Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CO[C:3](=[O:22])[C@H:4]([CH2:6][CH2:7][CH2:8][CH2:9][NH:10][C:11]([O:13][CH2:14][C:15]1[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][CH:16]=1)=[O:12])[NH2:5].[CH3:23][N:24]=[C:25]=[S:26]>>[CH3:21][C:18]1[CH:17]=[CH:16][C:15]([CH2:14][O:13][C:11]([NH:10][CH2:9][CH2:8][CH2:7][CH2:6][CH:4]2[NH:5][C:25](=[S:26])[N:24]([CH3:23])[C:3]2=[O:22])=[O:12])=[CH:20][CH:19]=1
Reactant: CN=C=S
Reactant: COC(=O)[C@@H](N)CCCCNC(=O)OCc1ccc(C)cc1
Product: Cc1ccc(COC(=O)NCCCCC2NC(=S)N(C)C2=O)cc1

Procedure:
Using an analogous procedure to Example 1 Nε-p-methylbenzyloxycarbonyl-L-lysine methyl ester may be reacted with methyl isothiocyanate to give the title compound.
Reaction SMILES: CO[C:3](=[O:18])[C:4]([C:8](=[O:17])[C:9]1[CH:14]=[CH:13][C:12]([CH3:15])=[C:11]([CH3:16])[CH:10]=1)=[CH:5]OC.[CH3:19][C:20]1[CH:25]=[CH:24][N:23]=[CH:22][C:21]=1[NH2:26]>C1(OC2C=CC=CC=2)C=CC=CC=1>[CH3:16][C:11]1[CH:10]=[C:9]([CH:14]=[CH:13][C:12]=1[CH3:15])[C:8]([C:4]1[C:3](=[O:18])[C:22]2[C:21](=[C:20]([CH3:19])[CH:25]=[CH:24][N:23]=2)[NH:26][CH:5]=1)=[O:17]
Reactant: COC=C(C(=O)OC)C(=O)c1ccc(C)c(C)c1
Reactant: Cc1ccncc1N
Solvent: c1ccc(Oc2ccccc2)cc1
Product: Cc1ccc(C(=O)c2c[nH]c3c(C)ccnc3c2=O)cc1C
Yield: 16.1 %

Procedure:
Experimental conditions analogous to those described for Step 1 of Example 1 were used with 0.50 g (2.01 mmol) 2-(3,4-Dimethyl-benzoyl)-3-methoxy-acrylic acid methyl ester, 0.22 g (2.01 mmol) of 4-Methyl-pyridin-3-ylamine, and 30 mL of diphenyl ether to yield 94.4 mg of 3-(3,4-Dimethyl-benzoyl)-8-methyl-1H-[1,5]naphthyridin-4-one as a brown solid.
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[CH2:8]([S:10]([N:13]1[CH2:18][CH2:17][CH:16]([C:19]2[C:27]3[C:22](=[C:23]([C:38]([NH2:40])=[O:39])[CH:24]=[C:25]([C:28]4[CH:33]=[C:32]([CH2:34][NH:35][CH3:36])[CH:31]=[C:30]([F:37])[CH:29]=4)[CH:26]=3)[NH:21][CH:20]=2)[CH2:15][CH2:14]1)(=[O:12])=[O:11])[CH3:9].[CH3:41]N>>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[CH:36]1([NH:35][CH2:34][C:32]2[CH:33]=[C:28]([C:25]3[CH:26]=[C:27]4[C:22](=[C:23]([C:38]([NH2:40])=[O:39])[CH:24]=3)[NH:21][CH:20]=[C:19]4[CH:16]3[CH2:17][CH2:18][N:13]([S:10]([CH2:8][CH3:9])(=[O:11])=[O:12])[CH2:14][CH2:15]3)[CH:29]=[C:30]([F:37])[CH:31]=2)[CH2:3][CH2:2][CH2:41]1
Reactant: CN
Reactant: CCS(=O)(=O)N1CCC(c2c[nH]c3c(C(N)=O)cc(-c4cc(F)cc(CNC)c4)cc23)CC1
Solvent: O=C(O)C(F)(F)F
Product: CCS(=O)(=O)N1CCC(c2c[nH]c3c(C(N)=O)cc(-c4cc(F)cc(CNC5CCC5)c4)cc23)CC1
Yield: 75.2 %

