Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][S:2][C:3]1[CH:8]=[C:7]([NH2:9])[N:6]=[C:5]([NH2:10])[CH:4]=1.I[CH2:12][CH2:13][F:14].C([O-])([O-])=O.[Cs+].[Cs+]>C(#N)C>[F:14][CH2:13][CH2:12][NH:10][C:5]1[CH:4]=[C:3]([S:2][CH3:1])[CH:8]=[C:7]([NH2:9])[N:6]=1
Reactant: FCCI
Reactant: CSc1cc(N)nc(N)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Product: CSc1cc(N)nc(NCCF)c1

Procedure:
In a glass vessel were mixed together the above prepared 4-methylsulfanyl-pyridine-2,6-diamine (0.100 g, 0.644 mmol), 1-iodo-2-fluoroethane, 0.123 g, 1.10 eq.), and 1.2 eq. of Cs2CO3 (0.252 g) in 1.0 mL of abs. acetonitrile, and the mixture allowed to react for 1 h at 125° C. in a microwave oven. Cooling, pouring onto crashed ice, twofold extraction with AcOEt, washing with water and brine, drying over sodium sulfate, and evaporation of the solvents, followed by flash chromatography (SiO2, hexane/AcOEt=3/7) afforded 0.037 g of the title compound as brown solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4](/[CH:9]=[CH:10]/[C:11]([N:13]2[CH2:19][CH2:18][C:17](=[O:20])[N:16]([CH2:21][CH2:22][CH2:23][CH2:24]I)[CH2:15][CH2:14]2)=[O:12])[CH:5]=[CH:6][C:7]=1[Cl:8].[C:26]([Si:30]([CH3:47])([CH3:46])[O:31][C@H:32]1[C@H:37]([O:38][Si:39]([C:42]([CH3:45])([CH3:44])[CH3:43])([CH3:41])[CH3:40])[CH2:36][CH2:35][NH:34][CH2:33]1)([CH3:29])([CH3:28])[CH3:27]>>[C:26]([Si:30]([CH3:47])([CH3:46])[O:31][CH:32]1[CH:37]([O:38][Si:39]([C:42]([CH3:45])([CH3:44])[CH3:43])([CH3:41])[CH3:40])[CH2:36][CH2:35][N:34]([CH2:24][CH2:23][CH2:22][CH2:21][N:16]2[C:17](=[O:20])[CH2:18][CH2:19][N:13]([C:11](=[O:12])/[CH:10]=[CH:9]/[C:4]3[CH:5]=[CH:6][C:7]([Cl:8])=[C:2]([Cl:1])[CH:3]=3)[CH2:14][CH2:15]2)[CH2:33]1)([CH3:29])([CH3:28])[CH3:27]
Reactant: O=C(/C=C/c1ccc(Cl)c(Cl)c1)N1CCC(=O)N(CCCCI)CC1
Reactant: CC(C)(C)[Si](C)(C)O[C@@H]1CCNC[C@H]1O[Si](C)(C)C(C)(C)C
Product: CC(C)(C)[Si](C)(C)OC1CCN(CCCCN2CCN(C(=O)/C=C/c3ccc(Cl)c(Cl)c3)CCC2=O)CC1O[Si](C)(C)C(C)(C)C

Procedure:
In analogy to the procedure described in example 163A, 1-[(E)-3-(3,4-dichloro-phenyl)-acryloyl]-4-(4-iodo-butyl)-[1,4]diazepan-5-one (example 9B) and (trans)-(rac)-3,4-Bis-(tert-butyl-dimethyl-silanyloxy)-piperidine (intermediate 26) gave the title compound as colorless oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[CH:10][C:6]([C:7]([OH:9])=O)=[CH:5][C:4]=1/[CH:12]=[CH:13]/[C:14]1[CH:19]=[CH:18][C:17]([O:20][C:21]([F:24])([F:23])[F:22])=[CH:16][CH:15]=1.Cl.[CH2:26]([NH2:28])[CH3:27]>>[CH2:26]([NH:28][C:7](=[O:9])[C:6]1[CH:10]=[CH:11][C:3]([O:2][CH3:1])=[C:4](/[CH:12]=[CH:13]/[C:14]2[CH:15]=[CH:16][C:17]([O:20][C:21]([F:22])([F:24])[F:23])=[CH:18][CH:19]=2)[CH:5]=1)[CH3:27]
Reactant: COc1ccc(C(=O)O)cc1/C=C/c1ccc(OC(F)(F)F)cc1
Reactant: CCN
Agent: Cl
Product: CCNC(=O)c1ccc(OC)c(/C=C/c2ccc(OC(F)(F)F)cc2)c1

