Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([N:14]2[CH:18]=[C:17]([C:19]3[CH:20]=[N:21][C:22]([NH2:34])=[C:23](B4OC(C)(C)C(C)(C)O4)[CH:24]=3)[CH:16]=[N:15]2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:35]1[C:44]2[C:39](=[CH:40][CH:41]=[CH:42][CH:43]=2)[CH2:38][CH2:37][NH:36]1.N1C=CC=CC=1.C(Cl)Cl>>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][CH:11]([N:14]2[CH:18]=[C:17]([C:19]3[CH:20]=[N:21][C:22]([NH2:34])=[C:23]([N:36]4[CH2:37][CH2:38][C:39]5[C:44](=[CH:43][CH:42]=[CH:41][CH:40]=5)[CH2:35]4)[CH:24]=3)[CH:16]=[N:15]2)[CH2:12][CH2:13]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCC(n2cc(-c3cnc(N)c(B4OC(C)(C)C(C)(C)O4)c3)cn2)CC1
Reactant: c1ccc2c(c1)CCNC2
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCC(n2cc(-c3cnc(N)c(N4CCc5ccccc5C4)c3)cn2)CC1
Temperature: 25 °C

Procedure:
A mixture of 4-{4-[6-Amino-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyridin-3-yl]-pyrazol-1-yl}-piperidine-1-carboxylic acid tert-butyl ester (BB4) (93.9 mg, 0.200 mmol), 1,2,3,4-tetrahydroisoquinoline (53.3 mg, 0.400 mmol), cupric acetate (36.3 mg, 0.200 mmol), pyridine (32 μL, 0.40 mmol) and DCM (5 mL, 80 mmol) was stirred at rt under an atmosphere of air (Reaction A). Another reaction was set up with the same amount of above reagents, and 4 Å molecular sieves (53 mg, 264 mg/mmol SM) was added (Reaction B). After stirring overnight at rt, the same amount of molecular sieve as in reaction B was added to reaction A. After stirring at rt for 7 h, both reaction mixtures were combined, washed with EDTA solution (2%, 3×30 ml), water (30 ml) and brine (30 ml), dried over MgSO4, filtered, and concentrated in vacuo to give a dark-blue solid. Purification by prep. TLC eluting with 5% MeOH/DCM gave 4-{4-[6-amino-5-(3,4-dihydro-1H-isoquinolin-2-yl)-pyridin-3-yl]-pyrazol-1-yl}-piperidine-1-carboxylic acid tert-butyl ester as brown oil; MS(ES+): m/z=475.12 [MH+]. This brown oil was dissolved in MeOH (10 mL), 1.0 M of HCl in Et2O (10 mL) was added, and the solution was stirred at rt for 3 d. The solvent was removed; the residue was dissolved in DMSO and purified by Gilson HPLC to give the title compound as light-brown oil. 1H NMR (400 MHz, DMSO-d6): δ=1.99-2.11 (m, 2H), 2.12-2.19 (m, 2H), 2.89-2.99 (m, 2H), 3.00-3.05 (m, 2H), 3.12-3.18 (m, 2H), 3.26-3.33 (m, 2H), 4.10 (s, 2H), 4.33-4.43 (m, 1H), 5.51 (brs, 2H), 7.13-7.19 (m, 4H), 7.47 (d, J=2.0 Hz, 1H), 7.82 (s, 1H), 7.99 (d, J=2.0 Hz, 1H), 8.13 (s, 1H), 8.30 (brs, 2H). MS(ES+): m/z=375.17 (42) [MH+]. HPLC: tR=1.73 min (ZQ2, polar—5 min).
Reaction SMILES: [CH3:1][CH2:2][C@@H:3]([C@@H:5]1[NH:34][C:32](=[O:33])[CH2:31][NH:30][C:28](=[O:29])[C@H:27]2[NH:35][C:36]([C@H:38]([C@H:58]([C@@H:60]([OH:63])[CH2:61][OH:62])[CH3:59])[NH:39][C:40]([C@H:42]3[N:46]([C:47]([C@H:49]([CH2:53][C:54]([NH2:56])=[O:55])[NH:50][C:51](=[O:52])[C@@H:13]([CH2:14][S+:15]([O-:64])[C:16]4[NH:24][C:23]5[CH:22]=[C:21]([OH:25])[CH:20]=[CH:19][C:18]=5[C:17]=4[CH2:26]2)[NH:12][C:10](=[O:11])[CH2:9][NH:8][C:6]1=[O:7])=[O:48])[CH2:45][C@H:44]([OH:57])[CH2:43]3)=[O:41])=[O:37])[CH3:4].[O:65]=P12OP3(OP(OP(O3)(O1)=O)(=O)O2)=O.[C:79]1(=[O:86])[O:85][C:83](=[O:84])[CH2:82][CH2:81][CH2:80]1>N1C=CC=CC=1>[CH3:1][CH2:2][C@@H:3]([C@@H:5]1[NH:34][C:32](=[O:33])[CH2:31][NH:30][C:28](=[O:29])[C@H:27]2[NH:35][C:36]([C@H:38]([C@H:58]([C@@H:60]([OH:63])[CH2:61][OH:62])[CH3:59])[NH:39][C:40]([C@H:42]3[N:46]([C:47]([C@H:49]([CH2:53][C:54]([NH2:56])=[O:55])[NH:50][C:51](=[O:52])[C@@H:13]([CH2:14][S+:15]([O-:64])[C:16]4[NH:24][C:23]5[CH:22]=[C:21]([OH:25])[CH:20]=[CH:19][C:18]=5[C:17]=4[CH2:26]2)[NH:12][C:10](=[O:11])[CH2:9][NH:8][C:6]1=[O:7])=[O:48])[CH2:45][C@H:44]([OH:57])[CH2:43]3)=[O:41])=[O:37])[CH3:4].[C:79]([O-:85])(=[O:86])[CH2:80][CH2:81][CH2:82][C:83]([O-:65])=[O:84]
Reactant: O=P12OP3(=O)OP(=O)(O1)OP(=O)(O2)O3
Reactant: O=C1CCCC(=O)O1
Agent: CC[C@H](C)[C@@H]1NC(=O)CNC(=O)[C@@H]2Cc3c([nH]c4cc(O)ccc34)[S+]([O-])C[C@@H](NC(=O)CNC1=O)C(=O)N[C@@H](CC(N)=O)C(=O)N1C[C@H](O)C[C@H]1C(=O)N[C@@H]([C@@H](C)[C@@H](O)CO)C(=O)N2
Solvent: c1ccncc1
Product: O=C([O-])CCCC(=O)[O-]

