Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:4][C@H:5]([CH2:9][C:10]([NH:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]2[C:23]([NH:24][C:25]([O:27][CH:28]([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=3[Cl:36])[CH3:29])=[O:26])=[CH:22][O:21][N:20]=2)=[CH:15][CH:14]=1)=[O:11])[C:6]([OH:8])=[O:7])(=O)C.[OH-].[Na+].Cl>CO>[Cl:36][C:31]1[CH:32]=[CH:33][CH:34]=[CH:35][C:30]=1[CH:28]([O:27][C:25]([NH:24][C:23]1[C:19]([C:16]2[CH:17]=[CH:18][C:13]([NH:12][C:10](=[O:11])[CH2:9][C@@H:5]([OH:4])[C:6]([OH:8])=[O:7])=[CH:14][CH:15]=2)=[N:20][O:21][CH:22]=1)=[O:26])[CH3:29]
Reactant: CC(=O)O[C@H](CC(=O)Nc1ccc(-c2nocc2NC(=O)OC(C)c2ccccc2Cl)cc1)C(=O)O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CC(OC(=O)Nc1conc1-c1ccc(NC(=O)C[C@@H](O)C(=O)O)cc1)c1ccccc1Cl
Temperature: 25 °C
Reaction time: 1 h
Yield: 91.5 %

Procedure:
(2R)-2-Acetoxy-4-[(4-{4-[1-(2-chlorophenyl)ethoxycarbonylamino]-3-isoxazolyl}phenyl)amino]-4-oxobutanoic acid (132 mg, 0.256 mmol) was dissolved in methanol (2.5 ml), 1N aqueous sodium hydroxide solution (2.5 ml) was added, and the mixture was stirred at room temperature for 1 hour. 1N Hydrochloric acid (2.6 ml) was added at 0° C. to weak-acidify the reaction system, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium chloride solution and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure to give the title compound (111 mg, 92%).
Reaction SMILES: [C:1]([O:5][C:6]1[CH:7]=[C:8]([C@@H:19]2[CH2:21][O:20]2)[C:9]2[S:13][C:12]([O:14][CH:15]([CH3:17])[CH3:16])=[N:11][C:10]=2[CH:18]=1)([CH3:4])([CH3:3])[CH3:2].[CH2:22]([O:26][C:27]1[CH:32]=[CH:31][C:30]([CH2:33][C:34]([NH2:37])([CH3:36])[CH3:35])=[CH:29][CH:28]=1)[CH2:23][CH2:24][CH3:25].O.CC(OC)(C)C>CS(C)=O>[C:1]([O:5][C:6]1[CH:7]=[C:8]([C@@H:19]([OH:20])[CH2:21][NH:37][C:34]([CH3:35])([CH3:36])[CH2:33][C:30]2[CH:31]=[CH:32][C:27]([O:26][CH2:22][CH2:23][CH2:24][CH3:25])=[CH:28][CH:29]=2)[C:9]2[S:13][C:12]([O:14][CH:15]([CH3:17])[CH3:16])=[N:11][C:10]=2[CH:18]=1)([CH3:3])([CH3:4])[CH3:2]
Reactant: CC(C)Oc1nc2cc(OC(C)(C)C)cc([C@@H]3CO3)c2s1
Reactant: CCCCOc1ccc(CC(C)(C)N)cc1
Solvent: COC(C)(C)C
Solvent: CS(C)=O
Solvent: O
Product: CCCCOc1ccc(CC(C)(C)NC[C@H](O)c2cc(OC(C)(C)C)cc3nc(OC(C)C)sc23)cc1
Temperature: 80 °C
Reaction time: 27 h