Procedure:
The captioned compound was synthesized from 4-methoxy-3-[(E)-2-(4-trifluoromethoxyphenyl)vinyl]benzoic acid and ethylamine hydrochloride in accordance with the same procedure as in the methods described in step C of Example 1-2-3.
Reaction SMILES: [Cu][C:2]#[N:3].C(ON=O)(C)(C)C.[Br:11][C:12]1[CH:18]=[C:17]([Br:19])[CH:16]=[CH:15][C:13]=1N.Cl>CS(C)=O>[Br:11][C:12]1[CH:18]=[C:17]([Br:19])[CH:16]=[CH:15][C:13]=1[C:2]#[N:3]
Reactant: N#C[Cu]
Reactant: Nc1ccc(Br)cc1Br
Agent: CC(C)(C)ON=O
Agent: Cl
Solvent: CS(C)=O
Product: N#Cc1ccc(Br)cc1Br
Temperature: 45 °C
Reaction time: 1 h
Yield: 31 %

Procedure:
A solution of copper(I) cyanide (2.32 g, 25.9 mmol) in anhydrous dimethylsulfoxide (50 mL) is stirred at 60° C., and to this solution is added tert-butylnitrite (7.1 mL, 59.7 mmol) all at once. A solution of 2,4-dibromoaniline (5.0 g, 19.9 mmol) in anhydrous dimethylsulfoxide (30 mL) is added dropwise, via cannula, to the mixture. After the addition is complete the reaction mixture is stirred for 1 hr, cooled to 45° C., and then treated slowly with 5N HCl (50 mL). Five minutes later, the reaction mixture is cooled to ambient temperature and extracted with 1:1 ethyl acetate:hexane (2×300 mL). The combined organic layers are washed with water (100 mL) and saturated aqueous sodium chloride (100 mL), dried, concentrated under reduced pressure and the residue subjected to silica gel chromatography, eluting with hexane containing from 0–5% ethyl acetate. Fractions containing product are combined and concentrated under reduced pressure to provide the title compound (1.61 g, 31% yield).
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([N:22]2[CH2:27][CH2:26][O:25][CH2:24][CH2:23]2)[C:5]2[S:10][C:9]([CH2:11][N:12]3[CH2:17][CH2:16][N:15]([S:18]([CH3:21])(=[O:20])=[O:19])[CH2:14][CH2:13]3)=[CH:8][C:6]=2[N:7]=1.[CH3:28][N:29]([CH3:45])[C:30]1[N:35]=[CH:34][C:33](B2OC(C)(C)C(C)(C)O2)=[CH:32][N:31]=1>>[CH3:28][N:29]([CH3:45])[C:30]1[N:35]=[CH:34][C:33]([C:2]2[N:3]=[C:4]([N:22]3[CH2:27][CH2:26][O:25][CH2:24][CH2:23]3)[C:5]3[S:10][C:9]([CH2:11][N:12]4[CH2:17][CH2:16][N:15]([S:18]([CH3:21])(=[O:20])=[O:19])[CH2:14][CH2:13]4)=[CH:8][C:6]=3[N:7]=2)=[CH:32][N:31]=1
Reactant: CS(=O)(=O)N1CCN(Cc2cc3nc(Cl)nc(N4CCOCC4)c3s2)CC1
Reactant: CN(C)c1ncc(B2OC(C)(C)C(C)(C)O2)cn1
Product: CN(C)c1ncc(-c2nc(N3CCOCC3)c3sc(CN4CCN(S(C)(=O)=O)CC4)cc3n2)cn1

Procedure:
2-Chloro-6-(4-methanesulfonyl-piperazin-1-ylmethyl)-4-morpholin-4-yl-thieno[3,2-d]pyrimidine, prepared via General Procedure B-3, was reacted with 2-dimethylamino-pyrimidine-5-boronic acid pinacol ester in General Procedure A. Purification on silica and ether trituration gave 244. NMR (CDCl3): 2.68-2.72 (4H, m), 2.82 (3H, s), 3.29 (6H, s), 3.29-3.33 (4H, m), 3.90 (2H, s), 3.90-3.94 (4H, m), 4.05-4.10 (4H, m), 7.31 (1H, br. s), 9.30 (2H, s). MS (ESI+): 519.3 (100%)
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([C:14](=[O:28])[C:15]2[CH:20]=[CH:19][C:18]([CH2:21][N:22]3[CH2:27][CH2:26][O:25][CH2:24][CH2:23]3)=[CH:17][CH:16]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.[C:29](OC(N1CCN(C(=O)C2C=CC(C=O)=CC=2)CC1)=O)([CH3:32])(C)[CH3:30].N1CCOCC1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>CO>[CH:32]1([N:8]2[CH2:13][CH2:12][N:11]([C:14]([C:15]3[CH:20]=[CH:19][C:18]([CH2:21][N:22]4[CH2:27][CH2:26][O:25][CH2:24][CH2:23]4)=[CH:17][CH:16]=3)=[O:28])[CH2:10][CH2:9]2)[CH2:29][CH2:30]1
Reactant: CC(C)(C)OC(=O)N1CCN(C(=O)c2ccc(CN3CCOCC3)cc2)CC1
Reactant: CC(C)(C)OC(=O)N1CCN(C(=O)c2ccc(C=O)cc2)CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: C1COCCN1
Solvent: CO
Product: O=C(c1ccc(CN2CCOCC2)cc1)N1CCN(C2CC2)CC1
Reaction time: 3 h
Yield: 48 %