Procedure:
3.0 mg (3.3 μmol) of α-amanitin, dried in vacuo over P4O10 was dissolved in 0.25 ml of dry pyridine and reacted with 0.9 mg (79 μmol) glutaric anhydride in 0.1 ml pyridine for 24 h at RT in the dark. The peptide was precipitated by addition of 7 ml of dry diethylether, centrifuged, and the solid washed a second time with diethylether and centrifuged.
Reaction SMILES: [NH:1]1[C:5]([C:6]2[CH:11]=[CH:10][C:9]([Br:12])=[CH:8][N:7]=2)=[N:4][N:3]=[N:2]1.I[CH3:14].[OH-].[K+]>CN(C)C=O>[CH3:14][N:4]1[C:5]([C:6]2[CH:11]=[CH:10][C:9]([Br:12])=[CH:8][N:7]=2)=[N:1][N:2]=[N:3]1
Reactant: Brc1ccc(-c2nnn[nH]2)nc1
Reactant: CI
Agent: [K+]
Agent: [OH-]
Solvent: CN(C)C=O
Product: Cn1nnnc1-c1ccc(Br)cn1
Yield: 25.9 %

Procedure:
In 5 ml of dimethylformamide was dissolved 400 mg of 2-(5-tetrazolyl)-5-bromopyridine and the solution was reacted with 502 mg of iodomethane in the presence of 300 mg of potassium hydroxide at room temperature for 1 hour with stirring. After completion of the reaction, a post-treatment similar to that of Preparation Example 3 was conducted to obtain 110 mg of 2-(1-methyl-5-tetrazolyl)-5-bromopyridine (thin layer chromatography eluting with a mixture of 1:4 ethyl acetate:hexane, Rf: 0.3) and 220 mg of 2-(2-methyl-5-tetrazolyl)-5-bromopyridine (thin layer chromatography eluting with a mixture of 1:4 ethyl acetate:hexane, Rf: 0.5).
Reaction SMILES: [C:1]([C:3]1[S:4][C:5]2[CH:11]=[C:10]([OH:12])[CH:9]=[CH:8][C:6]=2[N:7]=1)#[N:2].N1C=CC=CC=1.[C:19](Cl)(=[O:24])[C:20]([CH3:23])([CH3:22])[CH3:21]>C1COCC1.O>[C:1]([C:3]1[S:4][C:5]2[CH:11]=[C:10]([O:12][C:19](=[O:24])[C:20]([CH3:23])([CH3:22])[CH3:21])[CH:9]=[CH:8][C:6]=2[N:7]=1)#[N:2]
Reactant: N#Cc1nc2ccc(O)cc2s1
Reactant: CC(C)(C)C(=O)Cl
Solvent: c1ccncc1
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)C(=O)Oc1ccc2nc(C#N)sc2c1
Temperature: 25 °C
Reaction time: 15 h
Yield: 92.2 %

