Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([S:3]([C:6]1[CH:7]=[CH:8][C:9](F)=[C:10]([CH:14]=1)[C:11]([OH:13])=[O:12])(=[O:5])=[O:4])[CH3:2].[F:16][C:17]([F:22])([F:21])[CH:18]([OH:20])[CH3:19]>>[CH2:1]([S:3]([C:6]1[CH:7]=[CH:8][C:9]([O:20][CH:18]([CH3:19])[C:17]([F:22])([F:21])[F:16])=[C:10]([CH:14]=1)[C:11]([OH:13])=[O:12])(=[O:5])=[O:4])[CH3:2]
Reactant: CC(O)C(F)(F)F
Reactant: CCS(=O)(=O)c1ccc(F)c(C(=O)O)c1
Product: CCS(=O)(=O)c1ccc(OC(C)C(F)(F)F)c(C(=O)O)c1

Procedure:
Prepared in analogy to Example B4(c) from 5-Ethanesulfonyl-2-fluoro-benzoic acid and rac-1,1,1-Trifluoro-propan-2-ol (commercial). White solid. MS (m/e): 325.1([M−H], 100%).
Reaction SMILES: [C:1]1([C@@H:7]2[CH2:9][C@H:8]2[NH2:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:11][N:12]1[CH2:17][CH2:16][CH:15]([CH:18]=O)[CH2:14][CH2:13]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C([O-])(O)=O.[Na+]>C(Cl)(Cl)Cl.CC(O)=O>[CH3:11][N:12]1[CH2:17][CH2:16][CH:15]([CH2:18][NH:10][C@@H:8]2[CH2:9][C@H:7]2[C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[CH2:14][CH2:13]1
Reactant: CN1CCC(C=O)CC1
Reactant: N[C@@H]1C[C@H]1c1ccccc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: CC(=O)O
Product: CN1CCC(CN[C@@H]2C[C@H]2c2ccccc2)CC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 17.1 %

Procedure:
A mixture of [trans-2-phenylcyclopropyl]amine (540 mg, 4.05 mmol), 1-methyl-4-piperidinecarbaldehyde (506 mg, 3.98 mmol) and AcOH (l μL, 0.017 mmol) in chloroform (15 mL) was stirred at room temperature for 18 hours. Sodium triacetoxyborohydride (947 mg, 4.47 mmol) was added and stirring continued for 18 hours. Upon completion, saturated NaHCO3 was added to the reaction mixture and the mixture was extracted with THF—CHCl3 (2×50mL). The organics were combined, dried over Na2SO4 and concentrated. The residue was adsorbed onto silica and purified via column chromatography on the ISCO Companion (gradient 0-100% 80:20:2 [CHCl3/MeOH/NH4OH]/CHCl3; 40 g column) to obtain pure final compound (166 mg, 13% yield) as an off white solid: LC-MS (ES) m/z=245 (M+H)+, 1H NMR (400 MHz, DMSO-d6) δ ppm 7.17-7.27 (m, 2H), 7.06-7.15 (m, 1H), 6.97-7.06 (m, 2H), 2.64-2.77 (m, 2H), 2.41-2.49 (m, 2H), 2.27 (br. s., 1H), 2.18 (ddd, J=3.28, 4.23, 7.14 Hz, 1H), 2.08-2.15 (m, 3H), 1.70-1.83 (m, 2H), 1.57-1.70 (m, 2H), 1.30 (ddd, J=4.29, 7.26, 10.93 Hz, 1H), 1.01-1.16 (m, 2H), 0.86-0.98 (m, 2H).
Reaction SMILES: [C:1]([CH:6]=P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)(OCC)=[O:2].[Cl:26][C:27]1[C:32]([O:33][C:34]2[N:39]=[CH:38][CH:37]=[CH:36][N:35]=2)=[CH:31][C:30]([NH:40][N:41]=[CH:42][C:43](=O)[C:44]([F:47])([F:46])[F:45])=[C:29]([F:49])[CH:28]=1>C1(C)C=CC=CC=1>[Cl:26][C:27]1[C:32]([O:33][C:34]2[N:39]=[CH:38][CH:37]=[CH:36][N:35]=2)=[CH:31][C:30]([N:40]2[C:1](=[O:2])[CH:6]=[C:43]([C:44]([F:47])([F:46])[F:45])[CH:42]=[N:41]2)=[C:29]([F:49])[CH:28]=1
Reactant: O=C(C=NNc1cc(Oc2ncccn2)c(Cl)cc1F)C(F)(F)F
Reactant: CCOC(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: Cc1ccccc1
Product: O=c1cc(C(F)(F)F)cnn1-c1cc(Oc2ncccn2)c(Cl)cc1F
Yield: 76.9 %