Procedure:
4-(4-Morpholin-4-ylmethyl-benzoyl)-piperazine-1-carboxylic acid tert-butyl ester. A solution of 4-(4-formyl-benzoyl)-piperazine-1-carboxylic acid tert-butyl ester (2.06 g) in methanol (100 mL) was treated with morpholine (4 mL) and NaB(OAc)3H (6.98 g, in portions over 1 h). After 3 h, the mixture was diluted with satd. aq. NaHCO3 and extracted with CH2Cl2. The organic layer was dried (Na2SO4) and concentrated. The residue was purified by column chromatography (SiO2) to give the title compound (1.22 g, 48%). MS (ESI): mass calcd. for C21H31N3O4, 389.23; m/z found, 390.4 [M+H]+. 1H NMR (CDCl3): 7.39-7.33 (m, 4H), 3.75-3.66 (m, 6H), 3.50 (s, 2H), 3.51-3.33 (m, 6H), 2.45-2.41 (m, 4H), 1.46 (s, 9H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([NH:31][C:32]([NH:34][C:35](=[O:43])[CH2:36][C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)=[S:33])[CH:5]=[CH:6][C:7]=1[O:8][C:9]1[CH:14]=[CH:13][N:12]=[C:11]2[CH:15]=[C:16]([C:18]3[CH:23]=[CH:22][C:21]([CH2:24][N:25]4[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]4)=[CH:20][CH:19]=3)[S:17][C:10]=12.CCN(CC)CC.[N:51]([CH3:54])=[C:52]=[O:53]>ClCCl>[F:1][C:2]1[CH:3]=[C:4]([NH:31][C:32]([NH:34][C:35](=[O:43])[CH2:36][C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)=[S:33])[CH:5]=[CH:6][C:7]=1[O:8][C:9]1[CH:14]=[CH:13][N:12]=[C:11]2[CH:15]=[C:16]([C:18]3[CH:19]=[CH:20][C:21]([CH2:24][N:25]4[CH2:30][CH2:29][N:28]([C:52]([NH:51][CH3:54])=[O:53])[CH2:27][CH2:26]4)=[CH:22][CH:23]=3)[S:17][C:10]=12
Reactant: O=C(Cc1ccccc1)NC(=S)Nc1ccc(Oc2ccnc3cc(-c4ccc(CN5CCNCC5)cc4)sc23)c(F)c1
Reactant: CN=C=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CNC(=O)N1CCN(Cc2ccc(-c3cc4nccc(Oc5ccc(NC(=S)NC(=O)Cc6ccccc6)cc5F)c4s3)cc2)CC1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 39.9 %

