Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH-].[Na+].[O:3]1[CH:7]=[CH:6][CH:5]=[C:4]1/[C:8](=[N:16]/[O:17][CH2:18][C:19]1[CH:24]=[CH:23][C:22]([O:25][CH2:26][C:27]2[N:28]=[C:29]([C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)[O:30][C:31]=2[CH3:32])=[CH:21][CH:20]=1)/[CH2:9][CH2:10][C:11]([O:13]CC)=[O:12].CO.Cl>O1CCCC1>[O:3]1[CH:7]=[CH:6][CH:5]=[C:4]1/[C:8](=[N:16]/[O:17][CH2:18][C:19]1[CH:24]=[CH:23][C:22]([O:25][CH2:26][C:27]2[N:28]=[C:29]([C:33]3[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=3)[O:30][C:31]=2[CH3:32])=[CH:21][CH:20]=1)/[CH2:9][CH2:10][C:11]([OH:13])=[O:12]
Reactant: CCOC(=O)CC/C(=N\OCc1ccc(OCc2nc(-c3ccccc3)oc2C)cc1)c1ccco1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: Cc1oc(-c2ccccc2)nc1COc1ccc(CO/N=C(\CCC(=O)O)c2ccco2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 78.2 %

Procedure:
A 1N aqueous saturated solution of sodium hydroxide (5 ml) was added to a solution of ethyl E-4-(2-furyl)-4-[4-(5-methyl-2-phenyl-4-oxazolylmethoxy)benzyloxyimino]butyrate (190 mg) in tetrahydrofuran (10 ml)-methanol (5 ml) and stirred at room temperature for 1 hour. 1N hydrochloric acid (5.5 ml) was added to the reaction mixture and extracted with ethyl acetate. The ethyl acetate layer was washed with an aqueous saturated solution of sodium chloride, dried (MgSO4) and concentrated. The residue was recrystallized from ethyl acetate-hexane to obtain E-4-(2-furyl)-4-[4-(5-methyl-2-phenyl-4-oxazolylmethoxy)benzyloxyimino]butyric acid (140 mg, yield 78%) as colorless crystals. m.p. 124-125° C.
Reaction SMILES: [CH:1]1([O:4][C:5]2[CH:6]=[C:7]([C:15]3[NH:32][C:18]4[CH:19]=[N:20][N:21](COCC[Si](C)(C)C)[C:22](=[O:23])[C:17]=4[C:16]=3[CH2:33][O:34][CH2:35][CH:36]([CH3:38])[CH3:37])[CH:8]=[CH:9][C:10]=2[O:11][CH:12]([F:14])[F:13])[CH2:3][CH2:2]1.C1(OCC2C3C(=O)N(COCC[Si](C)(C)C)N=CC=3NC=2C2C=CC(OC(F)F)=C(OC3CC3)C=2)CCC1>>[CH:1]1([O:4][C:5]2[CH:6]=[C:7]([C:15]3[NH:32][C:18]4[CH:19]=[N:20][NH:21][C:22](=[O:23])[C:17]=4[C:16]=3[CH2:33][O:34][CH2:35][CH:36]([CH3:38])[CH3:37])[CH:8]=[CH:9][C:10]=2[O:11][CH:12]([F:13])[F:14])[CH2:2][CH2:3]1
Reactant: CC(C)COCc1c(-c2ccc(OC(F)F)c(OC3CC3)c2)[nH]c2cnn(COCC[Si](C)(C)C)c(=O)c12
Agent: C[Si](C)(C)CCOCn1ncc2[nH]c(-c3ccc(OC(F)F)c(OC4CC4)c3)c(COC3CCC3)c2c1=O
Product: CC(C)COCc1c(-c2ccc(OC(F)F)c(OC3CC3)c2)[nH]c2cn[nH]c(=O)c12
Yield: 63.5 %

Procedure:
Reaction and post treatment were carried out in the same manner as in Example 13-(c) except for using 0.83 g (1.51 mmol) of 2-(3-cyclopropoxy-4-difluoromethoxyphenyl)-3-isobutoxymethyl-5-(2-trimethylsilylethoxymethyl)-1,5-dihydropyrrolo[2,3-d]pyridazin-4-one obtained in Example 62-(b) in place of 3-cyclobutoxymethyl-2-(3-cyclopropoxy-4-difluoromethoxyphenyl)-5-(2-trimethylsilylethoxymethyl)-1,5-dihydropyrrolo[2,3-d]pyridazin-4-one, whereby 402 mg of the title compound was obtained as a white solid. (Yield: 64%)
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:8]([O:11][CH3:12])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[Br:13][CH2:14][C:15](Br)=[O:16]>CN(C=O)C.O1CCOCC1.O>[Br:13][CH2:14][C:15]([NH:1][C:2]1[CH:10]=[CH:9][C:8]([O:11][CH3:12])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5])=[O:16]
Reactant: O=C(Br)CBr
Reactant: COc1ccc(N)c(C(=O)O)c1
Solvent: O
Solvent: C1COCCO1
Solvent: CN(C)C=O
Product: COc1ccc(NC(=O)CBr)c(C(=O)O)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 65.4 %