Procedure:
Carboethoxymethylenetriphenylphosphorane (0.235 g) was added to a suspension of 3,3,3-trifluoro-2-oxopropanal 4-chloro-2-fluoro-5-(pyrimidyloxy)-phenylhydrazone (0.122 g) in toluene (15.0 ml) and the mixture was heated at reflux for 1 hour. The solvent was removed under reduced pressure and the residue chromatographed on silica gel to give the titled compound (0.10 g) mp=156-60° C. 1H NMR (CDCl3, TMS): 7.11(1H, br t), 7.32(1H, m), 7.42(1H, d, J=6.9 Hz), 7.43(1H, d J=9.0 Hz), 8.05(1H, br d), 8.58(2H, br d).
Reaction SMILES: O.[Cl-].[NH4+].[Br:4][C:5]1[CH:6]=[C:7]([C:11]23[O:17][CH:16]2[CH2:15][O:14][CH2:13][CH2:12]3)[CH:8]=[CH:9][CH:10]=1.[N-:18]=[N+:19]=[N-:20].[Na+]>CO>[N:18]([C@@:11]1([C:7]2[CH:8]=[CH:9][CH:10]=[C:5]([Br:4])[CH:6]=2)[CH2:12][CH2:13][O:14][CH2:15][C@@H:16]1[OH:17])=[N+:19]=[N-:20]
Reactant: [N-]=[N+]=[N-]
Reactant: Brc1cccc(C23CCOCC2O3)c1
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: [N-]=[N+]=N[C@@]1(c2cccc(Br)c2)CCOC[C@@H]1O
Temperature: 25 °C
Yield: 108.1 %

Procedure:
Water (88 mL) and ammonium chloride (11.7 g) were added to a solution of (±)-6-(3-bromophenyl)-3,7-dioxa-bicyclo[4.1.0]heptane (17.5 g) in methanol (700 mL), followed by stirring at room temperature. Then, sodium azide (32.1 g) was added, followed by stirring at 80° C. for eight hours. After returning to room temperature, the excess of methanol was evaporated under reduced pressure. The residual aqueous layer was extracted with chloroform three times, and the organic layers were dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography to obtain the title compound (22.1 g).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[CH:10]=2)=[CH:4][C:3]=1[N:21]([CH3:29])[C:22](=[O:28])[O:23][C:24]([CH3:27])([CH3:26])[CH3:25].[O:30]=[C:31]1[NH:35][C:34](=[O:36])[CH:33]([CH2:37][C:38]2[CH:48]=[CH:47][C:41]([O:42][CH2:43][C:44](O)=[O:45])=[CH:40][CH:39]=2)[S:32]1.C(P(=O)(OCC)OCC)#N.C(N(CC)CC)C>O1CCCC1>[O:30]=[C:31]1[NH:35][C:34](=[O:36])[CH:33]([CH2:37][C:38]2[CH:39]=[CH:40][C:41]([O:42][CH2:43][C:44]([NH:1][C:2]3[CH:7]=[CH:6][C:5]([O:8][C:9]4[CH:14]=[CH:13][CH:12]=[C:11]([C:15]5[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=5)[CH:10]=4)=[CH:4][C:3]=3[N:21]([CH3:29])[C:22](=[O:28])[O:23][C:24]([CH3:25])([CH3:26])[CH3:27])=[O:45])=[CH:47][CH:48]=2)[S:32]1
Reactant: O=C(O)COc1ccc(CC2SC(=O)NC2=O)cc1
Reactant: CN(C(=O)OC(C)(C)C)c1cc(Oc2cccc(-c3ccccc3)c2)ccc1N
Agent: CCOP(=O)(C#N)OCC
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CN(C(=O)OC(C)(C)C)c1cc(Oc2cccc(-c3ccccc3)c2)ccc1NC(=O)COc1ccc(CC2SC(=O)NC2=O)cc1
Yield: 95.9 %