Procedure:
(R)-5-tert-butoxy-2-isopropoxy-7-oxiranyl-benzothiazole (145 g, 471.7 mmol) and 2-(4-butoxy-phenyl)-1,1-dimethyl-ethylamine (114.8 g, 518.9 mmol) were dissolved in DMSO (850 ml). The reaction mixture was heated to 80° C. and stirred for 27 h. The mixture was then cooled to 25° C. and added to a stirred mixture of water (1500 ml) and TBME (1500 ml). The aqueous layer was separated and extracted with TBME (1000 ml). The combined organic layers were sequentially washed with water (1500 ml) and brine (1000 ml), dried with anhydrous Na2SO4. After concentration, the residue was purified by column chromatography (eluting with 10% of EtOAc in n-heptane to 33% of EtOAc in n-heptane). Solid product (R)-1-(5-tert-butoxy-2-isopropoxybenzo[d]thiazol-7-yl)-2-(1-(4-butoxyphenyl)-2-methylpropan-2-ylamino)ethanol was obtained (140 g) as off-white solid.
Reaction SMILES: [Br:1][C:2]1[C:10]2[C:5](=[N:6][CH:7]=[CH:8][CH:9]=2)[S:4][C:3]=1[C:11]([O:13]CC)=[O:12].[OH-].[K+]>O.CO>[Br:1][C:2]1[C:10]2[C:5](=[N:6][CH:7]=[CH:8][CH:9]=2)[S:4][C:3]=1[C:11]([OH:13])=[O:12]
Reactant: CCOC(=O)c1sc2ncccc2c1Br
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: O=C(O)c1sc2ncccc2c1Br

Procedure:
A solution of ethyl 3-bromothieno[2,3-b]pyridine-2-carboxylate (14a) (50 mg, 0.17 mmol) and potassium hydroxide (96 mg, 1.7 mmol) in water (2 mL) and methanol (2 mL) was stirred at 80° C. for 1 hour. Water (10 mL) was added to the reaction mixture which was washed with diethyl ether (10 mL). The aqueous layer was acidified to pH 4 with a hydrochloric acid aqueous solution 1N and extracted with ethyl acetate (2×10 mL). The organic layer was washed with brine (10 mL), dried over sodium sulfate, filtered and evaporated under reduced pressure to afford the desired acid (14b) as a white solid without further purification (30 mg, 0.12 mmol, 68%).
Reaction SMILES: [CH3:1][C:2]1[NH:3][CH:4]=[C:5]([CH3:10])[C:6]=1[C:7](=[O:9])[CH3:8].[C:11]([OH:16])(=[O:15])[C:12]([CH3:14])=O>I.[PH2](O)=O>[CH3:1][C:2]1[NH:3][C:4]([CH:12]([C:11]([OH:16])=[O:15])[CH3:14])=[C:5]([CH3:10])[C:6]=1[C:7](=[O:9])[CH3:8]
Reactant: CC(=O)c1c(C)c[nH]c1C
Reactant: CC(=O)C(=O)O
Agent: I
Agent: O=[PH2]O
Product: CC(=O)c1c(C)[nH]c(C(C)C(=O)O)c1C
Reaction time: 0.17 h

Procedure:
A solution of 548 mg. of 2,4-dimethyl-3-acetyl-pyrrole in 10 ml of hydriodic acid and 2 ml of 50% hypophosphorous acid was treated with 0.4 ml of pyruvic acid and stirred for 10 min, when yellow crystals separated. After standing for 2 days at 0° C. the crystals were separated, dried and slurried with 5 ml of water. The resulting colourless product was separated, washed with water, dried and recrystallized from ether (thimble) as pale yellow plates (46%), m.p. 156°-158° C. (dec.).
Reaction SMILES: [CH:1]([N:4]1[CH2:9][CH2:8][CH:7]([O:10][C:11]2[CH:12]=[C:13]3[C:17](=[CH:18][CH:19]=2)[NH:16][C:15]([C:20]([OH:22])=O)=[CH:14]3)[CH2:6][CH2:5]1)([CH3:3])[CH3:2].[Cl-].[Li+].[NH:25]1[CH2:30][CH2:29][S:28](=[O:32])(=[O:31])[CH2:27][CH2:26]1>>[O:31]=[S:28]1(=[O:32])[CH2:29][CH2:30][N:25]([C:20]([C:15]2[NH:16][C:17]3[C:13]([CH:14]=2)=[CH:12][C:11]([O:10][CH:7]2[CH2:6][CH2:5][N:4]([CH:1]([CH3:2])[CH3:3])[CH2:9][CH2:8]2)=[CH:19][CH:18]=3)=[O:22])[CH2:26][CH2:27]1
Reactant: O=S1(=O)CCNCC1
Reactant: CC(C)N1CCC(Oc2ccc3[nH]c(C(=O)O)cc3c2)CC1
Agent: [Cl-]
Agent: [Li+]
Product: CC(C)N1CCC(Oc2ccc3[nH]c(C(=O)N4CCS(=O)(=O)CC4)cc3c2)CC1