Procedure:
The title compound was prepared according to the general procedure of 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-{3-fluoro-5-[(methylamino)methyl]phenyl}-1H-indole-7-carboxamide trifluoroacetate, substituting cyclobutylamine (21.5 mg, 0.42 mmol) for methanamine to afford 33 mg of the title compound (75.2%).
Reaction SMILES: [Cl:1][C:2]1[C:3]([O:30][C@H:31]2[CH2:35][C:34]([F:37])([F:36])[CH2:33][C@@H:32]2[C:38]2[N:42]([CH3:43])[N:41]=[CH:40][CH:39]=2)=[CH:4][C:5]([F:29])=[C:6]([S:8]([N:11](CC2C=CC(OC)=CC=2OC)[C:12]2[CH:17]=[CH:16][N:15]=[CH:14][N:13]=2)(=[O:10])=[O:9])[CH:7]=1.C([SiH](CC)CC)C.FC(F)(F)C(O)=O>ClCCl>[Cl:1][C:2]1[C:3]([O:30][C@H:31]2[CH2:35][C:34]([F:37])([F:36])[CH2:33][C@@H:32]2[C:38]2[N:42]([CH3:43])[N:41]=[CH:40][CH:39]=2)=[CH:4][C:5]([F:29])=[C:6]([S:8]([NH:11][C:12]2[CH:17]=[CH:16][N:15]=[CH:14][N:13]=2)(=[O:9])=[O:10])[CH:7]=1
Reactant: COc1ccc(CN(c2ccncn2)S(=O)(=O)c2cc(Cl)c(O[C@H]3CC(F)(F)C[C@@H]3c3ccnn3C)cc2F)c(OC)c1
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cn1nccc1[C@H]1CC(F)(F)C[C@@H]1Oc1cc(F)c(S(=O)(=O)Nc2ccncn2)cc1Cl
Yield: 98.1 %

Procedure:
The reaction and aftertreatment were conducted in the same manner as in Example 1b by using the 5-chloro-4-{[(1S*,2R*)-4,4-difluoro-2-(1-methyl-1H-pyrazol-5-yl)cyclopentyl]oxy}-N-(2,4-dimethoxybenzyl)-2-fluoro-N-(pyrimidin-4-yl)benzenesulfonamide (316 mg, 0.495 mmol) prepared in Example 146a, triethylsilane (0.30 mL), trifluoroacetic acid (2.0 mL) and dichloromethane (3.0 mL), to yield the title compound (237 mg, 98%) as a colorless solid.
Reaction SMILES: [CH3:1][O:2][C:3]([CH:5]1[CH2:9][CH2:8][S:7](=[O:11])(=[O:10])[NH:6]1)=[O:4].C(=O)([O-])[O-].[K+].[K+].[C:18]([C:20]1[CH:21]=[C:22]([CH:25]=[CH:26][CH:27]=1)[CH2:23]Br)#[N:19].C([N+](CCCC)(CCCC)CCCC)CCC>CN(C)C=O.C(OCC)(=O)C>[CH3:1][O:2][C:3]([CH:5]1[CH2:9][CH2:8][S:7](=[O:11])(=[O:10])[N:6]1[CH2:23][C:22]1[CH:25]=[CH:26][CH:27]=[C:20]([C:18]#[N:19])[CH:21]=1)=[O:4]
Reactant: COC(=O)C1CCS(=O)(=O)N1
Reactant: N#Cc1cccc(CBr)c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COC(=O)C1CCS(=O)(=O)N1Cc1cccc(C#N)c1
Temperature: 0 °C
Reaction time: 5 h
Yield: 52.5 %

Procedure:
To a stirred solution of 1,1-dioxo-1λ6-isothiazolidine-3-carboxylic acid methyl ester (Intermediate 1, 0.200 g, 1.10 mmol) in N,N-dimethylformamide (5 mL) was added potassium carbonate (0.450 g, 3.20 mmol) at room temperature under nitrogen. The reaction mixture was cooled to 0° C. and 3-cyano benzyl bromide (available from Aldrich; 0.240 g, 1.22 mmol) was added into the reaction mixture slowly and followed by the addition of tetra-n-butylammonium (0.025 g, 0.07 mmol). The reaction was completed in 5 h at room temperature as monitored by silica TLC. The reaction mixture was diluted with ethyl acetate (25 mL), washed with water (3×15 mL), dried over sodium sulfate and concentrated under reduced pressure to provide crude material, which was purified by silica gel column chromatography (100-200 mesh) using a gradient of 20-30% ethyl acetate/hexanes to give 2-(3-cyano-benzyl)-1,1-dioxo-1λ6-isothiazolidine-3-carboxylic acid methyl ester (0.170 g, 56%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]2=[C:6]([CH:34]=1)[O:7][CH2:8][C:9]1[CH:33]=[CH:32][CH:31]=[CH:30][C:10]=1/[C:11]/2=[CH:12]\[C:13]1[CH:18]=[CH:17][C:16]([NH:19][C@H:20]2[CH2:24][N:23]([CH3:25])[CH2:22][C@@H:21]2[OH:26])=[C:15]([N+:27]([O-])=O)[CH:14]=1.C(N(CC)CC)C.C1C=CC(O[C:49](OC2C=CC=CC=2)=[N:50][C:51]#[N:52])=CC=1>C(O)(C)C.[Pt]>[F:1][C:2]1[CH:3]=[CH:4][C:5]2=[C:6]([CH:34]=1)[O:7][CH2:8][C:9]1[CH:33]=[CH:32][CH:31]=[CH:30][C:10]=1/[C:11]/2=[CH:12]\[C:13]1[CH:18]=[CH:17][C:16]2[N:19]([C@@H:20]3[C@@H:21]([OH:26])[CH2:22][N:23]([CH3:25])[CH2:24]3)/[C:49](=[N:50]/[C:51]#[N:52])/[NH:27][C:15]=2[CH:14]=1
Reactant: N#CN=C(Oc1ccccc1)Oc1ccccc1
Reactant: CN1C[C@H](Nc2ccc(/C=C3\c4ccccc4COc4cc(F)ccc43)cc2[N+](=O)[O-])[C@@H](O)C1
Agent: [Pt]
Solvent: CCN(CC)CC
Solvent: CC(C)O
Product: CN1C[C@H](O)[C@@H](n2/c(=N/C#N)[nH]c3cc(/C=C4\c5ccccc5COc5cc(F)ccc54)ccc32)C1
Reaction time: 1.5 h
Yield: 64 %