Procedure:
Compound 450 (0.367 g, 0.60 mmol) was dissolved in dichloromethane (2 mL) at RT and then Et3N (0.25 mL, 1.803 mmol) was added. The reaction mixture was cooled to 0° C., treated with isocyanatomethane (0. 16 mL, 3.43 mmol) and stirred for 10 min at 0° C. The reaction mixture was then warmed to RT over a 30 min period, and then was quenched with MeOH. It was then concentrated to dryness and the residue was purified by flash chromatography (eluent 9/1/10 MeOH/NH4Cl/DCM) to give title compound 455 as a pale yellow solid (0.16 g, 39% yield). 1H NMR δ (400 MHz, DMSO-d6): 12.48 (s, 1H), 11.83 (s, 1 H), 8.51 (dd, J=1.2, 5.5 Hz, 1H), 8.01 (m, 2H), 7.84 (m, 2H), 7.53 (m, 2H), 7.42 (d, J=8.4 Hz, 2H), 7.23-7.38 (m, 5H) 6.65 (dd, J=0.8, 5.5 Hz, 1H), 6.39 (q, J=4.2 Hz, 1 H), 3.81 (s, 2 H), 3.51 (s, 2H), 3.25 (m, 4H), 2.53 (d, J=4.3 Hz, 3H), 2.31 (m, 4H). LCMS: 669 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[C:3]([NH:10][C:11]2[CH:16]=[CH:15][C:14]([I:17])=[CH:13][C:12]=2[F:18])=[CH:4][C:5](=[O:9])[N:6]([CH3:8])[CH:7]=1.[CH2:19]([C:22]1([S:25](Cl)(=[O:27])=[O:26])[CH2:24][CH2:23]1)[CH:20]=[CH2:21].Cl>N1C=CC=CC=1>[CH2:19]([C:22]1([S:25]([NH:1][C:2]2[C:3]([NH:10][C:11]3[CH:16]=[CH:15][C:14]([I:17])=[CH:13][C:12]=3[F:18])=[CH:4][C:5](=[O:9])[N:6]([CH3:8])[CH:7]=2)(=[O:27])=[O:26])[CH2:24][CH2:23]1)[CH:20]=[CH2:21]
Reactant: C=CCC1(S(=O)(=O)Cl)CC1
Reactant: Cn1cc(N)c(Nc2ccc(I)cc2F)cc1=O
Agent: Cl
Solvent: c1ccncc1
Product: C=CCC1(S(=O)(=O)Nc2cn(C)c(=O)cc2Nc2ccc(I)cc2F)CC1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
5-Amino-4-(2-fluoro-4-iodophenylamino)-1-methylpyridin-2(1H)-one (prepared as described in steps a-e in example 1 above) was dissolved in dry pyridine at 0° C. under an ice-salt bath, and 1-allylcyclopropane-1-sulfonyl chloride was added. The resultant reaction mixture was allowed to warm to room temperature. After stirring for 16 hours at room temperature, aqueous HCl (1N) was added and the mixture was stirred for 15 minutes. The formed precipitate was filtered and dried under vacuum, and purified by preparative TLC (SiO2, EtOAc:MeOH=9:1 (v:v), Rf˜0.4).
Reaction SMILES: [NH2:1][C:2]1[C:7]([F:8])=[C:6](F)[N:5]=[C:4]([C:10]([O:12][CH:13]([CH3:15])[CH3:14])=[O:11])[CH:3]=1.C([O-])(O)=O.[Na+].[ClH:21]>CCOC(C)=O>[NH2:1][C:2]1[C:7]([F:8])=[C:6]([Cl:21])[N:5]=[C:4]([C:10]([O:12][CH:13]([CH3:15])[CH3:14])=[O:11])[CH:3]=1
Reactant: CC(C)OC(=O)c1cc(N)c(F)c(F)n1
Reactant: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Product: CC(C)OC(=O)c1cc(N)c(F)c(Cl)n1
Temperature: 100 °C
Reaction time: 8 h
Yield: 46 %

Procedure:
Propan-2-yl 4-amino-5,6-difluoropicolinate (4.25 g, 19.7 mmol) was dissolved in hydrochloric acid (HCl, 4 M in dioxane; 65 mL) in a 100 mL Hastalloy stiffed Parr reactor. The reactor was heated to 100° C. for 2 h. Upon standing at room temperature overnight, a yellow crystalline solid formed. This solid was not soluble in EtOAc, but did dissolve upon shaking with satd aq NaHCO3 solution (500 mL) and EtOAc (300 mL). The aqueous layer was extracted with EtOAc (2×250 mL). The combined organic extracts were washed with water (5×50 mL) and then brine. The extracts were dried (MgSO4) and concentrated under vacuum to provide an off-white solid. The crude product was purified by column chromatography (120 g silica column; 0-100% hexane-EtOAc gradient) to give a white solid (2.11 g, 46%): mp 190.7-192.4° C.; 1H NMR (400 MHz, DMSO-d6) δ 7.543 (d, JF-H=5.7 Hz, 1H), 6.91 (br s, 2H, NH2), 5.09 (septet, J=6 Hz, 1H, CHMe2), 1.29 (d, J=6 Hz, 6H, CHMe2); 13C{1H} NMR (101 MHz, DMSO-d6) δ 162.8 (CO2R), 144.8 (d, JF-C=12 Hz, C2/C4), 143.4 (d, JF-C=254 Hz, C5), 142.7 (d, JF-C=4.8 Hz, C2/C4), 136.5 (d, JF-C=17 Hz, C6), 112.8 (d, JF-C=5 Hz, C3), 68.9 (CHMe2), 21.6 (Me); 19F NMR (376 MHz, DMSO-d6) δ −141.0 (d, JF-H=6 Hz). Anal. Calcd for C9H10ClFN2O2: C, 46.47; H, 4.33; N, 12.04. Found: C, 46.50; H, 4.33; N, 11.96.
Reaction SMILES: [Si:1]([O:8][CH2:9][CH2:10][C@H:11]([OH:21])[C@H:12]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[Cl:20])[OH:13])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[Si](OCC[C@@H](O)[C@@H](C1C=CC=CC=1Cl)O)([C:25](C)([CH3:27])[CH3:26])(C)C>>[C:4]([Si:1]([O:8][CH2:9][CH2:10][C@H:11]1[C@H:12]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[Cl:20])[O:13][C:25]([CH3:27])([CH3:26])[O:21]1)([CH3:3])[CH3:2])([CH3:6])([CH3:7])[CH3:5]
Reactant: CC(C)(C)[Si](C)(C)OCC[C@@H](O)[C@H](O)c1ccccc1Cl
Reactant: CC(C)(C)[Si](C)(C)OCC[C@H](O)[C@@H](O)c1ccccc1Cl
Product: CC1(C)O[C@@H](CCO[Si](C)(C)C(C)(C)C)[C@H](c2ccccc2Cl)O1
Yield: 70 %

