in a round-bottomed flask and dissolved in 50 ml of anhydrous tetrahydrofuran. The solution is cooled to 5° C. and 70 ml (70 mmol) of a lithium hexamethyldisilazane solution (1M in tetrahydrofuran) are added dropwise. After addition, the mixture is stirred at ambient temperature for 2 h and cooled to 5° C., and then 100 ml of water are gradually added. The medium is subsequently diluted with 250 ml of ethyl acetate and 100 ml of water. The organic phase is separated and the aqueous phase is extracted twice with 100 ml of ethyl acetate. The organic phases are subsequently combined, dried over sodium sulphate and filtered. 15 g of silica are subsequently added to the filtrate and the mixture is concentrated under reduced pressure. The powder obtained is used as solid deposit for chromatography on silica gel, with a mixture of cyclohexane and ethyl acetate (9/1) as eluent. 8.4 g (93%) of compound are obtained in the form of a yellow powder.
Reaction SMILES: Cl.C([O:5][C:6]1[C:11]([Cl:12])=[CH:10][C:9]([Cl:13])=[CH:8][C:7]=1[CH:14]([NH:20][C:21]1[CH:26]=[CH:25][C:24]([C:27](=[NH:29])[NH2:28])=[CH:23][CH:22]=1)[C:15]([O:17][CH2:18][CH3:19])=[O:16])C=C.[H][H]>C(O)C.[Pt](=O)=O>[ClH:12].[C:27]([C:24]1[CH:25]=[CH:26][C:21]([NH:20][CH:14]([C:7]2[CH:8]=[C:9]([Cl:13])[CH:10]=[C:11]([Cl:12])[C:6]=2[OH:5])[C:15]([O:17][CH2:18][CH3:19])=[O:16])=[CH:22][CH:23]=1)(=[NH:28])[NH2:29]
Reactant: [H][H]
Reactant: C=CCOc1c(Cl)cc(Cl)cc1C(Nc1ccc(C(=N)N)cc1)C(=O)OCC
Agent: O=[Pt]=O
Agent: Cl
Solvent: CCO
Product: CCOC(=O)C(Nc1ccc(C(=N)N)cc1)c1cc(Cl)cc(Cl)c1O
Yield: 197.2 %

Procedure:
A solution of 300 mg of ethyl (RS)-(2-allyloxy-3,5-dichloro-phenyl)-(4-carbamimidoyl-phenylamino)-acetate hydrochloride (1:1) (see Example 293.3) in 5 ml of ethanol was treated with hydrogen in ther presence of a catalytic amount of platinum dioxide for 45 minutes while stirring. The reaction mixture was suction filtered over Speedex. The filtrate was concentrated and gave 270 mg of ethyl (RS)-(4-carbamimidoyl-phenylamino)-(3,5-dichloro-2-hydroxy-phenyl)-acetate hydrochloride (1:1); MS (ISP) m/z 382/384 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:24]=[CH:23][C:5]([O:6][CH2:7][CH:8]2[CH2:14][N:13](CC3C=CC=CC=3)[CH:12]([CH3:22])[CH2:11][CH2:10][CH2:9]2)=[CH:4][C:3]=1[CH3:25]>[OH-].[OH-].[Pd+2].CO>[F:1][C:2]1[CH:24]=[CH:23][C:5]([O:6][CH2:7][CH:8]2[CH2:14][NH:13][CH:12]([CH3:22])[CH2:11][CH2:10][CH2:9]2)=[CH:4][C:3]=1[CH3:25]
Reactant: Cc1cc(OCC2CCCC(C)N(Cc3ccccc3)C2)ccc1F
Agent: [Pd+2]
Agent: [OH-]
Solvent: CO
Product: Cc1cc(OCC2CCCC(C)NC2)ccc1F
Temperature: 23 °C
Reaction time: 1 h

Procedure:
A mixture of 6-[(4-fluoro-3-methylphenoxy)methyl]-1-benzyl-2-methylazepane (2-6, 250 mg, 0.74 mmol, 1.0 equiv) and Pearlman's catalyst (wet 20% Pd(OH)2/C) (78 mg, 0.11 mmol, 0.15 equiv) in methanol (30 mL) was stirred under a hydrogen balloon for 1 hour at 23° C. The suspension was filtered and the filtrate was concentrated to give 6-[(4-fluoro-3-methylphenoxy)methyl]-2-methylazepane (2-7). δ 6.90 (m, 1H), 6.71 (m, 2H), 3.72-1.75 (m, 19H). LRMS m/z (M+H) 252.3 found, 252.2 required.
Reaction SMILES: [O:1]1[CH:3]([CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH3:13])[CH2:2]1.[Na].[CH3:15][OH:16]>>[CH3:15][O:16][CH2:2][CH:3]([OH:1])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH3:13]
Reactant: CO
Reactant: CCCCCCCCCCC1CO1
Agent: [Na]
Product: CCCCCCCCCCC(O)COC
Yield: 88 %