Procedure:
To a solution of (3S,4S)-4-(4-((E)-(3-fluorodibenzo[b,e]oxepin-11(6H)-ylidene)methyl)-2-nitrophenylamino)-1-methylpyrrolidin-3-ol (3.10 mmol, 1.43 g) in isopropanol (85 mL) and triethylamine (9.3 mmol, 1.30 mL) add 5% Pt/C (420 mg) and hydrogenate at 50 psi for 1.5 h. Filter through a plug of diatomaceous earth and wash with isopropanol (50 mL). Add diphenyl cyanocarbonimidate (3.1 mmol, 0.74 g) and stir at room temperature overnight, then heat to reflux for 3 h. Remove the solvent and purify the residue by column chromatography eluting with a gradient from 0% to 20% methanol in methylene chloride to give the title compound as a light brown solid (955 mg, 57%). [α]D23+13.8 (c 0.17, CH3OH); ESI MS m/z 482 [M+H]+.
Reaction SMILES: [CH:1]1([N:6]2[CH2:12][C:11]([F:14])([F:13])[C:10](=[O:15])[N:9]([CH3:16])[C:8]3[CH:17]=[N:18][C:19]([NH:21][C:22]4[CH:30]=[CH:29][C:25]([C:26]([OH:28])=O)=[C:24]([O:31][CH3:32])[CH:23]=4)=[N:20][C:7]2=3)[CH2:5][CH2:4][CH2:3][CH2:2]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH3:57][N:58]1[CH2:63][CH2:62][CH:61]([NH2:64])[CH2:60][CH2:59]1>>[CH:1]1([N:6]2[CH2:12][C:11]([F:14])([F:13])[C:10](=[O:15])[N:9]([CH3:16])[C:8]3[CH:17]=[N:18][C:19]([NH:21][C:22]4[CH:30]=[CH:29][C:25]([C:26]([NH:64][CH:61]5[CH2:62][CH2:63][N:58]([CH3:57])[CH2:59][CH2:60]5)=[O:28])=[C:24]([O:31][CH3:32])[CH:23]=4)=[N:20][C:7]2=3)[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: CN1CCC(N)CC1
Reactant: COc1cc(Nc2ncc3c(n2)N(C2CCCC2)CC(F)(F)C(=O)N3C)ccc1C(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Product: COc1cc(Nc2ncc3c(n2)N(C2CCCC2)CC(F)(F)C(=O)N3C)ccc1C(=O)NC1CCN(C)CC1