Procedure:
The substantially same method as described in Example 351 was conducted, except that (1S,2S)-4-(tert-butyldimethylsilyloxy)-1-(2-chlorophenyl)butane-1,2-diol (Preparation example 353) was used instead of 1R, 2R)-4-(tert-butyldimethylsilyloxy)-1-(2-chlorophenyl)butane-1,2-diol (Preparation example 349), to obtain the title compound (0.7 g, 70˜95%)
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[C:7](=[O:14])[NH:6][N:5]=1.[O:15]1[CH:19]=[CH:18][C:17]([C:20](Cl)=[O:21])=[N:16]1>>[O:14]=[C:7]1[C:8]2[C:13](=[CH:12][CH:11]=[CH:10][CH:9]=2)[C:4]([CH2:3][NH:2][C:20]([C:17]2[CH:18]=[CH:19][O:15][N:16]=2)=[O:21])=[N:5][NH:6]1
Reactant: O=C(Cl)c1ccon1
Reactant: NCc1n[nH]c(=O)c2ccccc12
Agent: Cl
Product: O=C(NCc1n[nH]c(=O)c2ccccc12)c1ccon1

Procedure:
The title compound was prepared from 4-aminomethyl-2H-phthalazine-1-one hydrochloride (Geterotsikl, Soedin, 1972, (9), 15) and isoxazol-3-carbonyl chloride using the procedure described in Example 1, Part a. 1H NMR (360 MHz, d6-DMSO) δ 4.80 (d, J=6 Hz, 2H), 6.93 (s, 1H), 7.87 (t, J=7 Hz, 1H), 7.95 (t, J=7 Hz, 1H), 8.1 (d, J=7 Hz, 1H), 8.28 (dd, J=2 Hz, 7 Hz, 1H), 9.08 (s, 1H), 9.09 (t, J=2 Hz, 1H), 12.62 (s, 1H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]([CH2:13][O:14][C:15]3[CH:23]=[CH:22][C:18]([C:19]([OH:21])=O)=[CH:17][N:16]=3)=[C:11]([CH3:24])[N:10]=[N:9]2)=[CH:4][CH:3]=1.[CH3:25][C:26]1([NH2:30])[CH2:29][O:28][CH2:27]1>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[C:12]([CH2:13][O:14][C:15]3[CH:23]=[CH:22][C:18]([C:19]([NH:30][C:26]4([CH3:25])[CH2:29][O:28][CH2:27]4)=[O:21])=[CH:17][N:16]=3)=[C:11]([CH3:24])[N:10]=[N:9]2)=[CH:6][CH:7]=1
Reactant: Cc1nnn(-c2ccc(F)cc2)c1COc1ccc(C(=O)O)cn1
Reactant: CC1(N)COC1
Product: Cc1nnn(-c2ccc(F)cc2)c1COc1ccc(C(=O)NC2(C)COC2)cn1
Yield: 91 %