Procedure:
A solution of 2-cyano-6-hydroxybenzothiazole (2.1 g, 12.5 mmol) in 30 mL of dry THF under inert atmosphere was treated with pyridine (2.0 g, 25 mmol) followed by pivaloyl chloride (1.95 g, 16.2 mmol). This reaction was stirred 15 h at room temperature. The reaction mixture was then diluted with 100 mL of distilled water, and this solution was extracted with ethyl acetate (4×50 mL). The combined organics were washed with aqueous sodium bicarbonate (2×100 mL) and distilled water (1×100 mL), then dried over Na2SO4 and concentrated under reduced pressure to afford 3.0 g of a thick oil. This material was chromatographed on silica gel and 1.8 g of the product was eluted with 10% ethyl acetate/hexanes. 1H NMR (CDCl3): δ 1.39 (s, 9H); 7.34-7.38 (m, 1H); 7.74-7.75 (d, 1H) ; 8.20-8.23 (d, 1H).
Reaction SMILES: [C:1]([O:5][CH3:6])(=[O:4])[CH:2]=[CH2:3].[CH3:7][O:8][CH2:9][CH2:10][NH2:11].Br[CH2:13][C:14]#[N:15]>C(OCC)(=O)C>[C:14]([CH2:13][N:11]([CH2:10][CH2:9][O:8][CH3:7])[CH2:3][CH2:2][C:1]([O:5][CH3:6])=[O:4])#[N:15]
Reactant: COCCN
Reactant: N#CCBr
Reactant: C=CC(=O)OC
Solvent: CCOC(C)=O
Product: COCCN(CC#N)CCC(=O)OC
Temperature: 70 °C
Reaction time: 2 h

Procedure:
At 20 to 30° C., 11.4 g of methyl acrylate was added to 10.0 g of 2-methoxyethylamine, which was allowed to stand for 2 hours. Then 7.92 g of bromoacetonitrile was added to the reaction solution, which was heated at 70° C. for 20 hours. The reaction solution was diluted with ethyl acetate and the resulting solids were filtered off. Vacuum concentration yielded methyl N-cyanomethyl-N-(2-methoxy-ethyl)-3-aminopropionate.
Reaction SMILES: Cl.[C:2]1([C:8]2([CH2:13][C:14]([NH2:16])=[NH:15])[CH2:12][CH2:11][CH2:10][CH2:9]2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:17]([O:21][C:22](=[O:37])/[C:23](/O)=[C:24](\[O:28][CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)/[C:25](O)=[O:26])([CH3:20])([CH3:19])[CH3:18].C[O-].[Na+]>CO>[C:17]([O:21][C:22]([C:23]1[C:24]([O:28][CH2:29][C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)=[C:25]([OH:26])[N:16]=[C:14]([CH2:13][C:8]2([C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)[CH2:12][CH2:11][CH2:10][CH2:9]2)[N:15]=1)=[O:37])([CH3:20])([CH3:18])[CH3:19]
Reactant: N=C(N)CC1(c2ccccc2)CCCC1
Reactant: CC(C)(C)OC(=O)/C(O)=C(\OCc1ccccc1)C(=O)O
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: CC(C)(C)OC(=O)c1nc(CC2(c3ccccc3)CCCC2)nc(O)c1OCc1ccccc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 23.9 %