Procedure:
The title compound was synthesized from 4-(9-cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-2-methoxybenzoic acid as described in the general procedure for amide bond synthesis using HATU and 1-methylpiperidin-4-amine. The final compound was purified by reverse phase HPLC. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.48-2.22 (m, 14H) 2.66-2.88 (m, 2H) 3.05 (m, 2H) 3.33 (s, 3H) 3.46 (d, J=11 Hz, 2H) 3.86 (s, 3H) 4.05 (t, J=14 Hz, 3H) 4.81 (m, 1H) 7.49 (m, 2H) 7.64 (m, 1H) 7.93 (d, J=7 Hz, 1H) 8.28 (s, 1H) 9.69 (s, 1H). [M+H] calc'd for C27H35F2N7O3, 544. found 544.
Reaction SMILES: C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1.O1[C:22]2([CH2:27][CH2:26][N:25]([C:28]([N:30]3[CH2:35][CH:34]([C:36]4[CH:41]=[CH:40][C:39]([C:42]([F:45])([F:44])[F:43])=[CH:38][CH:37]=4)[CH2:33][CH:32]([NH:46][C:47]([CH:49]4[CH2:53][CH2:52][CH2:51][CH2:50]4)=[O:48])[CH2:31]3)=[O:29])[CH2:24][CH2:23]2)[O:21]CC1>CC(C)=O.O>[O:21]=[C:22]1[CH2:27][CH2:26][N:25]([C:28]([N:30]2[CH2:35][CH:34]([C:36]3[CH:41]=[CH:40][C:39]([C:42]([F:45])([F:43])[F:44])=[CH:38][CH:37]=3)[CH2:33][CH:32]([NH:46][C:47]([CH:49]3[CH2:53][CH2:52][CH2:51][CH2:50]3)=[O:48])[CH2:31]2)=[O:29])[CH2:24][CH2:23]1
Reactant: O=C(NC1CC(c2ccc(C(F)(F)F)cc2)CN(C(=O)N2CCC3(CC2)OCCO3)C1)C1CCCC1
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: CC(C)=O
Solvent: O
Product: O=C1CCN(C(=O)N2CC(NC(=O)C3CCCC3)CC(c3ccc(C(F)(F)F)cc3)C2)CC1

Procedure:
14.3 mg of pyridinium p-toluenesulphonate (0.057 mmol) were added to a solution of the acetal from Example 63A (97.2 mg, 0.191 mmol) in 5.5 ml of acetone/water (10:1), and the mixture was stirred under reflux overnight. Another 14.3 mg of pyridinium p-toluenesulphonate (0.057 mmol) were added, and the mixture was stirred under reflux for another night. The mixture was then cooled, and the precipitate formed was filtered off. Yield: 66.2 mg (74% of theory)
Reaction SMILES: C(OC([NH:8][CH2:9][CH:10]([CH3:31])[CH2:11][N:12]1[C:20]2[C:15](=[CH:16][CH:17]=[C:18]([C:21]([O:23][CH2:24][CH3:25])=[O:22])[CH:19]=2)[CH:14]=[C:13]1[C:26](OCC)=[O:27])=O)(C)(C)C.N1C2C(=CC=C(C(OCC)=O)C=2)C=C1C(OCC)=O.C(O)(C(F)(F)F)=O.C(N(CC)CC)C.C([O-])([O-])=O.[K+].[K+]>C(Cl)Cl.C(O)C.O>[CH3:31][CH:10]1[CH2:11][N:12]2[C:20]3[CH:19]=[C:18]([C:21]([O:23][CH2:24][CH3:25])=[O:22])[CH:17]=[CH:16][C:15]=3[CH:14]=[C:13]2[C:26](=[O:27])[NH:8][CH2:9]1
Reactant: CCOC(=O)c1ccc2cc(C(=O)OCC)n(CC(C)CNC(=O)OC(C)(C)C)c2c1
Agent: CCOC(=O)c1ccc2cc(C(=O)OCC)[nH]c2c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O=C(O)C(F)(F)F
Solvent: O
Solvent: CCN(CC)CC
Product: CCOC(=O)c1ccc2cc3n(c2c1)CC(C)CNC3=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 66 %