Procedure:
As described for example 61b, 6-[3-(4-fluoro-phenyl)-5-methyl-3H-[1,2,3]triazol-4-ylmethoxy]-nicotinic acid (83 mg, 0.25 mmol) was converted, using 3-methyl-3-oxetanamine instead of 4-aminotetrahydropyran, to the title compound (91 mg, 91%) which was obtained as a white solid. MS: m/e=398.2 [M+H]+.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:25]=[CH:26][N:27]=1)[C:5]([NH:7][C:8]1[S:9][C:10]2[C:16]([CH:17]3[CH2:22][CH2:21][O:20][CH2:19][CH2:18]3)=[CH:15][CH:14]=[C:13]([O:23][CH3:24])[C:11]=2[N:12]=1)=[O:6].[H-].[Na+].[CH2:30]([OH:32])[CH3:31]>O1CCOCC1.CN(C=O)C>[CH2:30]([O:32][C:2]1[CH:3]=[C:4]([CH:25]=[CH:26][N:27]=1)[C:5]([NH:7][C:8]1[S:9][C:10]2[C:16]([CH:17]3[CH2:22][CH2:21][O:20][CH2:19][CH2:18]3)=[CH:15][CH:14]=[C:13]([O:23][CH3:24])[C:11]=2[N:12]=1)=[O:6])[CH3:31]
Reactant: CCO
Reactant: COc1ccc(C2CCOCC2)c2sc(NC(=O)c3ccnc(Br)c3)nc12
Agent: [H-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: CN(C)C=O
Product: CCOc1cc(C(=O)Nc2nc3c(OC)ccc(C4CCOCC4)c3s2)ccn1

Procedure:
From 2-bromo-N-[4-methoxy-7-(tetrahydro-pyran-4-yl)-benzothiazol-2-yl]-isonicotinamide with sodium hydride and ethanol in dioxane and DMF. ES-MS m/e (%): 414 (M+H+, 100).
Reaction SMILES: [CH3:1][O:2][N:3]([CH3:13])[C:4]([C:6]1[CH:11]=[CH:10][NH:9][C:8](=[O:12])[CH:7]=1)=[O:5].Cl.Cl[CH2:16][CH2:17][CH2:18][N:19]([CH3:21])[CH3:20].C([O-])([O-])=O.[K+].[K+].O>CC(C)=O>[CH3:20][N:19]([CH3:21])[CH2:18][CH2:17][CH2:16][N:9]1[CH:10]=[CH:11][C:6]([C:4]([N:3]([O:2][CH3:1])[CH3:13])=[O:5])=[CH:7][C:8]1=[O:12]
Reactant: CON(C)C(=O)c1cc[nH]c(=O)c1
Reactant: CN(C)CCCCl
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC(C)=O
Product: CON(C)C(=O)c1ccn(CCCN(C)C)c(=O)c1
Temperature: 25 °C
Yield: 86.9 %

Procedure:
A stirred mixture of N-methoxy-N-methyl-2-oxo-1,2-dihydropyridine-4-carbox-amide (200 mg, 1.0 eq), 3-chloro-N,N-dimethylpropan-1-amine hydrochloride (350 mg, 2.0 eq) and K2CO3 (455 mg, 3.0 eq) in 20 mL acetone was heated under reflux overnight. After cooling to rt, water was added, and the mixture was extracted with CH2Cl2. The extract was dried, concentrated, and purified by column chromatography to give the desired product (255 mg, 87% yield). 1H NMR (400 MHz, CDCl3) δ 7.40 (d, J=7.2 Hz, 1H), 6.75 (d, J=1.2 Hz, 1H), 6.30 (dd, J=6.8 Hz, 2.0 Hz, 1H), 4.02 (t, J=7.2 Hz, 2H), 3.62 (s, 3H), 3.33 (s, 3H), 2.30 (t, J=6.8 Hz, 2H), 2.23 (s, 6H), 1.93 (t, J=7.2 Hz, 2H).
Reaction SMILES: [N:1]([CH2:4][C:5]1[CH:9]=[C:8]([C:10]2[O:11][CH:12]=[CH:13][CH:14]=2)[O:7][N:6]=1)=[N+]=[N-]>CO.[Pd]>[O:11]1[CH:12]=[CH:13][CH:14]=[C:10]1[C:8]1[O:7][N:6]=[C:5]([CH2:4][NH2:1])[CH:9]=1
Reactant: [N-]=[N+]=NCc1cc(-c2ccco2)on1
Agent: [Pd]
Solvent: CO
Product: NCc1cc(-c2ccco2)on1
Yield: 63.4 %

