Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([NH:10][C:11]2[CH:16]=[CH:15][N:14]=[CH:13][N:12]=2)[C:5](=[O:9])[N:6]([CH3:8])[CH:7]=1.[C:17]([O:20][CH2:21][C:22]1[C:23]([N:37]2[CH2:49][CH2:48][N:40]3[C:41]4[CH2:42][CH2:43][CH2:44][CH2:45][C:46]=4[CH:47]=[C:39]3[C:38]2=[O:50])=[N:24][CH:25]=[CH:26][C:27]=1B1OC(C)(C)C(C)(C)O1)(=[O:19])[CH3:18].CC([O-])=O.[Na+].C(#N)C>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].O>[C:17]([O:20][CH2:21][C:22]1[C:23]([N:37]2[CH2:49][CH2:48][N:40]3[C:41]4[CH2:42][CH2:43][CH2:44][CH2:45][C:46]=4[CH:47]=[C:39]3[C:38]2=[O:50])=[N:24][CH:25]=[CH:26][C:27]=1[C:2]1[CH:3]=[C:4]([NH:10][C:11]2[CH:16]=[CH:15][N:14]=[CH:13][N:12]=2)[C:5](=[O:9])[N:6]([CH3:8])[CH:7]=1)(=[O:19])[CH3:18]
Reactant: CC(=O)OCc1c(B2OC(C)(C)C(C)(C)O2)ccnc1N1CCn2c(cc3c2CCCC3)C1=O
Reactant: Cn1cc(Br)cc(Nc2ccncn2)c1=O
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: CC(=O)[O-]
Solvent: CC#N
Solvent: O
Product: CC(=O)OCc1c(-c2cc(Nc3ccncn3)c(=O)n(C)c2)ccnc1N1CCn2c(cc3c2CCCC3)C1=O
Temperature: 110 °C
Yield: 39.4 %

Procedure:
A sealed tube equipped with a magnetic stirrer was charged with 142a (154.5 mg, 0.55 mmol), (2-(1-oxo-3,4,6,7,8,9-hexahydropyrazino[1,2-a]indol-2(1H)-yl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-3-yl)methyl acetate 113i (252.5 mg, 0.55 mmol), Pd(dppf)Cl2 (25.9 mg, 0.03135 mmol), NaOAc (108 mg, 1.1 mmol), K3PO4.3H2O (293 mg, 1.1 mmol), acetonitrile (6 mL), and water (0.5 mL). After three cycles of vacuum/argon flush, the mixture was heated at 110° C. for 2 h. It was then filtered and the filtrate was evaporated in vacuo. The residue was purified by silica gel column chromatography eluting with dichloromethane/methanol (15:1, UV) to afford 142b (117 mg, 30%) as a brown solid. LCMS: [M+H]+ 540.2
Reaction SMILES: [OH:1][C:2]1[C:7]2[S:8][C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=3[C:6]=2[S:5](=[O:16])(=[O:15])[N:4]([CH3:17])[C:3]=1[C:18](OCC)=[O:19].[NH2:23][C:24]1[CH:29]=[N:28][CH:27]=[CH:26][N:25]=1>>[OH:1][C:2]1[C:7]2[S:8][C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=3[C:6]=2[S:5](=[O:15])(=[O:16])[N:4]([CH3:17])[C:3]=1[C:18]([NH:23][C:24]1[CH:29]=[N:28][CH:27]=[CH:26][N:25]=1)=[O:19]
Reactant: CCOC(=O)C1=C(O)c2sc3ccccc3c2S(=O)(=O)N1C
Reactant: Nc1cnccn1
Product: CN1C(C(=O)Nc2cnccn2)=C(O)c2sc3ccccc3c2S1(=O)=O
Yield: 52 %

Procedure:
Prepared analogous to Example 1 from ethyl 4-hydroxy-2-methyl-2H-[1] benzothieno [2,3-e]-1,2-thiazine-3-carboxylate-1,1-dioxide and aminopyrazine with a yield of 52% of theory.
Reaction SMILES: [C:1]([OH:9])(=[O:8])[CH:2]([CH2:4][C:5]([OH:7])=[O:6])[OH:3].[OH-:10].[Cu+2:11].[OH-]>O>[C:1]([OH:9])(=[O:8])[CH:2]([CH2:4][C:5]([OH:7])=[O:6])[OH:3].[C:1]([O:9][OH:10])(=[O:8])[CH:2]([CH2:4][C:5]([O-:7])=[O:6])[OH:3].[Cu+2:11].[Cu+2:11].[OH:10][O:8][C:1](=[O:9])[CH:2]([CH2:4][C:5]([O-:7])=[O:6])[OH:3].[OH:10][O:8][C:1](=[O:9])[CH:2]([CH2:4][C:5]([O-:7])=[O:6])[OH:3].[OH:10][O:8][C:1](=[O:9])[CH:2]([CH2:4][C:5]([O-:7])=[O:6])[OH:3]
Reactant: [OH-]
Agent: [Cu+2]
Agent: O=C(O)CC(O)C(=O)O
Solvent: O
Product: O=C([O-])CC(O)C(=O)OO