Procedure:
To a stirred solution of 2-(1-phenyl-cyclopentyl)-acetamidine hydrochloride salt (281) (500 mg, 2.09 mmol) and (E)-3-benzyloxy-2-hydroxy-4-oxo-pent-2-enoic acid tert-butyl ester (4) (970 mg, 3.15 mmol) in methanol (10 mL) was added a sodium methoxide solution (25% in methanol) (1.4 mL, 6.29 mmol) at 0° C. and then the reaction mixture was allowed to warm slowly up to room temperature while stirring was continued for 16 h. After completion of the reaction, the reaction mixture was quenched with 1N HCl (5 mL) and the methanol was evaporated and water (20 mL) was added. The mixture was extracted with ethyl acetate (3×20 mL) and the phases separated. The organic part was dried and concentrated to get a crude product, which was purified by Combi-Flash column (eluted at 10-20% ethyl acetate in hexane) to obtain 5-benzyloxy-6-hydroxy-2-(1-phenyl-cyclopentylmethyl)-pyrimidine-4-carboxylic acid tert-butyl ester (282) (230 mg, 23.82%) as a white solid.
Reaction SMILES: [NH2:1][C:2]1[N:6]([C:7]2[CH:12]=[CH:11][C:10]([F:13])=[CH:9][CH:8]=2)[N:5]=[CH:4][C:3]=1[C:14](=[O:22])[C:15]1[CH:20]=[CH:19][CH:18]=[C:17](Br)[CH:16]=1.[CH:23]([S:25]([NH2:28])(=[O:27])=[O:26])=[CH2:24].C(N(CC)CC)C.Cl>CN(C)C=O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[NH2:1][C:2]1[N:6]([C:7]2[CH:12]=[CH:11][C:10]([F:13])=[CH:9][CH:8]=2)[N:5]=[CH:4][C:3]=1[C:14](=[O:22])[C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([CH:24]=[CH:23][S:25]([NH2:28])(=[O:27])=[O:26])[CH:16]=1
Reactant: Nc1c(C(=O)c2cccc(Br)c2)cnn1-c1ccc(F)cc1
Reactant: C=CS(N)(=O)=O
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: Nc1c(C(=O)c2cccc(C=CS(N)(=O)=O)c2)cnn1-c1ccc(F)cc1
Temperature: 100 °C
Reaction time: 16 h

Procedure:
A mixture of 5-amino-4-(3-bromobenzoyl)-1-(4-fluorophenyl)pyrazole (1.5 g, 4.14 mmol) [prepared as described in Example 1 above], vinylsulfonamide (1.33 g, 12.4 mmol), bis(triphenylphosphine)palladium chloride (0.3 g, 0.42 mmol) and triethylamine (6 ml, 43 mmol) in dimethylformamide (18 ml) was heated at 100° C. under argon. After 16 h, the reaction mixture was cooled to room temperature and poured into 1 N hydrochloric acid. The product was extracted into ethyl acetate, washed with brine, dried over sodium sulfate and filtered. The organic layer was removed in vacuo and the residue was purified by flash chromatography (elution gradient: 40-80% ethyl acetate/hexane) to give 5-amino-4-[3-(2-aminosulfonylethenyl)benzoyl]-1-(4-fluorophenyl)pyrazole which was recrystallized from a mixture of methanol/ethyl acetate/hexane to give 0.78 g of the desired product.
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]([OH:12])=O)=[CH:9][C:4]=2[N:3]=[CH:2]1.[CH3:13][C@@:14]12[C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=3[CH2:21][CH2:20][C@@H:19]1[NH:18][CH2:17][CH2:16][CH2:15]2.C[C@]12C3C=CC=CC=3CC[C@@H]1NCCC2>>[NH:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]([N:18]3[C@@H:19]4[C@@:14]([CH3:13])([C:23]5[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=5[CH2:21][CH2:20]4)[CH2:15][CH2:16][CH2:17]3)=[O:12])=[CH:9][C:4]=2[N:3]=[CH:2]1
Reactant: C[C@]12CCCN[C@H]1CCc1ccccc12
Reactant: O=C(O)c1ccc2[nH]cnc2c1
Agent: C[C@@]12CCCN[C@H]1CCc1ccccc12
Product: C[C@]12CCCN(C(=O)c3ccc4[nH]cnc4c3)[C@H]1CCc1ccccc12
Yield: 20 %