Procedure:
In analogy to the procedure described for the synthesis of example 1, step 3, the title compound was synthesized from 5-(1-isopropyl-piperidin-4-yloxy)-1H-indole-2-carboxylic acid hydrochloric salt with one equivalent of lithium chloride (example 2, step 1) and thiomorpholine-1,1-dioxide (purchased at Syntec, ref. M1201). The title product was obtained in 75% yield as white solid. MS (m/e): 420.5 (MH+, 100%).
Reaction SMILES: [O-]P([O-])([O-])=O.[K+].[K+].[K+].[Cl:9][C:10]1[C:29](I)=[CH:28][C:13]([C:14]([NH:16][C:17]2[CH:22]=[CH:21][C:20]([O:23][C:24]([Cl:27])([F:26])[F:25])=[CH:19][CH:18]=2)=[O:15])=[CH:12][N:11]=1.[CH3:31][C:32]1[CH:33]=[N:34][N:35]([CH:46]2[CH2:51][CH2:50][CH2:49][CH2:48][O:47]2)[C:36]=1B1OC(C)(C)C(C)(C)O1.O>C1(C)C=CC=CC=1.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>[Cl:9][C:10]1[C:29]([C:36]2[N:35]([CH:46]3[CH2:51][CH2:50][CH2:49][CH2:48][O:47]3)[N:34]=[CH:33][C:32]=2[CH3:31])=[CH:28][C:13]([C:14]([NH:16][C:17]2[CH:22]=[CH:21][C:20]([O:23][C:24]([Cl:27])([F:26])[F:25])=[CH:19][CH:18]=2)=[O:15])=[CH:12][N:11]=1
Reactant: O=C(Nc1ccc(OC(F)(F)Cl)cc1)c1cnc(Cl)c(I)c1
Reactant: Cc1cnn(C2CCCCO2)c1B1OC(C)(C)C(C)(C)O1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: Cc1ccccc1
Product: Cc1cnn(C2CCCCO2)c1-c1cc(C(=O)Nc2ccc(OC(F)(F)Cl)cc2)cnc1Cl
Temperature: 110 °C

Procedure:
K3PO4 (191 mg, 0.9 mmol) and Pd(PPh3)4 (17.33 mg, 0.015 mmol) were added to a solution of 6-Chloro-N-(4-(chlorodifluoromethoxy)phenyl)-5-iodonicotinamide (Stage 25.2, 138 mg, 0.3 mmol) and 4-methyl-1-(tetrahydro-2H-pyran-2-yl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (131 mg, 0.45 mmol) in toluene (1.5 mL) under an argon atmosphere in a vial, which was sealed and heated at 110° C. for 18 h. The RM was poured into 20 mL water and extracted with EtOAc. The combined extracts were dried over Na2SO4 and the solvent was evaporated off under reduced pressure to give a residue which was purified by flash chromatography (RediSep® Silica gel column, n-heptane/EtOAc, from 5 to 50% EtOAc) and crystallized from n-heptane to afford the title compound as an off-white powder. HPLC (Condition 4) tR=6.8 min, UPLC-MS (Condition 3) tR=1.26 min, m/z=495 [M−H]−.
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([C:6]2[CH:10]=[C:9]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[NH:8][N:7]=2)[N:3]=[CH:2]1.[C:16]1([C:22](Cl)([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.C(N(CC)CC)C>C(Cl)Cl>[C:22]([N:1]1[CH:5]=[C:4]([C:6]2[CH:10]=[C:9]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[NH:8][N:7]=2)[N:3]=[CH:2]1)([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)([C:29]1[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=1)[C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: CCOC(=O)c1cc(-c2c[nH]cn2)n[nH]1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOC(=O)c1cc(-c2cn(C(c3ccccc3)(c3ccccc3)c3ccccc3)cn2)n[nH]1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 60.3 %