Procedure:
An aqueous solution of malic acid is prepared by mixing 134.09 g of malic acid with 50 mL of water. An aqueous solution of copper(II)hydroxide is also prepared in a separate container by thoroughly mixing 195.12 g of copper(II)hydroxide in 50 mL of water. The copper(II)hydroxide solution is then slowly added to the malic acid solution. The resulting solution is spray dried to produce a powdered dicopper(II)hydroxy malate.
Reaction SMILES: [OH:1][CH2:2][C@@:3]1([NH:22][C:23](=[O:29])[O:24][C:25]([CH3:28])([CH3:27])[CH3:26])[CH2:7][CH2:6][C@H:5]([C:8]2[CH:13]=[CH:12][C:11]([CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])=[CH:10][CH:9]=2)[CH2:4]1.CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O.O>ClCCl>[CH:2]([C@@:3]1([NH:22][C:23](=[O:29])[O:24][C:25]([CH3:28])([CH3:27])[CH3:26])[CH2:7][CH2:6][C@H:5]([C:8]2[CH:13]=[CH:12][C:11]([CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])=[CH:10][CH:9]=2)[CH2:4]1)=[O:1]
Reactant: CCCCCCCCc1ccc([C@H]2CC[C@@](CO)(NC(=O)OC(C)(C)C)C2)cc1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: ClCCl
Solvent: O
Product: CCCCCCCCc1ccc([C@H]2CC[C@@](C=O)(NC(=O)OC(C)(C)C)C2)cc1
Reaction time: 3 h
Yield: 87.6 %

Procedure:
Tert-butyl (1R,3S)-1-(hydroxymethyl)-3-(4-octylphenyl)cyclopentylcarbamate (3.9 g, 9.66 mmol) was dissolved in dichloromethane (193 ml) under nitrogen to give a colorless solution. Dess-Martin periodinane (4.51 g, 10.63 mmol) (Aldrich) was added and the reaction stirred for about 3 h. LC/MS showed the reaction was complete. Methylene chloride (100 mL) and water (100 mL) were added and the layers separated and extracted with methylene chloride (2×50 mL). The combined extracts were washed with brine, dried over magnesium sulfate, filtered, and evaporated to an off-white solid. The residue was purified by flash column chromatography (120 g Redi-Sep) eluting with ethyl acetate/heptane and the product fractions combined. Solvents were removed under reduced pressure to provide tert-butyl (1R,3S)-1-formyl-3-(4-octylphenyl)cyclopentylcarbamate (3.40 g, 88%) as an off white solid: LC/MS (method f) Rt=3.58 min.; MS m/z: 401.36 (M+H)+.
Reaction SMILES: Br[CH2:2][C:3]([O:5][CH2:6][CH2:7][CH3:8])=[O:4].C[O:10][P:11]1[O:15][CH:14]([CH3:16])[CH:13]([CH3:17])[O:12]1>>[CH2:6]([O:5][C:3]([CH2:2][P:11]1(=[O:10])[O:15][CH:14]([CH3:16])[CH:13]([CH3:17])[O:12]1)=[O:4])[CH2:7][CH3:8]
Reactant: COP1OC(C)C(C)O1
Reactant: CCCOC(=O)CBr
Product: CCCOC(=O)CP1(=O)OC(C)C(C)O1
Yield: 95.1 %