Procedure:
The title compound is prepared from 1H-benzoimidazole-5-carboxylic acid and an isomeric mixture of cis-10b-methyl-1,2,3,4,4a,5,6,10b-octahydro-benzo[f]quinoline and trans-10b-methyl-1,2,3,4,4a,5,6,10b-octahydro-benzo[f]quinoline following a procedure analogous to that described in Example 1 yielding a mixture of Example 10 and Example 11 which is separated by HPLC on reversed phase (MeOH/H2O/NH4OH). Yield: 20% of theory; LC (method 2): tR=3.40 min; Mass spectrum (ESI+): m/z=346 [M+H]+; 1H NMR (400 MHz, DMSO-d6, mixture of 2 rotamers) δ 1.33 (s, 3H), 1.42-1.53 (m, 2H), 1.62-1.78 (m, 1H), 2.15-2.23 (m, 1H), 2.27-2.35 (m, 1H), 2.75-2.90 (m, 3H), 3.07-3.18 (m, 1H), 3.43-3.49 (m, 1H), 3.69-3.77 (m, 1H), 7.04-7.18 (m, 3H), 7.20-7.34 (m, 2H), 7.56 (broad s, 0.75H), 7.58 (broad s, 0.25H), 7.67 (broad s, 0.75H), 7.69 (broad s, 0.25H), 8.29 (s, 1H), 12.53-12.62 (m, 1H).
Reaction SMILES: [CH3:1][N:2]1[CH2:11][CH2:10][C:9]2[C:4](=[CH:5][C:6]([NH2:12])=[CH:7][CH:8]=2)[CH2:3]1.Cl[C:14]1[N:19]=[C:18]2[N:20]([CH3:34])[C:21](=[O:33])[N:22]([C:25]3[C:30]([Cl:31])=[CH:29][CH:28]=[CH:27][C:26]=3[Cl:32])[C:23](=[NH:24])[C:17]2=[CH:16][N:15]=1.ClC1N=C2NC(=O)N(C3C(Cl)=CC=CC=3Cl)C(=N)C2=CN=1>>[Cl:31][C:30]1[CH:29]=[CH:28][CH:27]=[C:26]([Cl:32])[C:25]=1[N:22]1[C:23](=[NH:24])[C:17]2[C:18](=[N:19][C:14]([NH:12][C:6]3[CH:5]=[C:4]4[C:9]([CH2:10][CH2:11][N:2]([CH3:1])[CH2:3]4)=[CH:8][CH:7]=3)=[N:15][CH:16]=2)[N:20]([CH3:34])[C:21]1=[O:33]
Reactant: Cn1c(=O)n(-c2c(Cl)cccc2Cl)c(=N)c2cnc(Cl)nc21
Reactant: CN1CCc2ccc(N)cc2C1
Agent: N=c1c2cnc(Cl)nc2[nH]c(=O)n1-c1c(Cl)cccc1Cl
Product: CN1CCc2ccc(Nc3ncc4c(=N)n(-c5c(Cl)cccc5Cl)c(=O)n(C)c4n3)cc2C1

Procedure:
28 mg of the entitled compound was obtained as a white solid according to the same method as in Example 2, for which, however, 2-methyl-1,2,3,4-tetrahydroisoquinolin-7-amine was used in place of 2,4,4-trimethyl-1,2,3,4-tetrahydroisoquinolin-7-amine in Example 2, and 7-chloro-3-(2,6-dichlorophenyl)-4-imino-1-methyl-3,4-dihydropyrimido[4,5-d]pyrimidin-2(1H)-one obtained in Production Example 7 was used in place of 7-chloro-3-(2,6-dichlorophenyl)-4-imino-3,4-dihydropyrimido[4,5-d]pyrimidin-2(1H)-one.
Reaction SMILES: [Br:1][C:2]1[C:3]([Cl:12])=[N:4][CH:5]=[C:6]([S:8](Cl)(=[O:10])=[O:9])[CH:7]=1.[NH2:13][C:14]([CH3:19])([CH2:17][OH:18])[CH2:15][OH:16]>>[OH:16][CH2:15][C:14]([NH:13][S:8]([C:6]1[CH:5]=[N:4][C:3]([Cl:12])=[C:2]([Br:1])[CH:7]=1)(=[O:10])=[O:9])([CH2:17][OH:18])[CH3:19]
Reactant: CC(N)(CO)CO
Reactant: O=S(=O)(Cl)c1cnc(Cl)c(Br)c1
Product: CC(CO)(CO)NS(=O)(=O)c1cnc(Cl)c(Br)c1
Yield: 83.4 %