Procedure:
To a solution of 2-amino-5-methoxybenzoic acid (5.0 g, 0.03 mol) in anhydrous DMF (30 mL) and dioxane (30 mL) was added, dropwise, bromoacetyl bromide (6.0 g, 2.6 mL, 100 mol %) while keeping the internal temperature between 0° and 2° C. After the addition was completed (~30 min), the reaction mixture was stirred overnight at rt. The reaction mixture was diluted with water (100 mL), and then the precipitated product was filtered, washed sequentially with 5% HBr (300 mL) and water (300 mL), and then dried in a vacuum oven at 40°-45° C., affording 5.6 g (65%) of the title compound as a light grey solid: mp 171.5°-172.7° C.; 1H NMR (DMSO-d6) δ11.26 (s, 1H, NH), 8.30 (d, 1H, J=9.2), 7.44 (d, 1H, J=3.2), 7.22 (dd, 1H, J=3.2, J=9.2), 4.22 (s, 2H), 3.78 (s, 3H); 13C NMR (DMSO-d6) δ168.69, 164.52, 154.75, 133.03, 122.13, 119.83, 119.04, 114.87, 55.40, 30.59; MS (EI, m/z)287 (M+). HRMS (EI) calcd for C10H10NO4Br 286.9793, found 286.9793.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([NH2:8])=[N:6][CH:7]=1.[F:9][C:10]1[CH:20]=[CH:19][CH:18]=[C:17]([F:21])[C:11]=1[C:12]([N:14]=[C:15]=[O:16])=[O:13]>>[F:9][C:10]1[CH:20]=[CH:19][CH:18]=[C:17]([F:21])[C:11]=1[C:12]([NH:14][C:15]([NH:8][C:5]1[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][N:6]=1)=[O:16])=[O:13]
Reactant: Nc1ccc(Cl)cn1
Reactant: O=C=NC(=O)c1c(F)cccc1F
Product: O=C(NC(=O)c1c(F)cccc1F)Nc1ccc(Cl)cn1

Procedure:
An 0.5 g. portion of 5-chloro-2-aminopyridine was reacted with 0.6 g. of 2,6-difluorobenzoyl isocyanate as described in Example 1. The isolated product was 0.8 g. of the product named in the heading above, m.p. 226°-229° C. Its elemental analysis showed the following results:
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([NH:16][C:17](=[O:19])[CH3:18])[CH:5]=[CH:6][C:7]=1[NH:8][CH2:9][CH:10]1[CH2:15][CH2:14][O:13][CH2:12][CH2:11]1.[CH3:20][C:21]([CH3:27])([CH2:25][CH3:26])[C:22](Cl)=[O:23]>CN(C1C=CN=CC=1)C.C(Cl)Cl>[C:17]([NH:16][C:4]1[CH:5]=[CH:6][C:7]([NH:8][CH2:9][CH:10]2[CH2:11][CH2:12][O:13][CH2:14][CH2:15]2)=[C:2]([NH:1][C:22](=[O:23])[C:21]([CH3:27])([CH3:20])[CH2:25][CH3:26])[CH:3]=1)(=[O:19])[CH3:18]
Reactant: CC(=O)Nc1ccc(NCC2CCOCC2)c(N)c1
Reactant: CCC(C)(C)C(=O)Cl
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: CCC(C)(C)C(=O)Nc1cc(NC(C)=O)ccc1NCC1CCOCC1

Procedure:
Following the same procedure in Example 1, Step E, using N-{3-Amino-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}acetamide (10.5 g, 40 mmol), DMAP (2.4 g, 20 mmol) and 2,2-dimethylbutyryl chloride (5.9 g, 44 mmol) in 350 mL of DCM. Yield: 14.2 g (98%); 1H NMR (400 MHz, CHLOROFORM-D) δ 0.94 (t, J=7.52 Hz, 3 H), 1.29 (s, 6 H), 1.32-1.46 (m, 2 H), 1.66 (q, J=7.42 Hz, 2 H), 1.68-1.75 (m, 2 H), 1.78-1.90 (m, 1 H), 2.13 (s, 3 H), 2.97 (d, J=7.03 Hz, 2 H), 3.34-3.45 (m, 2 H), 3.77-3.86 (m, 1 H), 3.94-4.06 (m, 2 H), 6.75 (d, J=8.79 Hz, 1 H), 7.05 (s, 1 H), 7.21 (dd, J=8.59, 2.54 Hz, 1 H), 7.49 (s, 1 H), 7.55 (d, J=2.34 Hz, 1 H); MS (ESI) (M+H)+=362.06.
Reaction SMILES: [C:1]1([C@@H:7]([NH:9][C:10]2[N:15]=[C:14]([N:16]3[C:20]4[CH:21]=[CH:22][C:23]([Sn](C)(C)C)=[CH:24][C:19]=4[N:18]=[CH:17]3)[CH:13]=[CH:12][N:11]=2)[CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Br[C:30]1[C:35]([F:36])=[C:34]([F:37])[N:33]=[C:32]([F:38])[C:31]=1[F:39]>>[C:1]1([C@@H:7]([NH:9][C:10]2[N:15]=[C:14]([N:16]3[C:20]4[CH:21]=[CH:22][C:23]([C:30]5[C:35]([F:36])=[C:34]([F:37])[N:33]=[C:32]([F:38])[C:31]=5[F:39])=[CH:24][C:19]=4[N:18]=[CH:17]3)[CH:13]=[CH:12][N:11]=2)[CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: C[C@H](Nc1nccc(-n2cnc3cc([Sn](C)(C)C)ccc32)n1)c1ccccc1
Reactant: Fc1nc(F)c(F)c(Br)c1F
Product: C[C@H](Nc1nccc(-n2cnc3cc(-c4c(F)c(F)nc(F)c4F)ccc32)n1)c1ccccc1