Procedure:
In a similar manner to that described in Example (2-1), a reaction was carried out using t-butyl N-[2-amino-5-(3-phenylphenoxy)phenyl]-N-methylcarbamate (1.60 g), 4-(2,4-dioxothiazolidin-5-ylmethyl)phenoxyacetic acid (1.26 g), diethyl cyanophosphonate (0.73 g), triethylamine (0.45 g) and anhydrous tetrahydrofuran (20 ml) and the reaction mixture was purified to give the desired product (2.57 g).
Reaction SMILES: [C:1]1([CH3:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.S(=O)(=O)(O)O.[CH2:13]=[CH:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.[OH-].[Na+]>O>[C:15]1([CH:14]([C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][C:1]=2[CH3:7])[CH3:13])[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: Cc1ccccc1
Reactant: C=Cc1ccccc1
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: Cc1ccccc1C(C)c1ccccc1
Reaction time: 0.5 h

Procedure:
Toluene 4423g was charged to a 12 liter bottom outlet Pyrex reactor equipped with a mechanical agitator, heating mantle, addition funnel, cooling coil, thermometer, and a reflux condenser. Sulfuric acid, 981g of 96% was charged in one portion with agitation. Styrene, 3749g, was added dropwise at 80°-85° over 90 min. The mixture was agitated for an additional 30 min. At 80°-85° C. after the styrene addition was complete, the mixture was allowed to settle for 45 min. and the lower sulfuric acid layer was drained off. A solution of sodium hyroxide (80g in 552g of water) was charged and the mixture was allowed to settle for 30 min, and the lower sodium hydroxide layer was drained off at 80° C. Hot water (1440g) was charged and the mixture was agitated for 15 min. then allowed to settle for 30 in. The water wash was separated leaving 7375g of crude phenyltolylethane alkylate. The phenyltolylethane alkylate was vacuum fractionated to remove excess toluene then pure phenyltolylethane, BP 205° C. 100 mmHg.
Reaction SMILES: [NH2:1][C:2]1[CH:31]=[CH:30][C:5]([O:6][C:7]2[CH:12]=[CH:11][N:10]=[C:9]3[CH:13]=[C:14]([C:16]4[CH:21]=[CH:20][C:19]([C:22]([N:24]5[CH2:29][CH2:28][O:27][CH2:26][CH2:25]5)=[O:23])=[CH:18][CH:17]=4)[S:15][C:8]=23)=[C:4]([F:32])[CH:3]=1.[NH:33]1[C:37]2[CH:38]=[CH:39][CH:40]=[CH:41][C:36]=2[N:35]=[C:34]1[CH2:42][C:43](O)=[O:44]>>[NH:33]1[C:37]2[CH:38]=[CH:39][CH:40]=[CH:41][C:36]=2[N:35]=[C:34]1[CH2:42][C:43]([NH:1][C:2]1[CH:31]=[CH:30][C:5]([O:6][C:7]2[CH:12]=[CH:11][N:10]=[C:9]3[CH:13]=[C:14]([C:16]4[CH:17]=[CH:18][C:19]([C:22]([N:24]5[CH2:25][CH2:26][O:27][CH2:28][CH2:29]5)=[O:23])=[CH:20][CH:21]=4)[S:15][C:8]=23)=[C:4]([F:32])[CH:3]=1)=[O:44]
Reactant: Nc1ccc(Oc2ccnc3cc(-c4ccc(C(=O)N5CCOCC5)cc4)sc23)c(F)c1
Reactant: O=C(O)Cc1nc2ccccc2[nH]1
Product: O=C(Cc1nc2ccccc2[nH]1)Nc1ccc(Oc2ccnc3cc(-c4ccc(C(=O)N5CCOCC5)cc4)sc23)c(F)c1
Yield: 6 %