Procedure:
Ethyl 3-(1H-imidazol-4-yl)-1H-pyrazole-5-carboxylate (6.79 mmol, 1.4 g) was suspended in DCM (20 ml) under nitrogen atmosphere. Triphenylmethyl chloride (8.15 mmol, 2.271 g) was added and stirred for 10 min at RT. Triethylamine (8.15 mmol, 1.136 ml) was added and the resulting mixture was stirred for 20 h at RT after which DCM (10 ml) and triphenylmethyl chloride (1 g) was added. The stirring was continued for another 4.5 days. More triphenylmethyl chloride (1.14 g) and triethylamine (0.6 ml) was added and the mixture was stirred for another day. The mixture was diluted with DCM and washed with NaHCO3. The organic phase was dried, filtered and evaporated. The residue was purified by trituration from ACN. 1.837 g of the title compound was obtained. 1H-NMR (400 MHz, DMSO-d6): δ 1.28 (t, 3H), 4.25 (q, 2H), 6.89 (s, 1H), 7.09-7.18 (m, 6H), 7.18-7.33 (m, 6H), 7.36-7.47 (m, 3H), 7.50 (s, 1H), 7.55 (s, 1H), 13.63 (bs, 1H).
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([C:10]2[O:11][CH2:12][CH2:13][CH:14]=2)[C:3]=1[C:4]#[N:5].C([O-])=O.[NH4+].[S:19](Cl)(=[O:22])(=[O:21])[NH2:20]>CO.[Pd]>[S:19]([NH:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([CH:10]2[CH2:14][CH2:13][CH2:12][O:11]2)[C:3]=1[C:4]#[N:5])(=[O:22])(=[O:21])[NH2:20]
Reactant: N#Cc1c(N)cccc1C1=CCCO1
Reactant: NS(=O)(=O)Cl
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CO
Product: N#Cc1c(NS(N)(=O)=O)cccc1C1CCCO1
Reaction time: 0.5 h
Yield: 17.4 %

Procedure:
2-Amino-6-(4,5-dihydrofuran-2-yl)benzonitrile (Example 202b) (0.24 g, 1.28 mmol), 10% Pd/C (0.24 g), and ammonium formate (2.40 g, 38.1 mmol) were refluxed in MeOH (25 mL) under nitrogen for 1.5 h. The insoluble solids were filtered out and discarded, and the solvent was removed under vacuum. The resultant residue was dissolved in EtOAc, washed with saturated Na2CO3 and brine, dried over MgSO4 and concentrated under vacuum. The residue was dissolved in anhydrous DMA (2.0 mL) and was treated with sulfamoyl chloride (0.11 g, 0.97 mmol). The reaction mixture was stirred under nitrogen for 30 minutes, quenched with water (5.0 mL) and extracted with EtOAc (3×50 mL). The combined extract was dried over MgSO4, filtered and concentrated under vacuum. The crude product was purified by silica gel prep-TLC using 65% EtOAc/hexanes to give 45.0 mg (13%) of the title compound as a white solid. 1H NMR (400 MHz, Acetone-d6) δ 1.71-1.78 (m, 1H), 2.02-2.07 (m, 2H), 2.45-2.52 (m, 1H), 3.90-3.95 (m, 1H), 4.10-4.15 (m, 1H), 5.08 (t, J=6.8 Hz, 1H), 6.6-6.8 (broad, 2H), 7.36-7.39 (m, 1H), 7.62-7.63 (m, 2H), 8.22 (broad s, 1H). MS 268 (MH+).
Reaction SMILES: C([N:8]1[CH2:17][CH2:16][C:15]2[C:14]([NH:18][C:19]3[CH:24]=[CH:23][C:22]([S:25]([C:28]([F:31])([F:30])[F:29])(=[O:27])=[O:26])=[CH:21][CH:20]=3)=[N:13][CH:12]=[N:11][C:10]=2[CH2:9]1)C1C=CC=CC=1>CO.[OH-].[Pd+2].[OH-]>[F:31][C:28]([F:29])([F:30])[S:25]([C:22]1[CH:23]=[CH:24][C:19]([NH:18][C:14]2[C:15]3[CH2:16][CH2:17][NH:8][CH2:9][C:10]=3[N:11]=[CH:12][N:13]=2)=[CH:20][CH:21]=1)(=[O:26])=[O:27]
Reactant: O=S(=O)(c1ccc(Nc2ncnc3c2CCN(Cc2ccccc2)C3)cc1)C(F)(F)F
Agent: [Pd+2]
Agent: [OH-]
Solvent: CO
Product: O=S(=O)(c1ccc(Nc2ncnc3c2CCNC3)cc1)C(F)(F)F
Reaction time: 24 h
Yield: 77 %