Procedure:
The title compound was prepared according to the procedure described in EXAMPLE 424, starting from 2-[(S)-1-Phenylethylamino]-4-[5-trimethylstannylbenzimidazol-1-yl]pyrimidine and 4-bromo-2,3,5,6-tetrafluoropyridine. Mass spectrum (ESI) 465.5 (M+1).
Reaction SMILES: [H-].[Na+].[CH3:3][NH:4][C:5]1[N:9]([CH3:10])[C:8]([C:11]2[CH:12]=[N:13][CH:14]=[CH:15][CH:16]=2)=[N:7][N:6]=1.Cl[CH:18]([C:20]1[N:24]=[C:23]([C:25]2[CH:30]=[CH:29][CH:28]=[C:27]([Cl:31])[CH:26]=2)[O:22][N:21]=1)[CH3:19]>CN(C=O)C.[Cl-].[Na+].O>[Cl:31][C:27]1[CH:26]=[C:25]([C:23]2[O:22][N:21]=[C:20]([CH:18]([N:4]([CH3:3])[C:5]3[N:9]([CH3:10])[C:8]([C:11]4[CH:12]=[N:13][CH:14]=[CH:15][CH:16]=4)=[N:7][N:6]=3)[CH3:19])[N:24]=2)[CH:30]=[CH:29][CH:28]=1
Reactant: CC(Cl)c1noc(-c2cccc(Cl)c2)n1
Reactant: CNc1nnc(-c2cccnc2)n1C
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(c1noc(-c2cccc(Cl)c2)n1)N(C)c1nnc(-c2cccnc2)n1C
Temperature: 60 °C
Yield: 43.5 %

Procedure:
NaH (14 mg, 0.35 mmol) was added to N,4-dimethyl-5-pyridin-3-yl-4H-1,2,4-triazol-3-amine (33 mg, 0.18 mmol) in DMF (3 mL). After 30 min 3-(1-chloroethyl)-5-(3-chlorophenyl)-1,2,4-oxadiazole (80 mg, 0.18 mmol) in DMF (1 mL) was added to the mixture and the reaction was stirred at 60° C. o.n. Brine was added and the mixture was extracted with EA. The organic phase was dried and concentrated. The product was purified by column chromatography (DCM to DCM-MeOH 30:1) to give 31 mg (43%) of the title compound. 1H NMR: 1.71 (d, 3H) 2.97 (s, 3H) 3.67 (s, 3H) 4.88 (q, 1H) 7.46 (m, 2H) 7.56 (d, 1H) 8.00 (d, 1H) 8.10 (d, 2H) 8.71 (bs, 1H) 8.92 (bs, 1H)
Reaction SMILES: [CH3:1][C@@:2]([OH:30])([C:26]([CH3:29])([CH3:28])[CH3:27])[C@@H:3]1[C@@:8]2([O:24][CH3:25])[C@@H:9]3[O:23][C:18]4=[C:19]([OH:22])[CH:20]=[CH:21][C:16]5=[C:17]4[C@:10]43[CH2:11][CH2:12][NH:13][C@H:14]([CH2:15]5)[C@@:5]4([CH2:6][CH2:7]2)[CH2:4]1.C([O-])(O)=O.[Na+].[CH:36]1([CH2:39]Br)[CH2:38][CH2:37]1>CN1CCCC1.O>[CH3:1][C@@:2]([OH:30])([C:26]([CH3:29])([CH3:28])[CH3:27])[C@@H:3]1[C@:8]2([O:24][CH3:25])[C@@H:9]3[O:23][C:18]4=[C:19]([OH:22])[CH:20]=[CH:21][C:16]5=[C:17]4[C@:10]43[CH2:11][CH2:12][N:13]([CH2:39][CH:36]3[CH2:38][CH2:37]3)[C@H:14]([CH2:15]5)[C@@:5]4([CH2:6][CH2:7]2)[CH2:4]1
Reactant: BrCC1CC1
Reactant: CO[C@]12CC[C@@]3(C[C@@H]1[C@](C)(O)C(C)(C)C)[C@H]1Cc4ccc(O)c5c4[C@@]3(CCN1)[C@H]2O5
Agent: CN1CCCC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Product: CO[C@@]12CC[C@@]3(C[C@@H]1[C@](C)(O)C(C)(C)C)[C@H]1Cc4ccc(O)c5c4[C@@]3(CCN1CC1CC1)[C@H]2O5
Reaction time: 18 h
Yield: 86 %