Procedure:
Prepared from (4-(7-(4-amino-2-fluorophenoxy)thieno[3,2-b]pyridin-2-yl)phenyl)(morpholino)methanone (Example 129, Step A) and 2-(1H-benzo[d]imidazol-2-yl)acetic acid according to the procedure of Example 89. The crude was purified by preparative HPLC to afford the desired product (1.9 mg, 6%). LRMS (ESI pos) m/e 607.9 (M+1). 1H-NMR (400 MHz, CD3OD) δ 8.53 (d, 1H), 7.94 (m, 4H), 7.81 (m, 2H), 7.61 (m, 4H), 7.47 (m, 2H), 6.74 (d, 1H), 3.73 (m, 8H), 3.50 (m, 2H); 19F NMR (376 MHz, CD3OD) δ −129.6.
Reaction SMILES: S(OC)(O[CH3:5])(=O)=O.[OH:8][C:9]1[CH:22]=[CH:21][C:20]2[S:19][C:18]3[C:13](=[CH:14][CH:15]=[CH:16][C:17]=3[S:23](=[O:28])(=[O:27])[N:24]([CH3:26])[CH3:25])[NH:12][C:11]=2[CH:10]=1.[OH-].[Na+]>C(C(C)=O)C>[CH3:5][O:8][C:9]1[CH:22]=[CH:21][C:20]2[S:19][C:18]3[C:13](=[CH:14][CH:15]=[CH:16][C:17]=3[S:23](=[O:28])(=[O:27])[N:24]([CH3:25])[CH3:26])[NH:12][C:11]=2[CH:10]=1
Reactant: COS(=O)(=O)OC
Reactant: CN(C)S(=O)(=O)c1cccc2c1Sc1ccc(O)cc1N2
Agent: [Na+]
Agent: [OH-]
Solvent: CCC(C)=O
Product: COc1ccc2c(c1)Nc1cccc(S(=O)(=O)N(C)C)c1S2
Yield: 45.4 %

Procedure:
2-Methoxy-6-dimethylsulphamoylphenothiazine (m.p. 196°-198°C.; 79.6 g.) is prepared by methylation, using dimethyl sulphate (74.5 g.), of 2-hydroxy-6-dimethylsulphamoylphenothiazine (168 g.) in the presence of powdered sodium hydroxide (30.8 g.) suspended in methyl ethyl ketone (1,820 cc.).
Reaction SMILES: CCCC[Sn]([O:14][Sn:15]([CH2:24][CH2:25][CH2:26][CH3:27])([CH2:20][CH2:21][CH2:22][CH3:23])[CH2:16][CH2:17][CH2:18][CH3:19])(CCCC)CCCC.[CH2:28]([N:32]([CH2:36][CH2:37][CH2:38][CH3:39])[CH2:33][CH2:34]O)[CH2:29][CH2:30][CH3:31].O>C1C=CC=CC=1>[CH2:24]([Sn:15]([O:14][CH2:34][CH2:33][N:32]([CH2:36][CH2:37][CH2:38][CH3:39])[CH2:28][CH2:29][CH2:30][CH3:31])([CH2:16][CH2:17][CH2:18][CH3:19])[CH2:20][CH2:21][CH2:22][CH3:23])[CH2:25][CH2:26][CH3:27]
Reactant: CCCC[Sn](CCCC)(CCCC)O[Sn](CCCC)(CCCC)CCCC
Reactant: CCCCN(CCO)CCCC
Solvent: O
Solvent: c1ccccc1
Product: CCCCN(CCCC)CCO[Sn](CCCC)(CCCC)CCCC

Procedure:
N,N-Dibutylaminoethyl Tributylstannyl Ether is prepared from 59.6 gm (0.1 mole) bis(tributyltin) oxide and 34.6 gm (0.2 mole) N,N-dibutylethanolamine in 200 ml benzene. This is stirred and heated to reflux in a system that contains a Dean-Starke tube. After 30 minutes water began to collect in the Dean-Starke tube and after refluxing for a period of 22 hours a total of 1.8 ml of water (theory 1.8 ml) had collected. A rotating evaporator is used to remove the benzene and to provide 95.1 gm of red-orange liquid. This is fractionated at reduced pressure with collection at 163°-166° C. at 0.7 mm of 73.1 gm of yellow liquid (Percent yield - 79). Infrared spectral analysis shows this to be the desired ether.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:16]=[CH:17][C:18]=1[F:19])[O:5][C:6]1[N:11]=[CH:10][C:9]([CH2:12][C:13]([OH:15])=[O:14])=[CH:8][CH:7]=1.S(=O)(=O)(O)O.C([O-])([O-])=O.[Na+].[Na+].[CH2:31](O)[CH3:32]>>[F:1][C:2]1[CH:3]=[C:4]([CH:16]=[CH:17][C:18]=1[F:19])[O:5][C:6]1[N:11]=[CH:10][C:9]([CH2:12][C:13]([O:15][CH2:31][CH3:32])=[O:14])=[CH:8][CH:7]=1
Reactant: O=C(O)Cc1ccc(Oc2ccc(F)c(F)c2)nc1
Reactant: CCO
Agent: O=C([O-])[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Product: CCOC(=O)Cc1ccc(Oc2ccc(F)c(F)c2)nc1
Temperature: 80 °C
Reaction time: 3 h
Yield: 78 %