Procedure:
Using the procedure of Step A of Example 1, 3.8 g of n-propyl bromoacetate and 2.42 g of 2-methoxy-4,5-dimethyl -1,3,2-dioxaphospholane were reacted to obtain 3.62 g of raw 2-propoxycarbonylmethyl-4,5-dimethyl-2-oxo-1,3,2-dioxaphospholane which was used as is for the next step.
Reaction SMILES: C1(O[C:8](=[O:26])[NH:9][C:10]2[C:11]([O:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)=[N:12][C:13]([CH3:18])=[C:14]([CH2:16][CH3:17])[CH:15]=2)C=CC=CC=1.[CH3:27][O:28][C:29]1[CH:30]=[C:31]([N:37]2[CH2:42][CH2:41][NH:40][CH2:39][CH2:38]2)[CH:32]=[C:33]([O:35][CH3:36])[CH:34]=1>>[CH2:16]([C:14]1[CH:15]=[C:10]([NH:9][C:8]([N:40]2[CH2:39][CH2:38][N:37]([C:31]3[CH:30]=[C:29]([O:28][CH3:27])[CH:34]=[C:33]([O:35][CH3:36])[CH:32]=3)[CH2:42][CH2:41]2)=[O:26])[C:11]([O:19][C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)=[N:12][C:13]=1[CH3:18])[CH3:17]
Reactant: COc1cc(OC)cc(N2CCNCC2)c1
Reactant: CCc1cc(NC(=O)Oc2ccccc2)c(Oc2ccccc2)nc1C
Product: CCc1cc(NC(=O)N2CCN(c3cc(OC)cc(OC)c3)CC2)c(Oc2ccccc2)nc1C
Yield: 75 %

Procedure:
Phenyl-N-(5-ethyl-6-methyl-2-phenoxypyridin-3-yl)carbamate and 1-(3,5-dimethoxyphenyl)piperazine were reacted by the same way with the example 1 to obtain the titled compound.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C:10]1[C:11]([NH2:25])=[N:12][CH:13]=[C:14](B2OC(C)(C)C(C)(C)O2)[CH:15]=1.Br[C:27]1[C:28]([CH3:45])=[N:29][N:30]([CH:32]2[CH2:37][CH2:36][N:35]([C:38]([O:40][C:41]([CH3:44])([CH3:43])[CH3:42])=[O:39])[CH2:34][CH2:33]2)[CH:31]=1.C1(P(C2CCCCC2)C2CCCCC2)CCCCC1.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>O1CCOCC1.O.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[NH2:25][C:11]1[N:12]=[CH:13][C:14]([C:27]2[C:28]([CH3:45])=[N:29][N:30]([CH:32]3[CH2:33][CH2:34][N:35]([C:38]([O:40][C:41]([CH3:43])([CH3:42])[CH3:44])=[O:39])[CH2:36][CH2:37]3)[CH:31]=2)=[CH:15][C:10]=1[C:2]1[O:1][C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=1
Reactant: Cc1nn(C2CCN(C(=O)OC(C)(C)C)CC2)cc1Br
Reactant: CC1(C)OB(c2cnc(N)c(-c3nc4ccccc4o3)c2)OC1(C)C
Agent: [Pd]
Agent: C1CCC(P(C2CCCCC2)C2CCCCC2)CC1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Solvent: O
Product: Cc1nn(C2CCN(C(=O)OC(C)(C)C)CC2)cc1-c1cnc(N)c(-c2nc3ccccc3o2)c1
Temperature: 100 °C
Reaction time: 3 h
Yield: 65.1 %

Procedure:
A mixture of 3-(1,3-benzoxazol-2-yl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-amine (600 mg), tert-butyl 4-(4-bromo-3-methyl-pyrazol-1-yl)piperidine-1-carboxylate (557 mg), tris(dibenzylideneacetone)dipalladium (74.1 mg), tricyclohexylphosphine (45.4 mg) and potassium phosphate (584 mg) in 1,4-dioxane (3.4 mL) and water (0.4 mL) was degassed with argon, then stirred at 100° C. for 3 h under argon. Solvents were removed. The crude product was adsorbed on silica gel and purified by flash chromatography on silica gel eluting with 5 to 10% methanol in dichloromethane. The solvent was evaporated to dryness to afford tert-butyl 4-[4-[6-amino-5-(1,3-benzoxazol-2-yl)-3-pyridyl]-3-methyl-pyrazol-1-yl]piperidine-1-carboxylate (500 mg); NMR Spectrum: (DMSOd6) 1.43 (s, 9H), 1.78 (dd, 1H), 1.83 (dd, 1H), 1.99-2.07 (m, 2H), 2.33 (s, 3H), 2.91 (bs, 2H), 4.01-4.11 (m, 2H), 4.24-4.32 (m, 1H), 7.42-7.50 (m, 2H), 7.65 (bs, 2H), 7.77-7.83 (m, 2H), 8.10 (s, 1H), 8.29 (d, 1H), 8.35 (d, 1H); Mass spectrum: M+H+: 475
Reaction SMILES: [Mg].[CH2:2]([C:10]1[CH:15]=[CH:14][C:13](Br)=[CH:12][CH:11]=1)[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH3:9].Br[C:18]1[CH:23]=[CH:22][C:21]([Br:24])=[CH:20][N:19]=1>O1CCCC1>[Br:24][C:21]1[CH:22]=[CH:23][C:18]([C:13]2[CH:14]=[CH:15][C:10]([CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH3:9])=[CH:11][CH:12]=2)=[N:19][CH:20]=1
Reactant: CCCCCCCCc1ccc(Br)cc1
Reactant: Brc1ccc(Br)nc1
Agent: [Mg]
Solvent: C1CCOC1
Product: CCCCCCCCc1ccc(-c2ccc(Br)cn2)cc1
Yield: 108.8 %