Procedure:
1,2-Epoxydodecane is reacted with sodium in methanol as in Example 1 to yield 1-methoxy-2-dodecanol as a colourless oil, bp 97° C./0.07 mbar, yield 88%.
Reaction SMILES: C([O:3][C:4]([C:6]1([NH:16][C:17](=[O:31])[C:18]2[CH:23]=[C:22]([Cl:24])[CH:21]=[C:20]([CH3:25])[C:19]=2[O:26][CH:27]2[CH2:30][CH2:29][CH2:28]2)[CH2:14][C:13]2[C:8](=[CH:9][CH:10]=[C:11]([F:15])[CH:12]=2)[CH2:7]1)=[O:5])C.O1CCOCC1.CO.[Li+].[OH-]>CO.C(Cl)Cl.O>[Cl:24][C:22]1[CH:21]=[C:20]([CH3:25])[C:19]([O:26][CH:27]2[CH2:30][CH2:29][CH2:28]2)=[C:18]([CH:23]=1)[C:17]([NH:16][C:6]1([C:4]([OH:5])=[O:3])[CH2:14][C:13]2[C:8](=[CH:9][CH:10]=[C:11]([F:15])[CH:12]=2)[CH2:7]1)=[O:31]
Reactant: CCOC(=O)C1(NC(=O)c2cc(Cl)cc(C)c2OC2CCC2)Cc2ccc(F)cc2C1
Agent: [Li+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: CO
Solvent: ClCCl
Product: Cc1cc(Cl)cc(C(=O)NC2(C(=O)O)Cc3ccc(F)cc3C2)c1OC1CCC1
Reaction time: 24 h
Yield: 98.8 %

Procedure:
A 100 mL flask containing 2-(5-chloro-2-cyclobutoxy-3-methyl-benzoylamino)-5-fluoro-indan-2-carboxylic acid ethyl ester (328, 0.49 g, 1.09 mmol) is charged with 1,4-dioxane (3 mL) and MeOH (3 mL). A stirring bar is added and stirring is initiated. After dissolution, water (1.5 mL) is added followed by the LiOH (117 mg, 2.78 mmol). After 1 day, tlc analysis (silica, 10% MeOH/DCM) indicates that the starting material is completely consumed. The pH of the reaction mixture is carefully adjusted to pH 2 by slowly adding dilute aqueous HCl (3%, ˜8 mL). The contents of the flask are poured into a separatory funnel which contains EtOAc (25 mL). The layers are separated. The aqueous layer is extracted with EtOAc (20 mL). The combined organic phases are washed with water (20 mL) and brine (20 mL), and then dried over MgSO4, filtered and concentrated by pumping to constant weight to give white solid (0.45 g, 98%).
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([C:11]3[CH:12]([CH3:18])[CH2:13][C:14](=[O:17])[NH:15][N:16]=3)[CH:9]=2)[CH2:4][NH:3][CH:2]=1>C(Cl)(Cl)Cl.[O-2].[O-2].[Mn+4]>[CH3:18][CH:12]1[C:11]([C:8]2[CH:9]=[C:10]3[C:5]([CH:4]=[N:3][CH:2]=[N:1]3)=[CH:6][CH:7]=2)=[N:16][NH:15][C:14](=[O:17])[CH2:13]1
Reactant: CC1CC(=O)NN=C1c1ccc2c(c1)N=CNC2
Agent: [Mn+4]
Agent: [O-2]
Solvent: ClC(Cl)Cl
Product: CC1CC(=O)NN=C1c1ccc2cncnc2c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 80.7 %

Procedure:
In 20 ml of chloroform was dissolved 0.25 g of Compound 71 obtained in Example 71, and 2.0 g of manganese dioxide was added to the solution, followed by stirring at room temperature for 1 hour. Insoluble substances were filtered off, and the filtrate was concentrated. The residue was crystallized by the addition of diethyl ether to give 0.2 g (83%) of 4,5-dihydro-5-methyl-6-(7-quinazolinyl)-3(2H)-pyridazinone (Compound 54).
Reaction SMILES: [H-].[Na+].[C:3]([N:13]1[CH2:17][CH2:16][C@H:15]([NH:18][CH:19]2[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]2)[CH2:14]1)([O:5][CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)=[O:4].Br[CH2:26][C:27]([O:29][CH3:30])=[O:28]>C1COCC1>[C:3]([N:13]1[CH2:17][CH2:16][C@H:15]([N:18]([CH:19]2[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]2)[CH2:26][C:27]([O:29][CH3:30])=[O:28])[CH2:14]1)([O:5][CH2:6][C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1)=[O:4]
Reactant: O=C(OCc1ccccc1)N1CC[C@H](NC2CCCCC2)C1
Reactant: COC(=O)CBr
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COC(=O)CN(C1CCCCC1)[C@H]1CCN(C(=O)OCc2ccccc2)C1
Reaction time: 0.5 h
Yield: 90 %

Procedure:
NaH (60% in mineral oil, 52.0 mg, 1.30 mmol) was placed in a round-bottom flask, filled with nitrogen, and then THF (10 mL) was added. A solution of (3S)-1-Cbz-3-(cyclohexylamino)pyrrolidine (302 mg, 1.00 mmol) prepared in Intermediate 2 in THF was added dropwise at 0° C., and the reaction mixture was stirred for 30 min until no further gas evolution occurred, followed by slow addition of methyl bromoacetate. After 4 h, the reaction, mixture was quenched with water and extracted with EtOAc. The extracts were dried over MgSO4 and concentrated in vacuo, and the residue was purified by column chomatography (EtOAc/Hex=1/2) to give the title compound (227 mg, 90.0%).