Procedure:
7-Benzyl-N-(4-(trifluoromethanesulphonyl)phenyl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-amine (0.15 g, 0.33 mmol) was dissolved in methanol (25 mL) and palladium hydroxide was added (0.15 g, 20% wt). The mixture was shaken on a Parr Shaker under H2 (g) atmosphere (60 PSI) for 24 hours. The mixture was filtered through celite and evaporated to give 91 mg of material as a white solid (77%), which was used directly in the next step.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:19]=[CH:20][CH:21]=1)[CH2:5][NH:6][C:7]([C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[N:15]=[CH:14][CH:13]=[CH:12]2)=[O:8].[OH-].[Na+].[CH:24]1([CH2:27]Br)[CH2:26][CH2:25]1.[I-].[Na+]>C(#N)C.O.FC(F)(F)C(O)=O.O1CCCC1>[CH:24]1([CH2:27][O:1][C:2]2[CH:3]=[C:4]([CH:19]=[CH:20][CH:21]=2)[CH2:5][NH:6][C:7]([C:9]2[CH:10]=[C:11]3[C:16](=[CH:17][CH:18]=2)[N:15]=[CH:14][CH:13]=[CH:12]3)=[O:8])[CH2:26][CH2:25]1
Reactant: O=C(NCc1cccc(O)c1)c1ccc2ncccc2c1
Reactant: BrCC1CC1
Agent: [I-]
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CC#N
Solvent: O
Product: O=C(NCc1cccc(OCC2CC2)c1)c1ccc2ncccc2c1
Reaction time: 3 h
Yield: 20 %

Procedure:
To a mixture of quinoline-6-carboxylic acid 3-hydroxybenzylamide described in Preparation Example E+-4 (87 mg, 0.31 mmol) and tetrahydrofuran (2 mL) was added an aqueous solution of 1N sodium hydroxide (0.31 mL, 0.31 mmol), and the solvent was evaporated in vacuo. To a mixture of a portion (5.0 mg) of the residue (93 mg) and N,N-dimethylformamide (1 mL) were added cyclopropylmethyl bromide (2.7 mg, 0.020 mmol) and catalytic amount of sodium iodide at room temperature, followed by stirring for 3 hours at the same temperature. The reaction solution was purified by reverse phase high performance liquid chromatography (acetonitrile-water mobile phase (containing 0.1% trifluoroacetic acid) was used), and trifluoroacetic acid salt of the title compound (1.50 mg, 0.0034 mmol, 20%) was obtained.
Reaction SMILES: COC(N[C@@H]1C(=O)N2[C@H](C(O)=O)CCCN2C(=O)CC1)=O.BrC1C=C(N)C(N)=CC=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[CH3:64][O:65][C:66](=[O:92])[NH:67][C@H:68]1[CH2:74][CH2:73][C:72](=[O:75])[N:71]2[CH2:76][CH2:77][CH2:78][C@@H:79]([C:80](=O)[NH:81][C:82]3[CH:87]=[CH:86][C:85]([Br:88])=[CH:84][C:83]=3[NH2:89])[N:70]2[C:69]1=[O:91].C(O)(=O)C>CN(C=O)C.C(OCC)(=O)C>[CH3:64][O:65][C:66](=[O:92])[NH:67][C@H:68]1[CH2:74][CH2:73][C:72](=[O:75])[N:71]2[CH2:76][CH2:77][CH2:78][C@@H:79]([C:80]3[NH:81][C:82]4[CH:87]=[CH:86][C:85]([Br:88])=[CH:84][C:83]=4[N:89]=3)[N:70]2[C:69]1=[O:91]
Reactant: COC(=O)N[C@H]1CCC(=O)N2CCC[C@@H](C(=O)Nc3ccc(Br)cc3N)N2C1=O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: COC(=O)N[C@H]1CCC(=O)N2CCC[C@@H](C(=O)O)N2C1=O
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COC(=O)N[C@H]1CCC(=O)N2CCC[C@@H](c3nc4cc(Br)ccc4[nH]3)N2C1=O
Temperature: 23 °C
Reaction time: 16 h
Yield: 79.5 %