Procedure:
To the solution of norbuprenorphine (Example 4, 0.07 g; 0.169 mmol) in N-methylpyrrolidine (1 mL) was added NaHCO3 (0.017 g; 0.203 mmol) and cyclopropylmethyl bromide (0.034 g; 0.253 mmol). The reaction mixture was placed into a pre-heated oil bath at 80° C. and stirred over 18 h. It was then diluted with water (10 mL), extracted three times with EtOAc, and the combined organic layers were washed with water (2×5 mL), brine, dried over Na2SO4 and concentrated. Column chromatography (eluent EtOAc:hexane/1:2) afforded 0.068 g (86%) of buprenorphine.
Reaction SMILES: [CH3:1][N:2]([CH3:39])[CH2:3][CH2:4][O:5][C:6]1[C:7]([CH3:38])=[C:8]([NH:12][C:13]2[N:18]=[C:17]([C:19]3[N:23]4[CH:24]=[CH:25][CH:26]=[CH:27][C:22]4=[N:21][C:20]=3[C:28]3[CH:29]=[C:30]([CH:35]=[CH:36][CH:37]=3)[C:31](OC)=[O:32])[CH:16]=[CH:15][N:14]=2)[CH:9]=[CH:10][CH:11]=1.[F:40][C:41]1[CH:47]=[CH:46][CH:45]=[C:44]([F:48])[C:42]=1[NH2:43].C[Si]([N-][Si](C)(C)C)(C)C.[Na+]>C1COCC1>[F:40][C:41]1[CH:47]=[CH:46][CH:45]=[C:44]([F:48])[C:42]=1[NH:43][C:31](=[O:32])[C:30]1[CH:35]=[CH:36][CH:37]=[C:28]([C:20]2[N:21]=[C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][N:23]3[C:19]=2[C:17]2[CH:16]=[CH:15][N:14]=[C:13]([NH:12][C:8]3[CH:9]=[CH:10][CH:11]=[C:6]([O:5][CH2:4][CH2:3][N:2]([CH3:1])[CH3:39])[C:7]=3[CH3:38])[N:18]=2)[CH:29]=1
Reactant: COC(=O)c1cccc(-c2nc3ccccn3c2-c2ccnc(Nc3cccc(OCCN(C)C)c3C)n2)c1
Reactant: Nc1c(F)cccc1F
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: C1CCOC1
Product: Cc1c(Nc2nccc(-c3c(-c4cccc(C(=O)Nc5c(F)cccc5F)c4)nc4ccccn34)n2)cccc1OCCN(C)C
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 98.2 %

Procedure:
To a solution of methyl 3-(3-{2-[(3-{[2-(dimethylamino)ethyl]oxy}-2-methylphenyl)amino]-4-pyrimidinyl}imidazo[1,2-a]pyridin-2-yl)benzoate (60.0 mg, 0.115 mmol) and 2,6-difluoroaniline (0.0350 mL, 0.345 mmol) in THF (5 mL) was added sodium bis(trimethylsilyl)amide (0.46 mL, 0.460 mmol, 1.0 M solution in THF), and the reaction mixture was stirred for 5 min at rt. The mixture was quenched with saturated NaHCO3, diluted with DCM, and the organic layer was separated. The solvent was removed and the crude material was purified via silica gel chromatography to give 70 mg (98% yield) of the title compound. 1H NMR (400 MHz, DMSO-d6) δ 10.24 (s, 1H), 9.36 (d, J=6.6 Hz, 1H), 9.08 (s, 1H), 8.32 (s, 1H), 8.20 (d, J=5.3 Hz, 1H), 8.06 (d, J=7.9 Hz, 1H), 7.83 (d, J=7.7 Hz, 1H), 7.72 (d, J=9.0 Hz, 1H), 7.62 (t, J=7.8 Hz, 1H), 7.42 (t, 2H), 7.12-7.28 (m, J=8.0, 8.0 Hz, 3H), 7.03 (d, J=7.5 Hz, 1H), 6.87 (d, 2H), 6.48 (d, J=5.3 Hz, 1H), 4.07 (t, J=5.8 Hz, 2H), 2.66 (t, J=5.7 Hz, 2H), 2.22 (s, 6H), 2.07 (s, 3H). MS (APCI+) m/z 620 [M+H].
Reaction SMILES: [NH2:1][C:2]1[N:3]=[CH:4][C:5]([C:12]2[CH:13]=[N:14][N:15]([CH:17]3[CH2:22][CH2:21][N:20](C(=O)C)[CH2:19][CH2:18]3)[CH:16]=2)=[C:6]2[CH:10]=[C:9]([Cl:11])[O:8][C:7]=12.[Cl:26][C:27]1[CH:32]=[CH:31][C:30](B(O)O)=[CH:29][C:28]=1[C:36]([O:38]C)=[O:37].C(=O)([O-])[O-].[Na+].[Na+].Cl>O1CCOCC1.C(OCC)(=O)C.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>[ClH:11].[NH2:1][C:2]1[N:3]=[CH:4][C:5]([C:12]2[CH:13]=[N:14][N:15]([CH:17]3[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]3)[CH:16]=2)=[C:6]2[CH:10]=[C:9]([C:30]3[CH:31]=[CH:32][C:27]([Cl:26])=[C:28]([CH:29]=3)[C:36]([OH:38])=[O:37])[O:8][C:7]=12
Reactant: CC(=O)N1CCC(n2cc(-c3cnc(N)c4oc(Cl)cc34)cn2)CC1
Reactant: COC(=O)c1cc(B(O)O)ccc1Cl
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: Nc1ncc(-c2cnn(C3CCNCC3)c2)c2cc(-c3ccc(Cl)c(C(=O)O)c3)oc12
Temperature: 120 °C
Yield: 33.4 %