Procedure:
Prepared by general procedure III from 3-bromo-2-chloropyridine-5-sulphonylchloride (580 mg, 2 mmol) and 2-amino-2-methyl-1,3-propanediol (231 mg, 2 mmol) to give 5-Bromo-6-chloro-pyridine-3-sulfonic acid (2-hydroxy-1-hydroxymethyl-1-methyl-ethyl)-amide (600 mg, 83%) as a yellow solid. MS (ISN) 357[(M−H)−], 359.0[(M+2−H)−], 361.0[(M+4−H)−].
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH:8]=[C:9]([CH2:11]Cl)[N:10]=2)[CH:7]=1.Cl.Cl.[Cl:15][C:16]1[CH:21]=[CH:20][C:19]([N:22]2[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]2)=[CH:18][CH:17]=1.C(N(CC)CC)C>C(O)CO>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH:8]=[C:9]([CH2:11][N:25]3[CH2:24][CH2:23][N:22]([C:19]4[CH:18]=[CH:17][C:16]([Cl:15])=[CH:21][CH:20]=4)[CH2:27][CH2:26]3)[N:10]=2)[CH:7]=1
Reactant: ClCc1cn2cc(Br)ccc2n1
Reactant: Clc1ccc(N2CCNCC2)cc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: OCCO
Product: Clc1ccc(N2CCN(Cc3cn4cc(Br)ccc4n3)CC2)cc1
Temperature: 80 °C
Reaction time: 1 h

Procedure:
A mixture of 6-bromo-2-(chloromethyl)imidazo[1,2-α]pyridine (Example 15, Step 1; 0.3042 g), 1-(4-chlorophenyl)piperazine dihydrochloride (Aldrich; 0.3708 g), triethylamine (Aldrich; 0.55 mL), and ethylene glycol (5.6 mL) is stirred for 1 h at 80° C. After cooling, the mixture is partitioned between water and dichloromethane. The combined organic layers are washed with brine, dried with MgSO4, and concentrated under reduced pressure. The residue is chromatographed on silica gel using methanol/dichloromethane (4/96) to give, after crystallization from ethyl acetate/methanol/dichlormetane, 0.1756 g of the title compound; mp 154-155° C.; MS m/z 404, 406, 408; IR (mineral oil) 1495, 1500, 1224, 823, 812 cm-1 ; 1H NMR (CDCl3) δ2.72, 3.19, 3.76, 6.83, 7.20, 7.22, 7.47, 7.52, 8.24.
Reaction SMILES: C[Si]([O:5][PH:6][O:7][Si](C)(C)C)(C)C.[PH2]([O-])=O.[NH4+].[C:16]([O:20][C:21]([NH:23][C:24]1[N:29]=[CH:28][C:27]([CH2:30][C:31](=[CH2:37])[C:32]([O:34][CH2:35][CH3:36])=[O:33])=[CH:26][CH:25]=1)=[O:22])([CH3:19])([CH3:18])[CH3:17].CO>C(Cl)Cl.O>[C:16]([O:20][C:21]([NH:23][C:24]1[N:29]=[CH:28][C:27]([CH2:30][CH:31]([C:32]([O:34][CH2:35][CH3:36])=[O:33])[CH2:37][PH:6](=[O:7])[OH:5])=[CH:26][CH:25]=1)=[O:22])([CH3:19])([CH3:17])[CH3:18]
Reactant: C=C(Cc1ccc(NC(=O)OC(C)(C)C)nc1)C(=O)OCC
Reactant: C[Si](C)(C)OPO[Si](C)(C)C
Agent: O=[PH2][O-]
Agent: [NH4+]
Solvent: CO
Solvent: O
Solvent: ClCCl
Product: CCOC(=O)C(Cc1ccc(NC(=O)OC(C)(C)C)nc1)C[PH](=O)O
Temperature: 0 °C
Reaction time: 8 h
Yield: 64 %

Procedure:
Bis(trimethylsilyl)phosphonite was generated as described in WO 01/042252 using N,O-bis-(trimethylsilyl)acetamide (3.0 mL; 12.1 mmol) and ammonium hypophosphite (1.0 g; 12.0 mmol). The resulting reaction mixture was cooled to 0° C. and a solution of ethyl 2-({6-[(tert-butoxycarbonyl)amino]pyridin-3-yl}methyl)acrylate (0.72 g; 2.35 mmol), in methylene chloride (4 mL) was added dropwise. The reaction was stirred overnight at room temperature. Methanol was added at 0° C. followed by water. The reaction mixture was concentrated. The remaining residue was dissolved in water and purified by preparative HPLC (0.1 M NH4Ac (aq)/CH3CN, 1/0→0/1), concentrated and lyophilized to afford 0.56 g (64%) of 2-({6-[(tert-butoxycarbonyl)amino]pyridin-3-yl}methyl)-3-ethoxy-3-oxopropylphosphinic acid.
Reaction SMILES: [Br:1][C:2]1[N:7]=[CH:6][C:5]2[CH:8]=[C:9]([C:11]3[CH:12]=[N:13][N:14]([CH3:16])[CH:15]=3)[NH:10][C:4]=2[CH:3]=1.Br[CH2:18][C:19]1[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=1>CN(C=O)C.C(OCC)(=O)C.O>[Br:1][C:2]1[N:7]=[CH:6][C:5]2[CH:8]=[C:9]([C:11]3[CH:12]=[N:13][N:14]([CH3:16])[CH:15]=3)[N:10]([CH2:18][C:19]3[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=3)[C:4]=2[CH:3]=1
Reactant: Cn1cc(-c2cc3cnc(Br)cc3[nH]2)cn1
Reactant: Fc1ccc(CBr)cc1
Solvent: O
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: Cn1cc(-c2cc3cnc(Br)cc3n2Cc2ccc(F)cc2)cn1
Temperature: 60 °C
Yield: 72.1 %