Procedure:
A solution of 1.50 g of 3-azidomethyl-5-furan-2-yl-isoxazole and 600 mg of 5% palladium in 50 ml of methanol was stirred for 15 hrs under hydrogen atmosphere and then filtered. The filtrate was concentrated in vacuo to provide 821 mg of C-(5-furan-2-yl-isoxazol-3-yl)-methylamine (Step 3 Yield 59%). This concentrate was used in the next step without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]2[CH2:12][NH:11][CH2:10][C@H:9]2[C:13]([O:15][CH3:16])=[O:14])=[CH:4][CH:3]=1.CCN(C(C)C)C(C)C.Cl[C:27]1[N:28]=[N:29][C:30]([CH3:33])=[CH:31][CH:32]=1>O1CCOCC1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]2[CH2:12][N:11]([C:27]3[N:28]=[N:29][C:30]([CH3:33])=[CH:31][CH:32]=3)[CH2:10][C@H:9]2[C:13]([O:15][CH3:16])=[O:14])=[CH:4][CH:3]=1
Reactant: Cc1ccc(Cl)nn1
Reactant: COC(=O)[C@@H]1CNC[C@H]1c1ccc(Cl)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1COCCO1
Product: COC(=O)[C@@H]1CN(c2ccc(C)nn2)C[C@H]1c1ccc(Cl)cc1
Reaction time: 0.08 h
Yield: 75 %

Procedure:
The product of Step A, methyl (3S,4R)-4-(4-chlorophenyl)pyrrolidine-3-carboxylate (0.46 g, 1.92 mmol) was dissolved in dioxane (2 ml). DIPEA (1.34 ml, 7.67 mmol) and 3-chloro-6-methylpyridazine (0.74 g, 5.76 mmol) were added. The reaction was conducted at 180° C. for 5 minutes with microwave. Then, the reaction mixture was concentrated in vacuo. EtOAc was added to the obtained residue. The mixture was diluted with EtOAc, washed with water and purified by column chromatography (eluent: EtOAc/Hex=1/2) to give the title compound (0.48 g, 75%).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@:9]1([CH:22]2[CH2:27][CH2:26][N:25]([C:28]([O:30][CH2:31][CH2:32][Si:33]([CH3:36])([CH3:35])[CH3:34])=[O:29])[CH2:24][CH2:23]2)[C:16](=[O:17])[N:15]2[C@@H:11]([S:12][CH2:13][C@H:14]2[C:18](OC)=O)[CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH3:37]>>[C:1]([O:5][C:6]([NH:8][C@@:9]1([CH:22]2[CH2:27][CH2:26][N:25]([C:28]([O:30][CH2:31][CH2:32][Si:33]([CH3:34])([CH3:36])[CH3:35])=[O:29])[CH2:24][CH2:23]2)[C:16](=[O:17])[N:15]2[C@@H:11]([S:12][CH2:13][C@H:14]2[C:18]#[N:37])[CH2:10]1)=[O:7])([CH3:2])([CH3:4])[CH3:3]
Reactant: COC(=O)[C@@H]1CS[C@H]2C[C@](NC(=O)OC(C)(C)C)(C3CCN(C(=O)OCC[Si](C)(C)C)CC3)C(=O)N21
Reactant: N
Product: CC(C)(C)OC(=O)N[C@]1(C2CCN(C(=O)OCC[Si](C)(C)C)CC2)C[C@@H]2SC[C@@H](C#N)N2C1=O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
153 mg of methyl (3R,6S,7aS)-6-tert-butoxycarbonylamino-5-oxo-6-[1-(2-trimethylsilanylethoxycarbonyl)piperidin-4-yl]hexahydropyrrolo[2,1-b]thiazole-3-carboxylate were dissolved at 0° C. in 30 ml of ammonia-saturated methanol. The mixture was allowed to reach room temperature over the course of 5 h, and then the solvents were removed in vacuo. The residue was taken up in 5 ml of THF, and 100 μl of triethylamine and 60 μl of trifluoroacetic anhydride were successively added. The mixture was stirred at room temperature for 2 h. It was then partitioned between 60 ml of 0.5 M HCl and 60 ml of ethyl acetate. The aqueous phase was extracted twice with 20 ml of ethyl acetate each time, and the combined organic phases were washed once with 30 ml of saturated sodium bicarbonate solution. After drying with MgSO4, the solvents were removed in vacuo. The residue was chromatographed on silica gel.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([C:12]([CH:14]1[CH2:16][CH2:15]1)=[O:13])=[C:5]2Cl.[F:18][C:19]1([F:31])[CH2:23][CH2:22][N:21]([CH:24]2[CH2:29][CH2:28][CH:27]([NH2:30])[CH2:26][CH2:25]2)[CH2:20]1>>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([C:12]([CH:14]1[CH2:16][CH2:15]1)=[O:13])=[C:5]2[NH:30][CH:27]1[CH2:26][CH2:25][CH:24]([N:21]2[CH2:22][CH2:23][C:19]([F:31])([F:18])[CH2:20]2)[CH2:29][CH2:28]1
Reactant: O=C(c1cnc2ccc(Br)cc2c1Cl)C1CC1
Reactant: NC1CCC(N2CCC(F)(F)C2)CC1
Product: O=C(c1cnc2ccc(Br)cc2c1NC1CCC(N2CCC(F)(F)C2)CC1)C1CC1
Yield: 45.6 %