Procedure:
A suspension of 1-{4-[4-(7-amino-2-chlorofuro[2,3-c]pyridin-4-yl)-1H-pyrazol-1-yl]piperidin-1-yl}ethanone (125 mg, 0.347 mmol), 4-chloro-3-(methoxycarbonyl)phenylboronic acid (89.4 mg, 0.417 mmol), and Pd(PPh3)4 (40.1 mg, 0.0347 mmol) in 1.0 M aqueous sodium carbonate (1.74 mL, 1.74 mmol) and 1,4-dioxane (1.63 mL) was heated to 120° C. in a microwave for 30 min. The reaction mixture was then diluted with ethyl acetate (10 mL) and acidified with aqueous 1 N hydrochloric acid (5 mL), causing formation of a precipitate. The precipitate was collected by vacuum filtration and then triturated from DMSO and methanol (10 mL, ˜1:10) to afford 55 mg (29%) of the title compound as a yellow solid. 1H NMR (400 MHz, DMSO-d6): δ 8.45 (d, J=1.5 Hz, 1H), 8.29 (s, 1H), 8.22 (dd, J=1.8, 8.3 Hz, 1H), 8.00 (d, J=8.1 Hz, 2H), 7.91 (s, 1H), 7.75 (d, J=8.6 Hz, 1H), 6.56 (br s, 2H), 4.61-4.30 (m, 2H), 3.94 (br s, 1H), 3.24 (br s, 1H), 2.74 (br s, 1H), 2.26-1.63 (m, 7H); MS (ESI): 480.10 [M+H]+; HPLC tR=2.35 min (ZQ3, polar—4 min).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([N:9]2[CH:13]=[C:12]([C:14]([OH:16])=O)[CH:11]=[N:10]2)=[CH:5][CH:4]=1)#[N:2].Cl.[Cl:18][C:19]1[CH:20]=[C:21]([NH:31]C(=O)C2C=CN=C(OCC)C=2)[CH:22]=[CH:23][C:24]=1[C@H:25]1[O:30][CH2:29][CH2:28][NH:27][CH2:26]1>>[ClH:18].[Cl:18][C:19]1[CH:20]=[C:21]([NH:31][C:14]([C:12]2[CH:11]=[N:10][N:9]([C:6]3[CH:5]=[CH:4][C:3]([C:1]#[N:2])=[CH:8][CH:7]=3)[CH:13]=2)=[O:16])[CH:22]=[CH:23][C:24]=1[C@@H:25]1[O:30][CH2:29][CH2:28][NH:27][CH2:26]1
Reactant: N#Cc1ccc(-n2cc(C(=O)O)cn2)cc1
Reactant: CCOc1cc(C(=O)Nc2ccc([C@@H]3CNCCO3)c(Cl)c2)ccn1
Agent: Cl
Product: N#Cc1ccc(-n2cc(C(=O)Nc3ccc([C@H]4CNCCO4)c(Cl)c3)cn2)cc1