Procedure:
To a mixture of diethyl 1-{3-[(tert-butoxycarbonyl)amino]-2-methylpropyl}-1H-indole-2,6-dicarboxylate and diethyl 1H-indole-2,6-dicarboxylate (3.2 g, 7.4 mmol) in CH2Cl2 (70 mL) is added TFA (30 mL). The mixture is stirred at room temperature for 2 h. The reaction is concentrated and the residue is dried in vacuo for 1 h. To a solution of the residue in ethanol (150 mL) are added triethylamine (3.1 mL, 22.2 mmol) and K2CO3 (6.1 g, 44.2 mmol). The mixture is heated at 80° C. for 5 h. Water (300 mL) is added and the mixture is extracted with EtOAc (3×200 mL). The organic layers are combined, dried (Na2SO4) and concentrated and the crude compound is purified by flash column chromatography to afford the title compound (1.4 g, 66% for 3 steps).
Reaction SMILES: C(OC(=O)[NH:7][C@@H:8]([CH:32]1[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]1)[C:9]([N:11]1[CH2:20][CH2:19][C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[C@H:12]1[C:21](=[O:31])[NH:22][C:23]1[C:28]([F:29])=[CH:27][CH:26]=[CH:25][C:24]=1[F:30])=[O:10])(C)(C)C.[C:39]([OH:45])([C:41]([F:44])([F:43])[F:42])=[O:40]>C(Cl)Cl>[F:42][C:41]([F:44])([F:43])[C:39]([OH:45])=[O:40].[F:30][C:24]1[CH:25]=[CH:26][CH:27]=[C:28]([F:29])[C:23]=1[NH:22][C:21]([C@@H:12]1[C:13]2[C:18](=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH2:19][CH2:20][N:11]1[C:9](=[O:10])[C@@H:8]([NH2:7])[CH:32]1[CH2:33][CH2:34][CH2:35][CH2:36][CH2:37]1)=[O:31]
Reactant: CC(C)(C)OC(=O)N[C@H](C(=O)N1CCc2ccccc2[C@H]1C(=O)Nc1c(F)cccc1F)C1CCCCC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: N[C@H](C(=O)N1CCc2ccccc2[C@H]1C(=O)Nc1c(F)cccc1F)C1CCCCC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of {(S)-1-cyclohexyl-2-[(S)-1-(2,6-difluoro-phenylcarbamoyl)-3,4-dihydro-1H-isoquinolin-2-yl]-2-oxo-ethyl}-carbamic acid tert-butyl ester (62 mg, 118 μmol, Eq: 1.00) in CH2Cl2 (3 mL) was added TFA (1 mL) dropwise. The reaction was stirred at RT for 1 h. The mixture was evaporated to afford (S)-2-((S)-2-amino-2-cyclohexyl-acetyl)-1,2,3,4-tetrahydro-isoquinoline-1-carboxylic acid (2,6-difluoro-phenyl)-amide trifluoroacetate which was used without further purification.
Reaction SMILES: NC1C=C([NH:8][C:9]2[N:14]=[C:13]([NH:15]C3C=CC=C(N)C=3)[C:12]([F:23])=[CH:11][N:10]=2)C=CC=1.C(OCCBr)C1C=CC=CC=1>>[F:23][C:12]1[C:13]([NH2:15])=[N:14][C:9]([NH2:8])=[N:10][CH:11]=1
Reactant: Nc1cccc(Nc2ncc(F)c(Nc3cccc(N)c3)n2)c1
Agent: BrCCOCc1ccccc1
Product: Nc1ncc(F)c(N)n1

Procedure:
In like manner to the preparation of N2,N4-bis(3-tert-butoxycarbonylmethyleneaminophenyl)-5-fluoro-2,4-pyrimidinediamine, N2,N4-bis(3-aminophenyl)-5-fluoro-2,4-pyrimidinediamine and 1-benzyloxy-2-bromoethane were reacted together to give N2,N4-bis[3-N-benzyloxyethyleneamino)phenyl]-5-fluoro-2,4-pyrimidinediamine. LCMS: ret. time: 32.92 min.; MS (m/e): 579.17 (MH+).
Reaction SMILES: [C:1]([C:3]1([C:9]2[CH:10]=[C:11]([S:15][C:16]3[CH:21]=[CH:20][C:19]([NH:22][C:23](NN)=[O:24])=[CH:18][CH:17]=3)[CH:12]=[CH:13][CH:14]=2)[CH2:8][CH2:7][O:6][CH2:5][CH2:4]1)#[N:2].Cl.[C:28]([NH2:31])(=[NH:30])[CH3:29]>>[CH3:29][C:28]1[NH:31][C:23](=[O:24])[N:22]([C:19]2[CH:20]=[CH:21][C:16]([S:15][C:11]3[CH:10]=[C:9]([C:3]4([C:1]#[N:2])[CH2:8][CH2:7][O:6][CH2:5][CH2:4]4)[CH:14]=[CH:13][CH:12]=3)=[CH:17][CH:18]=2)[N:30]=1
Reactant: N#CC1(c2cccc(Sc3ccc(NC(=O)NN)cc3)c2)CCOCC1
Reactant: CC(=N)N
Agent: Cl
Product: Cc1nn(-c2ccc(Sc3cccc(C4(C#N)CCOCC4)c3)cc2)c(=O)[nH]1
Temperature: 120 °C

Procedure:
A mixture of N-(4-{[3-(4-cyanotetrahydro-2H-pyran-4-yl)phenyl]thio}phenyl) hydrazinecarboxamide (1.0 g, 2.72 mmol) (example 6) and acetamidine hydrochloride (1.16 g, 12.22 mmol) was evacuated for about 15 minutes. Dry dimethylformamide (10 mL) was added under nitrogen atmosphere and the mixture was heated at about 120° C. for about 7-8 hours. The solvent was evaporated under vacuum and a saturated solution of potassium carbonate was added until the mixture became basic. The resulting mixture was extracted with ethyl acetate, washed with water, dried over anhydrous sodium sulphate, filtered and the solvent evaporated under vacuum to afford a colorless oily residue, which was purified by column chromatography over silica gel using ethyl acetate and hexane (4:1) to yield the title product as a white fluffy solid. Yield: 0.500 g.
Reaction SMILES: [CH3:1][N:2]([CH:4]=[N:5][C:6]1[CH:11]=[CH:10][N:9]=[CH:8][C:7]=1[OH:12])[CH3:3].CN[CH2:15][CH2:16][CH2:17]C.S([O-])([O-])(=O)=O.[NH4+].[NH4+]>C1(C)C=CC=CC=1>[CH3:3][N:2]([CH:4]=[N:5][C:6]1[CH:11]=[CH:10][N:9]=[CH:8][C:7]=1[OH:12])[CH2:1][CH2:15][CH2:16][CH3:17]
Reactant: CCCCNC
Reactant: CN(C)C=Nc1ccncc1O
Agent: O=S(=O)([O-])[O-]
Agent: [NH4+]
Solvent: Cc1ccccc1
Product: CCCCN(C)C=Nc1ccncc1O
Yield: 64.2 %