Procedure:
A solution of (1S,9S)-9-(methoxycarbonylamino)-6,10-dioxooctahydro-1H-pyridazino[1,2-a][1,2]diazepine-1-carboxylic acid (184.7 mg, 605 μmol), 4-bromobenzene-1,2-diamine (124 mg, 665 μmol), HATU (230 mg, 605 μmol, Eq: 1.00) in DMF (3 ml) was treated with N,N′-diisopropylethylamine (235 mg, 317 μl, 1.81 mmol, Eq: 3.00). The solution was stirred at 23° C. for 16 h. The reaction mixture was diluted with ethyl acetate, washed with water, brine and dried over MgSO4. The organic layer was concentrated to yield 317.3 mg a 1:1 mixture of [(4S,7S)-4-(2-Amino-4-bromo-phenylcarbamoyl)-6,10-dioxo-octahydro-pyridazino[1,2-a][1,2]diazepin-7-yl]-carbamic acid methyl ester and [(4S,7S)-4-(2-Amino-5-bromo-phenylcarbamoyl)-6,10-dioxo-octahydro-pyridazino[1,2a][1,2]diazepin-7-yl]-carbamic acid methyl ester, as a light brown solid. This mixture was used as such for the next step. A solution of the mixture (317 mg, 508 μmol) in acetic acid (3.12 g, 3 mL, 52.0 mmol) was heated for 1 hr at 90° C. The reaction mixture was cooled to 23° C., and concentrated in vacuo. The residue was dissolved in ethyl acetate (30 mL) washed with sat. NaHCO3, brine and dried (MgSO4). The organic layer was concentrated to yield [(4S,7S)-4-(5-bromo-1H-benzoimidazol-2-yl)-6,10-dioxo-octahydro-pyridazino[1,2-a][1,2]diazepin-7-yl]-carbamic acid methyl ester as light brown powder (191.3 mg, 79.5%). ESI-LRMS m/e calcd for C18H20BrN5O4 [M+] 449. found 450 [M+H1].
Reaction SMILES: [H-].[Na+].[CH2:3]([C:5]1[C:13]2[C:8](=[CH:9][CH:10]=[C:11]([C:14]([F:17])([F:16])[F:15])[CH:12]=2)[NH:7][CH:6]=1)[CH3:4].C[N:19](C=O)C>>[CH2:3]([C:5]1[C:13]2[C:8](=[CH:9][CH:10]=[C:11]([C:14]([F:17])([F:15])[F:16])[CH:12]=2)[N:7]([NH2:19])[CH:6]=1)[CH3:4]
Reactant: CCc1c[nH]c2ccc(C(F)(F)F)cc12
Reactant: CN(C)C=O
Agent: [H-]
Agent: [Na+]
Product: CCc1cn(N)c2ccc(C(F)(F)F)cc12
Temperature: 0 °C
Reaction time: 1 h
Yield: 50 %

Procedure:
A suspension of NaH (7 g, 176 mmol, 60% in mineral oil) in DMF (50 mL) at 0° C. is treated with 3-ethyl-5-trifluoromethyl-1H-indole (2.4 g, 11.3 mmol) and stirred at 0° C. for 1 h. The mixture is treated with HOSA (6.6 g, 59 mmol) portion wise and warmed to rt over 2 h. The mixture is then poured over ice, filtered through a pad of Celite, and extracted with EtOAc (3×150 mL). The combined organic layer is dried (Na2SO4), filtered and concentrated in vacuo. The residue is purified by silica gel chromatography eluting with 10%-50% EtOAc in heptane to afford 3-ethyl-5-trifluoromethyl-indol-1-ylamine (1.3 g, 50%). MS: 229 (M+H); 1H NMR (300 MHz, CDCl3): δ 7.84 (s, 1H), 7.45 (s, 2H), 7.02 (s, 1H), 4.74 (s, NH2, 2H), 2.77 (q, 2H), 1.31 (t, 3H).
Reaction SMILES: [CH2:1]([O:8][N:9]1[C:18]2[C:13](=[CH:14][CH:15]=[C:16]([C:19]([F:22])([F:21])[F:20])[CH:17]=2)[N:12]=[C:11](Cl)[C:10]1=[O:24])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O.[NH2:26][NH2:27]>ClCCl>[CH2:1]([O:8][N:9]1[C:18]2[C:13](=[CH:14][CH:15]=[C:16]([C:19]([F:22])([F:21])[F:20])[CH:17]=2)[N:12]=[C:11]([NH:26][NH2:27])[C:10]1=[O:24])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NN
Reactant: O=c1c(Cl)nc2ccc(C(F)(F)F)cc2n1OCc1ccccc1
Solvent: O
Solvent: ClCCl
Product: NNc1nc2ccc(C(F)(F)F)cc2n(OCc2ccccc2)c1=O
Temperature: 0 °C
Reaction time: 2 h
Yield: 85.6 %