Procedure:
To a solution of 2-(6-(3,4-difluorophenoxy)pyridin-3-yl)acetic acid (10 g, 37.7 mmol) in ethanol (100 mL) was added sulfuric acid (20 ml, 375 mmol) in ethanol (100 mL). The reaction mixture was stirred at 80° C. for 3 hr. and then the reaction mixture was made alkali with Na2CO3, and then extracted with CH2Cl2. The organic layer was separated and dried over Na2SO4, and then concentrated under reduced pressure to provide ethyl 2-(6-(3,4-difluorophenoxy)pyridin-3-yl)acetate (10 g, 78%).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][C@@H:10]([CH2:13][C:14]([OH:16])=O)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH:17]([C:19]1[N:20]=[C:21]2[CH:27]=[CH:26][N:25]([S:28]([C:31]3[CH:37]=[CH:36][C:34]([CH3:35])=[CH:33][CH:32]=3)(=[O:30])=[O:29])[C:22]2=[N:23][CH:24]=1)[NH2:18].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C.CCOC(C)=O>[O:16]=[C:14]([NH:18][NH:17][C:19]1[N:20]=[C:21]2[CH:27]=[CH:26][N:25]([S:28]([C:31]3[CH:37]=[CH:36][C:34]([CH3:35])=[CH:33][CH:32]=3)(=[O:30])=[O:29])[C:22]2=[N:23][CH:24]=1)[CH2:13][C@@H:10]1[CH2:11][CH2:12][N:8]([C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])[CH2:9]1
Reactant: Cc1ccc(S(=O)(=O)n2ccc3nc(NN)cnc32)cc1
Reactant: CC(C)(C)OC(=O)N1CC[C@@H](CC(=O)O)C1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: Cc1ccc(S(=O)(=O)n2ccc3nc(NNC(=O)C[C@@H]4CCN(C(=O)OC(C)(C)C)C4)cnc32)cc1
Temperature: 25 °C
Reaction time: 15 h
Yield: 111.9 %