Procedure:
In analogy to example 83, step a) using 1-(4-cyanophenyl)-1H-Pyrazole-4-carboxylic acid (CAS 1152945-21-5) instead of 2-(trifluoromethyl)-4-pyridinecarboxylic acid (CAS 131747-41-6) and (−)-(S)-2-(4-Amino-2-chloro-phenyl)-morpholine-4-carboxylic acid tert-butyl ester (preparation described in example 91) instead of (+)-(R)-2-(4-Amino-2-fluoro-phenyl)-morpholine-4-carboxylic acid tert-butyl ester. Yellow solid. MS (ISP): 408.2 ([M+H]+)
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][C:5]2[S:9][C:8]([S:10][CH3:11])=[N:7][C:6]=2[CH:12]=1.Br[CH2:14][CH2:15][Cl:16].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[Cl:16][CH2:15][CH2:14][O:1][C:2]1[CH:3]=[CH:4][C:5]2[S:9][C:8]([S:10][CH3:11])=[N:7][C:6]=2[CH:12]=1
Reactant: ClCCBr
Reactant: CSc1nc2cc(O)ccc2s1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CSc1nc2cc(OCCCl)ccc2s1
Temperature: 70 °C
Yield: 42 %

Procedure:
To a solution of 5-hydroxy-2-methylthio-benzothiazole (2.1 g, 11 mmol) in anhydrous DMF (25 mL) was added bromo-2-chloroethane (4.4 mL, 53 mmol) and powdered K2CO3 (7.3 g, 53 mmol). The reaction slurry was heated at 70° C. for 13 h. The slurry was filtered under vacuum and the filtrate was concentrated under reduced pressure. The crude material was chromatographed (SiO2, 0-20% EtOAc/Hex) to afford the title compound (1.2 g, 46%). 1H-NMR (CDCl3): δ 7.62 (1H, d), 7.39 (1H, d), 6.97 (1H, dd), 4.29 (2H, t), 3.85 (2H, t), 2.79 (3H, s); MS(ESI): 259 (MH+).
Reaction SMILES: [C:1]1(=[C:9]([C:25]2[CH:30]=[CH:29][C:28]([OH:31])=[CH:27][CH:26]=2)[C:10]2[CH:15]=[CH:14][C:13](/[CH:16]=[CH:17]/[C:18]([O:20]C(C)(C)C)=[O:19])=[CH:12][CH:11]=2)[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1>C(Cl)Cl.FC(F)(F)C(O)=O>[C:1]1(=[C:9]([C:25]2[CH:30]=[CH:29][C:28]([OH:31])=[CH:27][CH:26]=2)[C:10]2[CH:15]=[CH:14][C:13](/[CH:16]=[CH:17]/[C:18]([OH:20])=[O:19])=[CH:12][CH:11]=2)[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CC(C)(C)OC(=O)/C=C/c1ccc(C(=C2CCCCCCC2)c2ccc(O)cc2)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(O)/C=C/c1ccc(C(=C2CCCCCCC2)c2ccc(O)cc2)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 25.6 %

Procedure:
tert-Butyl (2E)-3-{4-[cyclooctylidene(4-hydroxyphenyl)methyl]phenyl}prop-2-enoate (50) (0.0586 g, 0.140 mmole) was dissolved in methylene chloride (1 mL) and trifluoroacetic acid (1 mL). The solution was stirred at RT for 4 h, then was concentrated. The residue was recrystallized from EtOAc to provide compound 51 (0.013 g, 25%) as a white solid. 1H NMR (DMSO-d6): δ 12.32 (s, 1H), 9.27 (s, 1H), 7.58 (d, J=8.1 Hz, 2H), 7.51 (d, J=16.1 Hz, 1H), 7.14 (d, J=8.1 Hz, 2H), 6.92 (d, J=8.4 Hz, 2H), 6.66 (d, J=8.4 Hz, 2H), 6.43 (d, J=16.1 Hz, 1H), 2.18 (m, 4H), 1.59 (m, 2H), 1.45 (m, 8H). LRMS (ESI): m/z 361 (M−H)−.
Reaction SMILES: [CH3:1][CH:2]([CH3:60])[C@H:3]([NH:55][C:56](=[O:59])[O:57][CH3:58])[C:4]([N:6]1[CH2:10][CH2:9][CH2:8][C@H:7]1[C:11]1[NH:12][CH:13]=[C:14]([C:16]2[CH:21]=[CH:20][C:19]([C:22]3[CH:27]=[CH:26][C:25]([C:28](=O)[CH2:29][NH:30][C:31]([CH:33]4[CH2:37][CH2:36][C:35]5([CH2:42][CH2:41][O:40][CH2:39][CH2:38]5)[N:34]4[C:43](=[O:53])[C@@H:44]([NH:48][C:49]([O:51][CH3:52])=[O:50])[CH:45]([CH3:47])[CH3:46])=O)=[CH:24][CH:23]=3)=[CH:18][CH:17]=2)[N:15]=1)=[O:5].C([O-])(=O)C.[NH4+:65]>O1CCOCC1>[CH3:60][CH:2]([CH3:1])[C@H:3]([NH:55][C:56](=[O:59])[O:57][CH3:58])[C:4]([N:6]1[CH2:10][CH2:9][CH2:8][C@H:7]1[C:11]1[NH:12][CH:13]=[C:14]([C:16]2[CH:17]=[CH:18][C:19]([C:22]3[CH:23]=[CH:24][C:25]([C:28]4[N:65]=[C:31]([CH:33]5[CH2:37][CH2:36][C:35]6([CH2:38][CH2:39][O:40][CH2:41][CH2:42]6)[N:34]5[C:43](=[O:53])[C@@H:44]([NH:48][C:49]([O:51][CH3:52])=[O:50])[CH:45]([CH3:47])[CH3:46])[NH:30][CH:29]=4)=[CH:26][CH:27]=3)=[CH:20][CH:21]=2)[N:15]=1)=[O:5]
Reactant: [NH4+]
Reactant: COC(=O)N[C@H](C(=O)N1CCC[C@H]1c1nc(-c2ccc(-c3ccc(C(=O)CNC(=O)C4CCC5(CCOCC5)N4C(=O)[C@@H](NC(=O)OC)C(C)C)cc3)cc2)c[nH]1)C(C)C
Agent: CC(=O)[O-]
Solvent: C1COCCO1
Product: COC(=O)N[C@H](C(=O)N1CCC[C@H]1c1nc(-c2ccc(-c3ccc(-c4c[nH]c(C5CCC6(CCOCC6)N5C(=O)[C@@H](NC(=O)OC)C(C)C)n4)cc3)cc2)c[nH]1)C(C)C
Temperature: 110 °C
Yield: 13.7 %