Procedure:
6-bromo-2-(1-methyl-1H-pyrazol-4-yl)-1H-pyrrolo[3,2-c]pyridine (Preparation 22, 50 mg, 0.18 mmol) was dissolved in dry DMF (1 ml). The solution was degassed and a solution of sodium bis(trimethylsilyl)amide (0.27 ml of a 1M solution in THF, 0.27 mmol) was added. After 20 minutes reaction, 1-(bromomethyl)-4-fluorobenzene (51 mg, 0.27 mmol) was added and the reaction heated to 60° C. for 3 hours. The reaction was cooled to room temperature and diluted with ethyl acetate and water. The organic solution was washed with brine, dried over sodium sulphate and concentrated in vacuum. The crude product was purified on silica gel column chromatography eluting with 20% hexane in ethyl acetate to afford the title compound as white foam (50 mg, 71.9%). 1H-NMR (500 MHz, CDCl3) 3.92 (s, 3H), 5.31 (s, 2H), 6.62 (s, 1H), 6.93 (m, 2H), 7.02 (m, 2H), 7.27 (s, 1H), 7.39 (s, 1H), 7.51 (s, 1H), 8.63 (s, 1H).
Reaction SMILES: C(OC(=O)[NH:7][CH:8]1[CH2:13][CH2:12][CH:11]([CH2:14][NH:15][C:16]2[C:21]([F:22])=[CH:20][N:19]=[C:18](Cl)[N:17]=2)[CH2:10][CH2:9]1)(C)(C)C.Cl.[F:26][C:27]([F:38])([F:37])[O:28][C:29]1[CH:36]=[CH:35][CH:34]=[CH:33][C:30]=1[CH2:31][NH2:32]>CCOC(C)=O>[NH2:7][C@H:8]1[CH2:9][CH2:10][C@H:11]([CH2:14][NH:15][C:16]2[C:21]([F:22])=[CH:20][N:19]=[C:18]([NH:32][CH2:31][C:30]3[CH:33]=[CH:34][CH:35]=[CH:36][C:29]=3[O:28][C:27]([F:26])([F:37])[F:38])[N:17]=2)[CH2:12][CH2:13]1
Reactant: CC(C)(C)OC(=O)NC1CCC(CNc2nc(Cl)ncc2F)CC1
Reactant: NCc1ccccc1OC(F)(F)F
Agent: Cl
Solvent: CCOC(C)=O
Product: N[C@H]1CC[C@H](CNc2nc(NCc3ccccc3OC(F)(F)F)ncc2F)CC1
Temperature: 180 °C
Reaction time: 1 h
Yield: 15 %