Procedure:
To a solution of (S)-3-carboxymethyl-pyrrolidine-1-carboxylic acid tert-butyl ester (0.756 g, 3.30 mmol, AstaTech) and 2-hydrazinyl-5-tosyl-5H-pyrrolo[2,3-b]pyrazine (1.0 g, 3.3 mmol, Example #1, Step D) in DMF (33 mL) was added TEA (1.38 mL, 9.89 mmol) followed by the addition of HATU (1.25 g, 3.30 mmol). The resulting mixture was stirred at ambient temperature for about 15 h then concd under reduced pressure. The residue was taken up in EtOAc (100 mL) and washed with water (100 mL). The organic portion was separated, washed with brine (100 mL), dried over anhydrous Na2SO4, filtered, and concd under reduced pressure to give (S)-tert-butyl 3-(2-oxo-2-(2-(5-tosyl-5H-pyrrolo[2,3-b]pyrazin-2-yl)hydrazinyl)ethyl)pyrrolidine-1-carboxylate as a sticky brown solid (1.90 g, 100%). This material was used without further purification: LC/MS (Table 1, Method c) Rt=1.38 min; MS m/z: 515 (M+H)+.
Reaction SMILES: CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(C(C)C)CC)(C)C.Br.[CH2:35]1[C:38]2([CH:42]([NH:43][C:44]3[C:45]4[N:46]([CH:53]=[C:54]([C:56]5[CH:57]=[N:58][N:59]([CH3:61])[CH:60]=5)[CH:55]=4)[N:47]=[CH:48][C:49]=3[C:50]([NH2:52])=[O:51])[CH2:41][NH:40][CH2:39]2)[CH2:37][CH2:36]1.[CH:62]1([C:65]([O-])=[O:66])[CH2:64][CH2:63]1>CN(C=O)C>[CH:62]1([C:65]([N:40]2[CH2:41][C@@H:42]([NH:43][C:44]3[C:45]4[N:46]([CH:53]=[C:54]([C:56]5[CH:57]=[N:58][N:59]([CH3:61])[CH:60]=5)[CH:55]=4)[N:47]=[CH:48][C:49]=3[C:50]([NH2:52])=[O:51])[C:38]3([CH2:37][CH2:36][CH2:35]3)[CH2:39]2)=[O:66])[CH2:64][CH2:63]1
Reactant: O=C([O-])C1CC1
Reactant: Cn1cc(-c2cc3c(NC4CNCC45CCC5)c(C(N)=O)cnn3c2)cn1
Agent: Br
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cn1cc(-c2cc3c(N[C@@H]4CN(C(=O)C5CC5)CC45CCC5)c(C(N)=O)cnn3c2)cn1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A 200 uL aliquot of HATU (23.41 mg, 0.062 mmol) and diisopropylethylamine (21.51 μl, 0.123 mmol) were added to a 200 uL aliquot of 4-(6-azaspiro[3.4]octan-8-ylamino)-6-(1-methyl-1H-pyrazol-4-yl)pyrrolo[1,2-b]pyridazine-3-carboxamide HBr (from Step 6, 15 mg, 0.041 mmol) and cyclopropane carboxylate (1.5 equiv.) in DMF. The reaction was stirred for 3 h at room temperature. The crude material was purified via preparative LC/MS with the following conditions: Column: Waters XBridge C18, 19×250 mm, 5-μm particles; Guard Column: Waters XBridge C18, 19×10 mm, 5-μm particles; Mobile Phase A: 5:95 acetonitrile:water with 10-mM ammonium acetate; Mobile Phase B: 95:5 acetonitrile:water with 10-mM ammonium acetate; Gradient: 0-100% B over 25 minutes, then a 5-minute hold at 100% B; Flow: 20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation to afford the title compound (3.9 mg). 1H NMR (500 MHz, METHANOL-d4/CDCl3) δ 8.11 (d, J=11.9 Hz, 1H), 7.80 (d, J=9.9 Hz, 1H), 7.78-7.71 (m, 2H), 6.91 (dd, J=14.1, 1.7 Hz, 1H), 4.83-4.75 (m, 1H), 4.13 (dd, J=10.4, 5.0 Hz, 1H), 4.07-3.99 (m, 1H), 3.96 (s, 1.5H), 3.94 (s, 1.5H), 3.98-3.76 (m, 2H), 2.37 (dd, J=11.1, 7.2 Hz, 1H), 2.28-1.95 (m, 5H), 1.12-0.70 (m, 4H)
Reaction SMILES: [BrH:1].[CH:2]1([N:5]([C:13]2[N:18]3[N:19]=[CH:20][C:21]([CH:22]=[O:23])=[C:17]3[N:16]=[C:15]([C:24]3[CH:28]=[C:27]([CH2:29]O)[S:26][CH:25]=3)[CH:14]=2)C(=O)OC(C)(C)C)[CH2:4][CH2:3]1>ClCCl>[Br:1][CH2:29][C:27]1[S:26][CH:25]=[C:24]([C:15]2[CH:14]=[C:13]([NH:5][CH:2]3[CH2:4][CH2:3]3)[N:18]3[N:19]=[CH:20][C:21]([CH:22]=[O:23])=[C:17]3[N:16]=2)[CH:28]=1
Reactant: Br
Reactant: CC(C)(C)OC(=O)N(c1cc(-c2csc(CO)c2)nc2c(C=O)cnn12)C1CC1
Solvent: ClCCl
Product: O=Cc1cnn2c(NC3CC3)cc(-c3csc(CBr)c3)nc12
Temperature: 40 °C
Yield: 20 %