Procedure:
To a solution of methyl ((1S)-2-methyl-1-{[(2S)-2-(4-{4′-[({[1-((2S)-3-methyl-2-{[(methyloxy)carbonyl]amino}butanoyl)-8-oxa-1-azaspiro[4.5]dec-2-yl]carbonyl}amino)acetyl]-4-biphenylyl}-1H-imidazol-2-yl)-1-pyrrolidinyl]carbonyl}propyl)carbamate (169) (71 mg, 0.09 mmol) in anhydrous dioxane (1 mL) was added ammonium acetate (66 mg, 0.86 mmol) and the reaction was degassed with nitrogen and heated to 110° C. for 48 h in a sealed tube. The reaction was purified by HPLC eluting with 10-90% water/acetonitrile/0.2% NH4OH to afford the title compound as an off-white solid (10 mg, 14% yield). 1H NMR (400 MHz, METHANOL-d4) δ ppm 7.56-7.86 (m, 9H) 7.16-7.44 (m, 2H) 6.88-7.09 (m, 1H) 5.72 (br. s., 1H) 5.09-5.21 (m, 1H) 4.03-4.28 (m, 1H) 3.80-4.04 (m, 6H) 3.42-3.71 (m, 9H) 2.11-2.56 (m, 8H) 1.88-2.11 (m, 6H) 0.80-1.06 (m, 12H). HRMS for C44H57N8O7 (M+H)+ calc: 809.4350, found: 809.4347. Purity (LC-MS): 93%.
Reaction SMILES: Br[C:2](=[N:8][NH:9][C:10]1[N:11]=[N:12][C:13]([Cl:16])=[CH:14][CH:15]=1)[C:3]([O:5][CH2:6][CH3:7])=[O:4].C(N(CC)CC)C>C(O)(C)C>[Cl:16][C:13]1[CH:14]=[CH:15][C:10]2[N:11]([C:2]([C:3]([O:5][CH2:6][CH3:7])=[O:4])=[N:8][N:9]=2)[N:12]=1
Reactant: CCOC(=O)C(Br)=NNc1ccc(Cl)nn1
Solvent: CC(C)O
Solvent: CCN(CC)CC
Product: CCOC(=O)c1nnc2ccc(Cl)nn12
Yield: 88.3 %

Procedure:
A mixture of compound ethyl 2-bromo-2-(2-(6-chloropyridazin-3-yl)hydrazono)acetate (1.25 g, 4 mmol) in 10 mL of isopropanol with 0.5 mL of triethylamine was refluxed for 1 h. The solution was evaporated and the residue was washed thoroughly with water to give product ethyl 6-chloro-[1,2,4]triazolo[4,3-b]pyridazine-3-carboxylate as a yellow solid (0.8 g, 67%). LRMS (M+H+) m/z: calcd 227.03; found 227. 1H NMR (300 MHz, CDCl3): δ 8.25-8.22 (d, J=9.6 Hz, 1H), 7.34-7.31 (d, J=9.6 Hz, 1H), 4.64-4.56 (q, 2H), 1.53-1.49 (t, 3H).
Reaction SMILES: Cl.[NH2:2][C@@H:3]([C:9]([OH:11])=[O:10])[CH2:4][CH2:5][CH2:6][CH2:7][NH2:8].N([C:15]([O:17][CH2:18][CH:19]1[C:31]2[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=2[C:25]2[C:20]1=[CH:21][CH:22]=[CH:23][CH:24]=2)=[O:16])=[N+]=[N-]>C(=O)([O-])[O-].[Na+].[Na+].CC(C)=O.O>[CH:30]1[C:31]2[CH:19]([CH2:18][O:17][C:15]([NH:2][C@@H:3]([C:9]([OH:11])=[O:10])[CH2:4][CH2:5][CH2:6][CH2:7][NH:8][C:15]([O:17][CH2:18][CH:19]3[C:20]4[CH:21]=[CH:22][CH:23]=[CH:24][C:25]=4[C:26]4[C:31]3=[CH:30][CH:29]=[CH:28][CH:27]=4)=[O:16])=[O:16])[C:20]3[C:25](=[CH:24][CH:23]=[CH:22][CH:21]=3)[C:26]=2[CH:27]=[CH:28][CH:29]=1
Reactant: NCCCC[C@@H](N)C(=O)O
Reactant: [N-]=[N+]=NC(=O)OCC1c2ccccc2-c2ccccc21
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC(C)=O
Solvent: O
Product: O=C(NCCCC[C@@H](NC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)O)OCC1c2ccccc2-c2ccccc21