Procedure:
A mixture of 4-[[(dimethylamino)methylene]amino]-3-pyridinol (7.50 g), N-methylbutylamine (8.10 g), ammonium sulfate (0.600 g), and anhydrous toluene (25 mL) was heated at reflux under nitrogen for 2.25 hours. The solution was concentrated under reduced pressure and the crude product chromatographed on silica gel (10% methanol in dichloromethane) to afford 6.04 g of solid. Recrystallization from ethyl acetate/hexanes afforded 3.90 g of a crystalline material, m.p. 83°-85° C.
Reaction SMILES: [CH:1]1([C:4]2[N:8]([C:9]3[CH:14]=[CH:13][CH:12]=[C:11]([C:15]([F:18])([F:17])[F:16])[CH:10]=3)[N:7]=[C:6]([CH3:19])[C:5]=2[C:20]([N:22]2[CH2:27][CH2:26][C:25](=O)[CH2:24][CH2:23]2)=[O:21])[CH2:3][CH2:2]1.[OH:29][C@@H:30]1[CH2:34][CH2:33][NH:32][CH2:31]1>>[CH:1]1([C:4]2[N:8]([C:9]3[CH:14]=[CH:13][CH:12]=[C:11]([C:15]([F:18])([F:17])[F:16])[CH:10]=3)[N:7]=[C:6]([CH3:19])[C:5]=2[C:20]([N:22]2[CH2:23][CH2:24][CH:25]([N:32]3[CH2:33][CH2:34][C@@H:30]([OH:29])[CH2:31]3)[CH2:26][CH2:27]2)=[O:21])[CH2:2][CH2:3]1
Reactant: O[C@@H]1CCNC1
Reactant: Cc1nn(-c2cccc(C(F)(F)F)c2)c(C2CC2)c1C(=O)N1CCC(=O)CC1
Product: Cc1nn(-c2cccc(C(F)(F)F)c2)c(C2CC2)c1C(=O)N1CCC(N2CC[C@@H](O)C2)CC1

Procedure:
The title compound was prepared from 1-[5-Cyclopropyl-3-methyl-1-(3-trifluoromethyl-phenyl)-1H-pyrazole-4-carbonyl]-piperidin-4-one (Example 181B) and (R)-3-hydroxyl-pyrrolidine in direct analogy to the general procedure used in example 129. MS: 463.3 (MH+).
Reaction SMILES: [N:1]([CH:4]1[CH2:10][O:9][CH:8]([C:11]2[N:15]([CH3:16])[N:14]=[CH:13][C:12]=2[N+:17]([O-])=O)[CH2:7][C:6]([F:21])([F:20])[CH2:5]1)=[N+:2]=[N-:3].[Cl-].[NH4+].[NH2:24][C:25]1[S:29][C:28]([C:30]2[C:35]([F:36])=[CH:34][CH:33]=[CH:32][C:31]=2[F:37])=[N:27][C:26]=1[C:38](O)=[O:39].CCN(C(C)C)C(C)C.CCCP(=O)=O>CCO.[Fe].O>[NH2:24][C:25]1[S:29][C:28]([C:30]2[C:35]([F:36])=[CH:34][CH:33]=[CH:32][C:31]=2[F:37])=[N:27][C:26]=1[C:38]([NH:17][C:12]1[CH:13]=[N:14][N:15]([CH3:16])[C:11]=1[CH:8]1[CH2:7][C:6]([F:21])([F:20])[CH2:5][CH:4]([N:1]=[N+:2]=[N-:3])[CH2:10][O:9]1)=[O:39]
Reactant: Nc1sc(-c2c(F)cccc2F)nc1C(=O)O
Reactant: Cn1ncc([N+](=O)[O-])c1C1CC(F)(F)CC(N=[N+]=[N-])CO1
Agent: [Fe]
Agent: CCCP(=O)=O
Agent: [Cl-]
Solvent: CCO
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: Cn1ncc(NC(=O)c2nc(-c3c(F)cccc3F)sc2N)c1C1CC(F)(F)CC(N=[N+]=[N-])CO1
Temperature: 80 °C
Reaction time: 1 h