Procedure:
A mixture of 1-benzyloxy-3-chloro-7-trifluoromethylquinoxalin-2(1H)-one (27 g, 76 mmol) and hydrazine hydrate (14.7 ml, 0.30 mol) in 250 ml of dichloromethane was stirred at 0° C. for 2 h. The precipitate was isolated by filtration, washed with dichloromethane and water and dried to give 22.8 g (76%) of the title compound. M.p. 174°-176° C.
Reaction SMILES: [CH2:1]([C:3]1[N:7]=[C:6]([CH2:8][N:9]2[C:14]3[CH:15]=[C:16]([C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)[S:17][C:13]=3[C:12](=[O:24])[N:11]([CH:25]3[CH2:30][CH2:29][N:28](C(OC(C)(C)C)=O)[CH2:27][CH2:26]3)[C:10]2=[O:38])[S:5][N:4]=1)[CH3:2].[F:39][C:40]([F:45])([F:44])[C:41]([OH:43])=[O:42]>C(Cl)Cl>[F:39][C:40]([F:45])([F:44])[C:41]([OH:43])=[O:42].[CH2:1]([C:3]1[N:7]=[C:6]([CH2:8][N:9]2[C:14]3[CH:15]=[C:16]([C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)[S:17][C:13]=3[C:12](=[O:24])[N:11]([CH:25]3[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]3)[C:10]2=[O:38])[S:5][N:4]=1)[CH3:2]
Reactant: CCc1nsc(Cn2c(=O)n(C3CCN(C(=O)OC(C)(C)C)CC3)c(=O)c3sc(-c4ccccc4)cc32)n1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCc1nsc(Cn2c(=O)n(C3CCNCC3)c(=O)c3sc(-c4ccccc4)cc32)n1

Procedure:
A solution of tert-butyl 4-{1-[(3-ethyl-1,2,4-thiadiazol-5-yl)methyl]-2,4-dioxo-6-phenyl-1,4-dihydrothieno[3,2-d]pyrimidin-3(2H)-yl}piperidine-1-carboxylate (321 mg; compound B22) in DCM (10 ml) is reacted with trifluoroacetic acid (2 ml) according to the procedure described in example B43 to afford the title compound as a solid.
Reaction SMILES: Cl.Cl.[F:3][C:4]1[CH:12]=[CH:11][C:10]2[C:6](=[CH:7][N:8]([CH3:13])[N:9]=2)[C:5]=1[C@@H:14]1[CH2:16][C@H:15]1[CH2:17][NH2:18].C(N(CC)CC)C.[C:26](OC(=O)C)(=[O:28])[CH3:27]>O1CCCC1.C(=O)([O-])O.[Na+]>[F:3][C:4]1[CH:12]=[CH:11][C:10]2[C:6](=[CH:7][N:8]([CH3:13])[N:9]=2)[C:5]=1[C@@H:14]1[CH2:16][C@H:15]1[CH2:17][NH:18][C:26](=[O:28])[CH3:27]
Reactant: CC(=O)OC(C)=O
Reactant: Cn1cc2c([C@@H]3C[C@H]3CN)c(F)ccc2n1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(=O)NC[C@@H]1C[C@H]1c1c(F)ccc2nn(C)cc12
Yield: 98.4 %