Procedure:
A Grignard reagent was prepared from magnesium (2.3 g) and 4-octyl-1-bromobenzene (25 g) dissolved in dry tetrahydrofuran (hereinafter abbreviated to THF, 200 ml). To this Grignard reagent were added 2,5-dibromopyridine (23 g) and tetrakistriphenylphosphin paradiun (0) complex (hereinafter abbreviated to Pd(TPP)4, 0.57 g). The reaction mixture was heated to keep refluxing for about 2 hours. After cooling the mixture, organic matter was extracted from the mixture with ether, followed by sequential washing the extract with aqueous ammonium chloride and distilled water to separate an organic layer which was dried over MgSO4. Filtering off the desiccant and distilling off the solvent from the organic layer, the layer gave a residue which was purified by silica gel column chromatography to give 5-bromo-2-(4-octylphenyl)pyridine (35 g).
Reaction SMILES: [Cl:1][C:2]1[C:7]([CH:8]([C:10]2[S:11][CH:12]=[CH:13][CH:14]=2)[OH:9])=[CH:6][N:5]=[C:4]([O:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[Cl:22])[N:3]=1>C1(C)C=CC=CC=1.O=[Mn]=O>[Cl:1][C:2]1[C:7]([C:8]([C:10]2[S:11][CH:12]=[CH:13][CH:14]=2)=[O:9])=[CH:6][N:5]=[C:4]([O:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[Cl:22])[N:3]=1
Reactant: OC(c1cccs1)c1cnc(Oc2ccccc2Cl)nc1Cl
Agent: O=[Mn]=O
Solvent: Cc1ccccc1
Product: O=C(c1cccs1)c1cnc(Oc2ccccc2Cl)nc1Cl