Procedure:
To a solution of 5-(6-azido-4,4-difluoro-oxepan-2-yl)-1-methyl-4-nitro-pyrazole (69 mg, 0.23 mmol) in EtOH (2.3 mL) was added ammonium chloride (61 mg 1.14 mmol) and water (0.23 mL) followed by iron powder (51 mg, 0.9 μmol). The reaction mixture was heated at 80° C. for 6 hr and then recharged with the same amounts of iron and ammonium chloride. Heating was continued for 60 min and the reaction mixture was cooled to room temperature. The crude slurry was filtered through Celite® washing with DCM (20 mL). The solution was passed through a phase separation cartridge and concentrated under reduced pressure. The crude residue was dissolved in MeOH (1 mL) and 5-amino-2-(2,6-difluorophenyl)thiazole-4-carboxylic acid (94 mg, 0.37 mmol) and DIPEA (0.24 mL, 1.40 mmol) were added. Propylphosphonic anhydride solution (50% wt in EtOAc, 0.19 mL, 0.39 mmol) was added dropwise and the reaction mixture was stirred at room temperature for 16 hr. The reaction mixture was concentrated under reduced pressure and the residue dissolved in EtOAc (10 mL). The organic layer was washed with 1 M aqueous NaOH (3×10 mL), 1 M aqueous HCl (2×10 mL), brine (10 mL), dried over Na2SO4 and concentrated under reduced pressure. Purification via silica gel chromatography (0-5% 7 M NH3 in MeOH/DCM) and preparative HPLC gave 5-amino-N-(5-(6-azido-4,4-difluorooxepan-2-yl)-1-methyl-1H-pyrazol-4-yl)-2-(2,6-difluorophenyl)thiazole-4-carboxamide as a colourless oil. The compound was dissolved in MeOH (10 mL) and passed through the H-Cube® (full H2, 70° C., flow rate: 1 mL/min, 30 mm 10% Pd/C cartridge). Purification via silica gel column chromatography (0-10% MeOH/DCM, 1% 7 M NH3 in MeOH) gave 114 (Diastereomer 1) as a colourless solid (2 mg, 2% over three steps). 1H NMR (400 MHz, CDCl3) δ 9.39 (s, 1H), 8.07 (s, 1H), 7.45-7.18 (m, 1H), 7.05-6.98 (m, 2H), 6.16 (s, 2H), 4.97-4.88 (m, 1H), 4.32-4.23 (m, 1H), 3.83 (s, 3H), 3.54-3.42 (m, 2H), 2.74-2.44 (m, 3H), 2.36-2.20 (m, 1H), 1.31-1.14 (m, 2H). LCMS (ES+) m/z 485 (M+1).
Reaction SMILES: [Si]([O:8][C@H:9]([C:34]1[CH:39]=[CH:38][C:37]([OH:40])=[C:36]([CH2:41][OH:42])[CH:35]=1)[CH2:10][NH:11][C:12]([CH3:33])([CH3:32])[CH2:13][C:14]1[CH:15]=[C:16]([CH:29]=[CH:30][CH:31]=1)[C:17]([NH:19][CH2:20][CH2:21][C:22]1[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][CH:23]=1)=[O:18])(C(C)(C)C)(C)C.[F-].[NH4+]>CO.O>[Cl:28][C:25]1[CH:26]=[CH:27][C:22]([CH2:21][CH2:20][NH:19][C:17](=[O:18])[C:16]2[CH:29]=[CH:30][CH:31]=[C:14]([CH2:13][C:12]([NH:11][CH2:10][C@H:9]([OH:8])[C:34]3[CH:39]=[CH:38][C:37]([OH:40])=[C:36]([CH2:41][OH:42])[CH:35]=3)([CH3:33])[CH3:32])[CH:15]=2)=[CH:23][CH:24]=1
Reactant: CC(C)(Cc1cccc(C(=O)NCCc2ccc(Cl)cc2)c1)NC[C@H](O[Si](C)(C)C(C)(C)C)c1ccc(O)c(CO)c1
Agent: [F-]
Agent: [NH4+]
Solvent: O
Solvent: CO
Product: CC(C)(Cc1cccc(C(=O)NCCc2ccc(Cl)cc2)c1)NC[C@H](O)c1ccc(O)c(CO)c1
Yield: 83.6 %