Procedure:
A solution of 1-[(1R,2R)-2-(5-fluoro-2-methyl-2H-indazol-4-yl) cyclopropyl]methanamine dihydrochloride (258 mg, 0.883 mmol) and triethylamine (615 μL, 4.415 mmol) in tetrahydrofuran (9 mL) was stirred at room temperature for 20 min. To the reaction solution was added acetic anhydride (125 μL, 1.325 mmol) under ice-cooling, and the mixture was stirred under ice-cooling for 15 min. The reaction solution was diluted with saturated aqueous sodium hydrogen carbonate solution. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography (NH, methanol/ethyl acetate=0/100→5/95) to give the title compound (227 mg, yield 98%).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5]C=CC=2)[C:3](=[O:10])[CH2:2]1.[CH:11]1(N)[CH2:13][CH2:12]1>C1(C)C=CC=CC=1.[Ti](Cl)(Cl)(Cl)Cl>[NH:1]1[C:2]2[C:13](=[CH:12][CH:5]=[CH:4][C:3]=2[OH:10])[CH:11]=[CH:9]1
Reactant: O=C1CNc2ccccc21
Reactant: NC1CC1
Agent: Cl[Ti](Cl)(Cl)Cl
Solvent: Cc1ccccc1
Product: Oc1cccc2cc[nH]c12
Temperature: -10 °C
Reaction time: 8 h

Procedure:
7-Chloroacetyloxy-1,4-dihydro-4-methylcyclopent b!indol-3(2H)-one (15.0 g) and cyclopropylamine (9.6 g) were dissolved in 300 ml toluene and cooled to -10° C. Titanium tetrachloride (6.3 g) dissolved in 50 ml toluene was added slowly to the first solution. The reaction mixture was allowed to come up to room temperature and stirred overnight. The next day another 1.5 equivalents of the amine (4.6 g) was added to the reaction mixture and the mixture was stirred for one hour. The reaction mixture was filtered through a pad of silica gel, eluting with 3:1 hexane/ethyl acetate, giving a yellow oil after removal of solvents. 3-Cyclopropylamino-4-methyl-1,2,3,4-tetrahydrocyclopent b!-indol-7-ol was isolated as a light yellow solid (3.3 g) after flash chromatography and recrystallization from ethyl acetate.
Reaction SMILES: O[CH2:2][CH2:3][N:4]([CH2:12][CH2:13]O)[CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.S(Cl)([Cl:17])=O.[ClH:19]>[N+](C)([O-])=O>[ClH:17].[Cl:19][CH2:2][CH2:3][N:4]([CH2:12][CH2:13][Cl:17])[CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: OCCN(CCO)Cc1ccccc1
Reactant: O=S(Cl)Cl
Agent: Cl
Solvent: C[N+](=O)[O-]
Product: ClCCN(CCCl)Cc1ccccc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of bis(2-hydroxyethyl)benzylamine (19.5 g 0.1 mol) in nitromethane (150 mL) cooled with a water/ice bath is added thionyl chloride (60 mL). The mixture is stirred at room temperature for 2 h, then at 80° C. for 1 h 30. After cooling again with a water/ice bath, diisopropyl oxyde (350 mL) is added, causing the hydrochloride to precipitate. This is filtrated, rinsed with diisopropyl oxide and dried to give bis(2-chloroethyl)benzylamine hydrochloride.
Reaction SMILES: [C:1]1([S:7]([NH:10][CH2:11][CH2:12][C:13]2[CH:23]=[CH:22][C:16]([O:17][CH2:18][C:19]([O-:21])=[O:20])=[C:15]([N+:24]([O-])=O)[CH:14]=2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Na+:27]>CO.[C].[Pd]>[C:1]1([S:7]([NH:10][CH2:11][CH2:12][C:13]2[CH:23]=[CH:22][C:16]([O:17][CH2:18][C:19]([O-:21])=[O:20])=[C:15]([NH2:24])[CH:14]=2)(=[O:8])=[O:9])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1.[Na+:27]
Reactant: O=C([O-])COc1ccc(CCNS(=O)(=O)c2ccccc2)cc1[N+](=O)[O-]
Agent: [Pd]
Agent: [Na+]
Solvent: CO
Product: Nc1cc(CCNS(=O)(=O)c2ccccc2)ccc1OCC(=O)[O-]
Reaction time: 3 h
Yield: 96.2 %

Procedure:
2.18 g of sodium 4-(2-benzenesulfonylaminoethyl)-2-nitrophenoxyacetate are dissolved in 50 ml of 80% methanol, and 0.44 g of 10% palladium-carbon is added thereto. After the mixture is subjected to catalytic hydrogenation for 3 hours at room temperature under atmospheric pressure, the catalyst is filtered off. The filtrate is condensed to dryness, and the residue is recrystallized from a mixture of isopropylether and water. 1.94 g of sodium 4-(2-benzenesulfonylaminoethyl)-2-aminophenoxyacetate are obtained as pale yellow scales.