Procedure:
Following General procedure C, (6-bromo-4-chloroquinolin-3-yl)(cyclopropyl)methanone (311 mg, 1 mmol) was reacted with 4-(3,3-difluoropyrrolidin-1-yl)cyclohexanamine (306 mg, 1.5 mmol) to afford the desired product (218 mg, 46%) as a yellow solid: ESI MS m/z 478 [C23H26BrF2N3O+H]+.
Reaction SMILES: [N:1]1([C:7]2[C:15]3[C:10](=[CH:11][C:12]([C:16]([OH:18])=O)=[CH:13][CH:14]=3)[N:9]([C:19]3[CH:23]=[CH:22][S:21][CH:20]=3)[N:8]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.Cl.[CH3:25][C:26]1[N:30]=[C:29]([C@H:31]([NH2:33])[CH3:32])[O:28][N:27]=1.CN1CCOCC1.ON1C2N=CC=CC=2N=N1>CN(C)C=O>[CH3:25][C:26]1[N:30]=[C:29]([C@H:31]([NH:33][C:16]([C:12]2[CH:11]=[C:10]3[C:15]([C:7]([N:1]4[CH2:2][CH2:3][O:4][CH2:5][CH2:6]4)=[N:8][N:9]3[C:19]3[CH:23]=[CH:22][S:21][CH:20]=3)=[CH:14][CH:13]=2)=[O:18])[CH3:32])[O:28][N:27]=1
Reactant: Cc1noc([C@@H](C)N)n1
Reactant: O=C(O)c1ccc2c(N3CCOCC3)nn(-c3ccsc3)c2c1
Agent: Cl
Agent: On1nnc2cccnc21
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Product: Cc1noc([C@@H](C)NC(=O)c2ccc3c(N4CCOCC4)nn(-c4ccsc4)c3c2)n1
Temperature: 50 °C
Reaction time: 1 h

Procedure:
To a solution of 3-(morpholin-4-yl)-1-(thiophen-3-yl)-1H-indazole-6-carboxylic acid (20.0 mg, 45.0 μmol), (1R)-1-(3-methyl-1,2,4-oxadiazol-5-yl)ethanamine hydrochloride (18.1 mg, 90 μmol, and N-methylmorpholine (24.8 μL, 226 μmol) in N,N-dimethylformamide (226 μL) were added N-[2-(dimethylamino)ethyl]-N-ethylcarbodiimide hydrochloride (15.1 mg, 79.0 μmol), 1-hydroxy-7-azabenzotriazole (3.1 mg, 23 pawl). The mixture was stirred at 50° C. for 1 h. Purification by reverse phase HPLC (C-18, 95% water/acetonitrile→5% water/acetonitrile with 0.05% ammonium hydroxide) gave the title compound (19 mg). HRMS [M+1] found=439.1545. 1H NMR (400 MHz, DMSO-d6) δ: 9.37 (1H, d, J=7.33 Hz), 8.20 (1H, s), 8.05 (1H, d, 8.57 Hz), 7.77-7.74 (2H, m), 7.64 (1H, dd, J=8.56, 1.33 Hz), 7.56 (1H, 4.58, 2.12 Hz), 5.43-5.37 (1H, m), 3.83 (4H, t, J=4.39 Hz), 3.43 (4H, t, J=4.39 Hz), 2.33 (3H, s), 1.64 (3H, d, J=7.15 Hz).
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:10]=[C:9]([N+:11]([O-])=O)[CH:8]=[C:7]([O:14][CH3:15])[CH:6]=1)(=[O:4])=[O:3]>CO.ClCCl.[Pd]>[CH3:1][S:2]([C:5]1[CH:10]=[C:9]([CH:8]=[C:7]([O:14][CH3:15])[CH:6]=1)[NH2:11])(=[O:3])=[O:4]
Reactant: COc1cc([N+](=O)[O-])cc(S(C)(=O)=O)c1
Agent: [Pd]
Solvent: ClCCl
Solvent: CO
Product: COc1cc(N)cc(S(C)(=O)=O)c1

Procedure:
1-Methylsulfonyl-3-methoxy-5-nitro-benzene (1.3 g; 5.6 mmol) was dissolved in methanol (40 ml) and 80 mg Pd/C (5% w/w) were added and the reaction mixture was hydrogenated at 2 bar. The mixture was then diluted with dichloromethane, filtrated above over a celite pad, concentrated and the residual was crystallized from methanol. 0.5 g (2.48 mmol; 44% yield) of a solid were obtained.