Procedure:
To a stirred solution of D-lysine hydrochloride (4.5 g) in 175 ml of a sodium carbonate solution (10% in water):acetone (6:1) solution is added dropwise a solution of 9-fluorenylmethyl azidoformate in acetone (150 ml). After 16 hours the mixture is diluted with water and washed three times with hexane. The mixture is then acidified with concentrated hydrochloric acid and extracted three times with ethyl acetate. The ethyl acetate solution is washed successively with dilute hydrochloric acid, water, saturated sodium bicarbonate solution, and brine, dried over magnesium sulfate, then concentrated in vacuo to about 20 ml. The solution is added to hexane (1 l.) and the precipitate is collected and dried to afford the title compound: NMR (dimethylsulfoxide) δ1.0-1.9 (m, 6H), 2.7-3.2 (m,2H), 3.8-4.7 (m,7H), 6.8-8.3 (m,19H).
Reaction SMILES: [C:1]1([C:7]2[S:11][C:10]([NH:12][C:13]3[CH:18]=[C:17]([CH2:19]O)[CH:16]=[CH:15][N:14]=3)=[N:9][CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CN(C)C=O.P(Cl)(Cl)([Cl:28])=O>C(Cl)Cl>[Cl:28][CH2:19][C:17]1[CH:16]=[CH:15][N:14]=[C:13]([NH:12][C:10]2[S:11][C:7]([C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)=[CH:8][N:9]=2)[CH:18]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: OCc1ccnc(Nc2ncc(-c3ccccc3)s2)c1
Solvent: ClCCl
Solvent: CN(C)C=O
Product: ClCc1ccnc(Nc2ncc(-c3ccccc3)s2)c1

Procedure:
[2-(5-Phenyl-thiazol-2-ylamino)-pyridin-4-yl]-methanol 8-7 (0.500 g, 1.77 mmol) was stirred in anh CH2Cl2 (5 mL) under N2. N,N-Dimethylformamide (0.137 mL, 1.76 mmol, 1 equiv) was added followed by the addition of phosphorous oxychloride (0.165 mL, 1.76 mmol). After 1.5 h the reaction was concentrated and quenched by the addition of saturated NaHCO3 (aq). A precipitate formed which was filtered and washed with water to provide the titled compound. 1H NMR (DMSO-d6) δ11.49 (bs, 1H), 8.34 (d, 1H, J=5.2 Hz), 7.81 (s, 1H), 7.60 (d, 2H, J=7.7 Hz), 7.39 (t, 2H, J=7.6 Hz), 7.26 (t, 1H, 7.0 Hz), 7.13 (s, 1H), 6.99 (d, 1H, J=5.3 Hz), 4.77 (s, 2H).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5](=[O:24])[NH:6][C:7]=1[NH:8][C:9](=O)[C:10]1[CH:15]=[CH:14][C:13]([NH:16][S:17]([CH3:20])(=[O:19])=[O:18])=[CH:12][C:11]=1[O:21][CH3:22]>C(O)(=O)C>[CH3:22][O:21][C:11]1[CH:12]=[C:13]([NH:16][S:17]([CH3:20])(=[O:19])=[O:18])[CH:14]=[CH:15][C:10]=1[C:9]1[N:8]=[C:7]2[NH:6][C:5](=[O:24])[CH2:4][CH:3]=[C:2]2[N:1]=1
Reactant: COc1cc(NS(C)(=O)=O)ccc1C(=O)Nc1[nH]c(=O)ccc1N
Solvent: CC(=O)O
Product: COc1cc(NS(C)(=O)=O)ccc1C1=NC2=CCC(=O)NC2=N1

Procedure:
2.7 g of 5-amino-6-(2-methoxy-4-methanesulfonylaminobenzoyl-amino)-2-pyridone were refluxed in 50 ml of glacial acetic acid for 1.5 hours. The mixture was then concentrated by evaporation in vacuo, and the residue was purified on silica gel (eluant: methylene chloride/ethanol 1:0 to 1:0.1).