Procedure:
{4-[(2-Chloro-5-fluoro-pyrimidin-4-ylamino)-methyl]-cyclohexyl}-carbamic acid tert-butyl ester (127 mg, 0.35 mmol) was dissolved in 2-trifluoromethoxybenzylamine (2.5 mL) and heated at 180° C. for 20 min. The reaction mixture was diluted with EtOAc and poured into 1N HCl. The aqueous layer was separated and extracted with EtOAc (×2). The combined organic phase was dried over anhydrous Na2SO4 and concentrated in vacuo. The resulting residue was dissolved in CH2Cl2 (2.5 mL) and TFA (2.5 mL) was added. The reaction mixture was stirred at room temperature for 1 h. The reaction mixture was concentrated in vacuo and the resulting residue was diluted with EtOAc. The solution was poured into 10% NaHCO3 and the aqueous layer was re-extracted with EtOAc. The combined organic phase was dried over anhydrous Na2SO4 and concentrated in vacuo. The resulting residue was purified by silica gel preparative TLC using 9:1:0.1 CH2Cl2:MeOH:NH4OH as an eluent to afford 22 mg (15%) of the title compound, m/z 414.6 (M+1)+.
Reaction SMILES: [CH3:1][N:2](S(C1C=CC=CC=1)(=O)=O)[N:3]=[C:4](Cl)[C:5]1[C:10]([F:11])=[CH:9][CH:8]=[CH:7][C:6]=1[Cl:12].[C:23]([C:25]1[S:26][C:27]([Cl:32])=[C:28]([Cl:31])[C:29]=1[Cl:30])#[N:24].[Cl-].[Al+3].[Cl-].[Cl-]>ClC1C=CC=CC=1Cl>[Cl:12][C:6]1[CH:7]=[CH:8][CH:9]=[C:10]([F:11])[C:5]=1[C:4]1[N:24]=[C:23]([C:25]2[S:26][C:27]([Cl:32])=[C:28]([Cl:31])[C:29]=2[Cl:30])[N:2]([CH3:1])[N:3]=1
Reactant: CN(N=C(Cl)c1c(F)cccc1Cl)S(=O)(=O)c1ccccc1
Reactant: N#Cc1sc(Cl)c(Cl)c1Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: Clc1ccccc1Cl
Product: Cn1nc(-c2c(F)cccc2Cl)nc1-c1sc(Cl)c(Cl)c1Cl
Temperature: 145 °C
Reaction time: 2 h
Yield: 55.3 %

Procedure:
To a mixture of N-methyl-N-benzenesulfonyl-2-chloro-6-fluorobenzhydrazonoyl chloride (47.5 g, 0.131 mol) and 2-cyano-3,4,5-trichlorothiophene (26.5 g 0.125 mol in o-dichlorobenzene (18 mL), was added aluminum chloride (11.1 g, 0.083 mol). The mixture was lowered into a preheated oil bath maintained at 140-150° C. The mixture was allowed to remain in the hot oil bath 40 min and was then removed from the bath and stirred for 2 hr as it gradually cooled. The reaction mixture was poured into 2N sodium hydroxide (300 mL-enough to dissolve the aluminum salts) and extracted with methylene chloride (3×250 mL). The organic phases were combined, washed with brine, dried (MgSO4), and the solvent removed in vacuo to give the crude product. The residue was placed on silica gel (150 g) and then chromatographed using ethyl acetate/hexanes as eluant to obtain 39.7 g (55.3% yield) of the title compound; 99.4% pure by GC analysis; mp 129-130° C.; 1H NMR (CDCl3) δ 7.3 (m, 2H), 7.1 (m, 1H), 4.0 (s, 3H); Anal. for C13H6Cl4FN3S: Calcd. C, 39.32; H, 1.52; N, 10.58. Found C, 39.08; H, 1.30; N, 10.34.
Reaction SMILES: C1O[C:4]2([CH2:9][CH2:8][C:7](=O)[CH2:6][CH2:5]2)[O:3]C1.Cl.[CH3:13][NH:14][CH3:15].C(N(CC)CC)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.Cl>ClCCCl.O>[CH3:13][N:14]([CH3:15])[CH:7]1[CH2:8][CH2:9][C:4](=[O:3])[CH2:5][CH2:6]1
Reactant: CNC
Reactant: O=C1CCC2(CC1)OCCO2
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Solvent: O
Solvent: ClCCCl
Solvent: CCN(CC)CC
Product: CN(C)C1CCC(=O)CC1
Reaction time: 0.17 h
Yield: 17 %

Procedure:
To a suspension of 1,4-cyclohexanedione monoethyleneketal (3.82 g, 24.6 mmol) and dimethylamine hydrochloride (2.00 g, 24.6 mmol) in 1,2-dichloroethane (50 ml) were dropwise added triethylamine (4.2 ml, 29.6 mmol) and DBU (1,8-diazabicyclo-[5.4.0]-7-undecene) (4.4 ml), and the mixture was stirred for 10 minutes. To the mixture was added triacetoxyborohydride (7.68 g, 34.4 mmol), and the mixture was stirred for 4.5 hours. Precipitate was filtered off, and the filtrate was concentrated to give crude product (6.34 g), which was dissolved in water (10 ml). To the mixture was dropwise added concentrated hydro-chloric acid (6 ml), and the mixture was stirred for 48 hours. The reaction mixture was diluted with water and washed twice with ether. The aqueous layer was made basic with sodium hydroxide and extracted with ether twice. The extract was washed with saturated sodium chloride solution, dried with potassium carbonate and purified by evaporation to give 4-dimethylaminocyclohexanone (0.59 g, 17%).