Procedure:
Hydrogen bromide (48% in water, 2.5 mL) was added dropwise to tert-butyl cyclopropyl(3-formyl-5-(5-(hydroxymethyl)thiophen-3-yl)pyrazolo[1,5-a]pyrimidine-7-yl)carbamate (561 mg, 1.35 mmol) suspended in dichloromethane (3.5 mL). The solution immediately became dark brown and homogeneous upon addition. The reaction was heated to 40° C. for 3 h, then diluted with dichloromethane (10 mL). The liquid was decanted and the gummy residue was washed with dichloromethane (3×10 mL). The combined liquids were washed successively with sat. NaHCO3 (20 mL) and brine (20 mL), and then dried over MgSO4, filtered and concentrated in vacuo. The residue was triturated with hexanes and then purified via flash column chromatography (15-40% EtOAc/hexanes) to provide 5-(5-(bromomethyl)thiophen-3-yl)-7-(cyclopropylamino)pyrazolo[1,5-a]pyrimidine-3-carbaldehyde (105 mg, 20%) as a yellow solid. 1H NMR (CDCl3, 400 MHz) δ: 10.26 (s, 1H), 8.44 (s, 1H), 8.12 (d, 1H, J=1.6 Hz), 7.80 (s, 1H), 6.73 (s, 1H), 6.65 (bs, 1H), 4.80 (s, 2H), 2.81 (m, 1H), 1.03-1.09 (m, 2H), 0.84-0.89 (m, 2H). LCMS (ES): >95% pure, m/z 378 [M+1]+.
Reaction SMILES: [C:1]([OH:9])(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[N:4][CH:3]=1.S(Cl)(Cl)=O.[CH3:14][O:15][NH:16][CH3:17].C(N(CC)CC)C>>[CH3:17][N:16]([O:15][CH3:14])[C:1](=[O:9])[C:2]1[CH:7]=[CH:6][CH:5]=[N:4][CH:3]=1
Reactant: CNOC
Reactant: O=C(O)c1cccnc1
Solvent: O=S(Cl)Cl
Solvent: CCN(CC)CC
Product: CON(C)C(=O)c1cccnc1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
A flask is charged with nicotinic acid (5.0 g, 40.6 mmol). Thionyl chloride (30.0 mL) is added and the reaction is refluxed for 1 h. It is then cooled to room temperature and concentrated in vacuo. The residue is dissolved in anhydrous dichloromethane (30 mL) and O,N-dimethyl-hydroxylamine (4.35 g, 44.0 mmol) is added, followed by addition of triethylamine (14.15 g, 100.0 mmol). The reaction mixture is stirred at room temperature for 1.5 h. It is then washed with water and the aqueous phase is extracted with dichloromethane. The combined organic layer is dried over sodium sulfate and concentrated in vacuo to afford N-methyl-N-methoxy-nicotinamide as a brown oil. MS (ESI) m/z 167.0 (M+H)+.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14](=[NH:17])[NH:15]O)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:18]([OH:21])(=[O:20])[CH3:19].C(OC(=O)C)(=O)C>[Pd]>[C:18]([OH:21])(=[O:20])[CH3:19].[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14](=[NH:15])[NH2:17])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCC(C(=N)NO)CC1
Agent: [Pd]
Solvent: CC(=O)O
Solvent: CC(=O)OC(C)=O
Product: CC(C)(C)OC(=O)N1CCC(C(=N)N)CC1
Reaction time: 7 h
Yield: 126.2 %

Procedure:
Add 10% Pd/C (0.079 g; 37.12 μmoles) to 4-(N-Hydroxycarbamimidoyl)-piperidine-1-carboxylic acid tert-butyl ester (805 mg; 1.00 equiv; 3.31 mmoles) in acetic acid (15 mL; 261.77 mmoles) and acetic acid anhydride (0.5 mL; 5.29 mmoles). Hydrogenate at room temperature for 7 hr at 20 PSI. Purge flask with nitrogen to provide 1.2 g of a foam. Triturate with acetonitrile and filter to provide 270 mg (28%) of the product as a white solid.
Reaction SMILES: C(OC([N:8]([C:13]1[CH:22]=[CH:21][C:16]([C:17]([O:19][CH3:20])=[O:18])=[CH:15][C:14]=1[O:23][CH2:24][CH:25]1[CH2:27][CH2:26]1)[S:9]([CH3:12])(=[O:11])=[O:10])=O)(C)(C)C.Cl.O1CCOCC1>C(Cl)Cl>[CH:25]1([CH2:24][O:23][C:14]2[CH:15]=[C:16]([CH:21]=[CH:22][C:13]=2[NH:8][S:9]([CH3:12])(=[O:11])=[O:10])[C:17]([O:19][CH3:20])=[O:18])[CH2:26][CH2:27]1
Reactant: COC(=O)c1ccc(N(C(=O)OC(C)(C)C)S(C)(=O)=O)c(OCC2CC2)c1
Agent: Cl
Solvent: ClCCl
Solvent: C1COCCO1
Product: COC(=O)c1ccc(NS(C)(=O)=O)c(OCC2CC2)c1
Temperature: 25 °C
Reaction time: 72 h
Yield: 96 %