Procedure:
3-{2-[(2R)-2-(tert-butydimethylsilanyloxy)-2-(4-hydroxy-3-hydroxymethyl-phenyl)ethylamino]-2-methylpropyl}-N-[2-(4-chlorophenyl)ethyl]benzamide (Preparation 38) (470 mg, 0.77 mmol) and ammonium fluoride (280 mg, 7.70 mmol) in methanol (3 ml) and water (1.7 ml) were heated to 43° C. for 18 hours. The solvent was removed in vacuo and the product purified by flash column chromatography on silica gel eluting with dichloromethane:methanol:ammonia (95:5:0.5 by volume). The resulting compound was taken up in methanol and evaporated (×3) to yield a white foam (320 mg). A small sample was recrystallised (hexane:ethyl acetate) to give a white solid (mp 139-140° C.).
Reaction SMILES: [CH3:1][N:2]=[C:3]=[O:4].C(O[CH:8](OCC)[CH2:9][NH:10][CH2:11][C:12]#[CH:13])C>CCOCC>[CH3:1][N:2]1[CH:8]=[CH:9][N:10]([CH2:11][C:12]#[CH:13])[C:3]1=[O:4]
Reactant: CN=C=O
Reactant: C#CCNCC(OCC)OCC
Solvent: CCOCC
Product: C#CCn1ccn(C)c1=O
Temperature: 50 °C
Yield: 77.1 %

Procedure:
Methyl isocyanate (1.3 g, 0.02 mol) was added to a stirred solution of 2,2-diethoxy-N-(2-propynyl)ethylamine (3.4 g, 0.02 mol) in ether (50 mL). After 30 min the ether was evaporated and the residue was dissolved in water (50 mL), oxalic acid (1.7 g) was added, and the solution was heated at 50° C. for 30 min. The solution was then concentrated to 10 mL and neutralized with 4N NaOH solution, and extracted with ethyl acetate (4×50 mL). The ethyl acetate was evaporated and the residue was chromatographed on silica gel to give 2.1 g of product which was recrystallized from ethyl acetate:Skellysolve B; m.p. 69°-72° C.
Reaction SMILES: Br[C:2]1[C:3]([Cl:23])=[C:4]([C:7]2[N:11]3[N:12]=[C:13]([CH3:21])[CH:14]=[C:15]([CH:16]([CH2:19][CH3:20])[CH2:17][CH3:18])[C:10]3=[N:9][C:8]=2[CH3:22])[S:5][CH:6]=1.[N:24]1[CH:29]=[CH:28][C:27](B(O)O)=[CH:26][CH:25]=1.C([O-])([O-])=O.[Na+].[Na+].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.Cl.CCO>C(OCC)(=O)C.CC([O-])=O.CC([O-])=O.[Pd+2].C(O)CC>[ClH:23].[Cl:23][C:3]1[C:2]([C:27]2[CH:28]=[CH:29][N:24]=[CH:25][CH:26]=2)=[CH:6][S:5][C:4]=1[C:7]1[N:11]2[N:12]=[C:13]([CH3:21])[CH:14]=[C:15]([CH:16]([CH2:19][CH3:20])[CH2:17][CH3:18])[C:10]2=[N:9][C:8]=1[CH3:22]
Reactant: CCC(CC)c1cc(C)nn2c(-c3scc(Br)c3Cl)c(C)nc12
Reactant: OB(O)c1ccncc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cl
Solvent: CCCO
Solvent: CCO
Solvent: CCOC(C)=O
Product: CCC(CC)c1cc(C)nn2c(-c3scc(-c4ccncc4)c3Cl)c(C)nc12
Temperature: 90 °C
Yield: 111.5 %

Procedure:
A solution of 3-(4-bromo-3-chloro-thiophen-2-yl)-8-(1-ethyl-propyl)-2,6-dimethyl-imidazo[1,2-b]pyridazine (0.25 g, 0.61 mmol), 4-pyridyl-boronic acid (0.82, 0.67 mmol), a 2 M solution of Na2CO3 (0.5 mL, 0.91 mmol), and n-PrOH (2.5 mL) are degassed with nitrogen for 10 minutes. Pd(OAc)2 (0.0027 g, 0.012 mmol) and PPh3 (0.0095 g, 0.036 mmol) are added, and the solution heated at a 90° C. overnight. The solution is diluted with ethyl acetate (40 mL) and washed with a 10% solution of Na2CO3 (30 mL). The organic layer is dried over MgSO4, filtered, and concentrated. The residue is purified by ISCO flash chromatography (20%-30% EtOAc gradient). The resulting product is dissolved in dichloromethane (5 mL), treated with a 1 M solution of HCl in EtOH (0.35 mL, 0.35 mmol), and concentrated. The residue is recrystallized from acetonitrile and ethyl acetate furnish the title compound (0.15 g, 0.34 mmol, 56%). 1H-NMR (CDCl3), δ 0.95 (t, J=7.5 Hz, 6H), 1.73-1.88 (m, 2H), 1.89-2.04 (m, 2H), 2.68 (s, 3H), 2.82 (s, 3H), 3.87-3.97 (m, 1H), 7.28 (s, 1H), 8.26-8.34 (m, 3H), 8.95 (d, J=5.3 Hz, 2H) ppm. LC/MS (m/z): calcd. for C22H24Cl2N4S (M+H)+: 411.1; found: 411.2.