Procedure:
[4-Chloro-2-(2-chloro-phenoxy)-pyrimidin-5-yl]-thiophen-2-yl-methanol (98 mg, 0.28 mmol) was dissolved in 15 mL dry toluene, and 250 mg of MnO2 was added. The reaction mixture was heated to reflux for 30 minutes, and water was removed using a Dean Stark apparatus. The hot reaction mixture was filtered through Celite, and the Celite was washed five times with 3.5 mL of hot EtOAc. The combined organics were evaporated under reduced pressure to yiled 82 mg of [4-Chloro-2-(2-chloro-phenoxy)-pyrimidin-5-yl]-thiophen-2-yl-methanone as an oil. Mass Spec. M+H=352.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([NH2:8])[CH:3]=1.[Cl:9]N1C(=O)CCC1=O>C(OCC)(=O)C>[CH:3]1[C:4]([NH2:8])=[N:5][CH:6]=[C:7]([Cl:9])[C:2]=1[Cl:1]
Reactant: Nc1cc(Cl)ccn1
Reactant: O=C1CCC(=O)N1Cl
Solvent: CCOC(C)=O
Product: Nc1cc(Cl)c(Cl)cn1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
4-Chloro-2-aminopyridine (Matrix Scientific, cat. #23809; 1.29 g, 0.01 mol) is dissolved by stirring in 500 ml of ethyl acetate. A thermometer is placed in the solution to monitor temperature. N-Chlorosuccinimide (13.3 g, 0.01 mol) is added in several portions to keep the solution at room temperature. The solution becomes dark in color and is stirred at room temperature overnight. The supernatant is decanted from the dark solids that formed and transferred to a separatory funnel. The organic solution is washed with 500 ml saturated aqueous sodium bisulfite and then 500 ml brine. The organic layer is dried with MgSO4 and concentrated on a rotovap. The dark brown crude product is chromatographed on 500 g of flash silica-gel eluting with CH2Cl2. Concentration of the appropriate fractions on a rotovap gives a light tan solid. The solid is dissolved in EtOAc and decolorized with activated carbon. EtoAc is removed using a rotovap and the resulting solid is suspended in ice-cold CH2Cl2 and filtered to give the product as a white solid. (MP 142-143° C.).
Reaction SMILES: S1C2C=CC=CC=2N=C1NC(C1C=CC=C2C=1CN(C1SC(CCCO)=C(C(OC)=O)N=1)CC2)=O.[S:36]1[C:40]2[CH:41]=[CH:42][CH:43]=[CH:44][C:39]=2[N:38]=[C:37]1[N:45]([CH2:71][O:72][CH2:73][CH2:74][Si:75]([CH3:78])([CH3:77])[CH3:76])[C:46]([C:48]1[CH:49]=[CH:50][CH:51]=[C:52]2[C:57]=1[CH2:56][N:55]([C:58]1[S:59][C:60]([C:67]#[C:68][CH2:69][OH:70])=[C:61]([C:63]([O:65][CH3:66])=[O:64])[N:62]=1)[CH2:54][CH2:53]2)=[O:47]>>[S:36]1[C:40]2[CH:41]=[CH:42][CH:43]=[CH:44][C:39]=2[N:38]=[C:37]1[N:45]([CH2:71][O:72][CH2:73][CH2:74][Si:75]([CH3:78])([CH3:77])[CH3:76])[C:46]([C:48]1[CH:49]=[CH:50][CH:51]=[C:52]2[C:57]=1[CH2:56][N:55]([C:58]1[S:59][C:60]([CH2:67][CH2:68][CH2:69][OH:70])=[C:61]([C:63]([O:65][CH3:66])=[O:64])[N:62]=1)[CH2:54][CH2:53]2)=[O:47]
Reactant: COC(=O)c1nc(N2CCc3cccc(C(=O)N(COCC[Si](C)(C)C)c4nc5ccccc5s4)c3C2)sc1C#CCO
Agent: COC(=O)c1nc(N2CCc3cccc(C(=O)Nc4nc5ccccc5s4)c3C2)sc1CCCO
Product: COC(=O)c1nc(N2CCc3cccc(C(=O)N(COCC[Si](C)(C)C)c4nc5ccccc5s4)c3C2)sc1CCCO

Procedure:
The title compound (47F) was prepared in a similar manner to the synthesis of compound 8E by substituting compound 8D with compound 47E: LC/MS (APCI): m/z 639 (M+H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:15]=1[N:14]=[C:13]1[N:8]([CH2:9][CH2:10][CH2:11][O:12]1)[C:7]2=[O:16].[Cl:17][C:18]1[CH:23]=[CH:22][C:21]([N:24]2[CH2:30][CH:29]3[NH:31][CH:26]([CH2:27][CH2:28]3)[CH2:25]2)=[CH:20][CH:19]=1.C(N(CC)CC)C.C1(C)C=CC(S(O)(=O)=O)=CC=1>CC(N(C)C)=O.O>[Cl:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:15]=1[NH:14][C:13](=[O:12])[N:8]([CH2:9][CH2:10][CH2:11][N:31]1[CH:29]3[CH2:28][CH2:27][CH:26]1[CH2:25][N:24]([C:21]1[CH:22]=[CH:23][C:18]([Cl:17])=[CH:19][CH:20]=1)[CH2:30]3)[C:7]2=[O:16]
Reactant: O=c1c2cccc(Cl)c2nc2n1CCCO2
Reactant: Clc1ccc(N2CC3CCC(C2)N3)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: CCN(CC)CC
Solvent: CC(=O)N(C)C
Product: O=c1[nH]c2c(Cl)cccc2c(=O)n1CCCN1C2CCC1CN(c1ccc(Cl)cc1)C2
Temperature: 120 °C
Yield: 83.3 %