Procedure:
To a solution of methyl 4-(N-(tert-butoxycarbonyl)methylsulfonamido)-3-(cyclopropylmethoxy)benzoate (for reference procedure see Example 18, WO 2010/089107, which is incorporated herein by reference) (3.00 g, 7.51 mmol) in dry DCM (40 ml), HCl 4M in Dioxane (9.39 ml, 37.6 mmol) was added, and the mixture was stirred at RT for 3 days. The solvent was evaporated, the residue was triturated with iPr2O (50 ml) and filtered to give methyl 3-(cyclopropylmethoxy)-4-(methylsulfonamido)benzoate as an off-white powder (2.15 g, 7.18 mmol, 96% yield, MS/ESI+ 299.9 [MH]+).
Reaction SMILES: [Br:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][CH:3]=1.N1C=CC=CC=1.[F:15][C:16]1[CH:24]=[CH:23][CH:22]=[C:21]([F:25])[C:17]=1[C:18](Cl)=[O:19]>C(Cl)Cl>[Br:1][C:2]1[CH:8]=[CH:7][C:5]([NH:6][C:18](=[O:19])[C:17]2[C:16]([F:15])=[CH:24][CH:23]=[CH:22][C:21]=2[F:25])=[CH:4][CH:3]=1
Reactant: Nc1ccc(Br)cc1
Reactant: O=C(Cl)c1c(F)cccc1F
Solvent: ClCCl
Solvent: c1ccncc1
Product: O=C(Nc1ccc(Br)cc1)c1c(F)cccc1F
Temperature: 0 °C
Yield: 66.3 %

Procedure:
To a stirred and 0° C. cooled solution of 4-bromoaniline (1.0 g, 5.8 mmol, 1.0 eq) and pyridine (0.61 mL, 7 mmol, 1.2 eq) in DCM (20 mL) was added drop wise a solution of 2,6-difluorobenzoyl chloride (0.8 mL, 6.4 mmol, 1.1 eq) in DCM (5 mL). After stirring the resulting mixture at the same temperature for 1 h, the solvent was removed under vacuum. The residue was taken into ethyl acetate (20 mL) and water (20 mL). The layers were separated. The aqueous layer was extracted with ethyl acetate (2×20 mL) and the combined organic layers were washed with brine (20 mL), dried (Na2SO4) and filtered. The filtrate was concentrated under vacuum to afford 1.20 g of the desired product as a white solid. 1HNMR (400 MHz, DMSO-d6) δ 7.78 (brs, 1H, D2O exchangeable), 7.53-7.37 (m, 5H), 7.02-6.95 (m, 2H); ESI-MS (m/z) 312, 314 [(MH)+ Br79,81].
Reaction SMILES: C(OC([NH:8][CH2:9][CH2:10][O:11][C:12]1[C:16]2[CH:17]=[C:18]([Cl:21])[CH:19]=[CH:20][C:15]=2[O:14][N:13]=1)=O)(C)(C)C.Cl.O1CCOCC1>>[ClH:21].[NH2:8][CH2:9][CH2:10][O:11][C:12]1[C:16]2[CH:17]=[C:18]([Cl:21])[CH:19]=[CH:20][C:15]=2[O:14][N:13]=1
Reactant: CC(C)(C)OC(=O)NCCOc1noc2ccc(Cl)cc12
Agent: Cl
Solvent: C1COCCO1
Product: NCCOc1noc2ccc(Cl)cc12
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 190.8 %

Procedure:
To 3-(2-(N-t-butoxycarbonylamino)-ethoxy)-5-chloro-1,2-benzisoxazole (0.50 g) was added a solution of 4 N-hydrochloric acid/1,4-dioxane (4.0 ml) and stirred at room temperature for 15 minutes. After filtering the precipitated crystals and washing with 1,4-dioxane, the title compound (0.38 g) was obtained as colorless crystals.