Procedure:
8-Chloro-3,4-dihydro-2H-1-oxa-4a,9-diaza-anthracen-10-one (6.18g, 26.02 mmol), 3-(4-Chloro-phenyl)-3,8-diaza-bicyclo[3.2.1] octane (HCl salt) (5.62 g, 21.68 mmol), triethylamine (3.6 ml, 26.02 mmol), p-toluene sulfonic acid (0.74 g, 3.90 mmol) were combined in dimethyl acetamide (38 ml) and heated at 120° C. for 15 hours. The reaction was cooled to room temperature, diluted with H2O and filtered the tan precipitate. Dissolved the tan solid in chloroform (400 ml), dried over magnesium sulfate, and concentrated to an off-white solid. Silica gel flash chromatography using 5% methanol/chloroform as the eluent yielded 8-Chloro-3-{3-[3-(4-chloro-phenyl)-3,8-diaza-bicyclo[3.2.1]oct-8-yl]-propyl}-1H-quinazoline-2,4-dione (8.3 g, 83.3%) as an off-white solid; Mp. 194-196° C. Maleate salt was formed by dissolving the solid in chloroform (100 ml) and maleic acid (2.52 g, 1.2 eq) in ethyl acetate (20 ml) was added. The mix was concentrated and the off-white solid was washed with ethyl acetate to yield maleate salt (8.95 g). A portion was recrystallized from acetonitrile yielding off-white crystalline solid which had the following properties: Mp. 186-188° C.; 1H NMR DMSO-d6 δ: 11.07 (brd s, 1H), 9.50 (brd s, 1H), 7.92 (dd, J=1.2, 6.6 Hz, 1H, 7.79 (dd, J=1.2, 6.6 Hz, 1H), 7.26-7.17 (m, 3H), 6.89 (d, J=9.1 Hz, 2H), 6.00 (s, 2H), 4.09 ( brd s, 2H), 3.99 (t, J=6.6 Hz, 2H), 3.70-3.65 (m, 2H), 3.17-2.98 (m, 4H), 2.20-2.00 (m, 4H), 1.95-1.86 (m, 2H). 13C NMR DMSO-d6 δ: 167.87, 162.14, 150.76, 149.18, 137.06, 136.53, 129.338, 127.26, 123.85, 119.35, 116.84, 116.63, 61.11, 52.08, 49.48, 38.43, 24.28, 23.88. IR (KBr): 3399, 3367, 32223, 3161, 3074, 2967, 2839, 2410, 1904, 1722, 1656, 1615, 1598, 1499, 1458, 1407, 1351, 1314, 1242, 1234, 1169, 1109, 1098, 1086,1059, 1032, 1003, 982, 945, 922, 863, 829, 814, 774, 756, 731, 691, 663, 580, 532, 513, 495, 480, 468, 445, 426, 407, (cm−1). Analysis calculated for C23H24Cl2N4O2.C4H4O4: C, 56.36; H, 4.90; N, 9.74; Found: C, 56.10; H, 5.06; N, 9.83
Reaction SMILES: Cl.[NH2:2][C@@H:3]([C:5]1[C:10]([F:11])=[CH:9][C:8]([NH:12][S:13]([CH3:16])(=[O:15])=[O:14])=[C:7]([CH3:17])[CH:6]=1)[CH3:4].F[P-](F)(F)(F)(F)F.C[N+](C)=C(N(C)C)ON1C2N=CC=CC=2N=N1.[OH:42][C:43]([C:46]1[CH:55]=[CH:54][C:53]2[CH2:52][CH:51]([C:56](O)=[O:57])[CH2:50][CH2:49][C:48]=2[N:47]=1)([CH3:45])[CH3:44].C(N(CC)C(C)C)(C)C>CN1CCCC1=O>[F:11][C:10]1[CH:9]=[C:8]([NH:12][S:13]([CH3:16])(=[O:15])=[O:14])[C:7]([CH3:17])=[CH:6][C:5]=1[C@H:3]([NH:2][C:56]([CH:51]1[CH2:50][CH2:49][C:48]2[N:47]=[C:46]([C:43]([OH:42])([CH3:44])[CH3:45])[CH:55]=[CH:54][C:53]=2[CH2:52]1)=[O:57])[CH3:4]
Reactant: CC(C)(O)c1ccc2c(n1)CCC(C(=O)O)C2
Reactant: Cc1cc([C@@H](C)N)c(F)cc1NS(C)(=O)=O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN1CCCC1=O
Product: Cc1cc([C@@H](C)NC(=O)C2CCc3nc(C(C)(C)O)ccc3C2)c(F)cc1NS(C)(=O)=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 53.9 %

Procedure:
A 4-mL vial was charged with (R)—N-(4-(1-aminoethyl)-5-fluoro-2-methylphenyl)methanesulfonamide hydrochloride (95 mg, 0.34 mmol) and N,N,N′,N′-tetramethyl-O-(7-azabenzotriazol-1-yl)uronium hexafluorophosphate (130 mg, 0.34 mmol). A solution of 2-(2-hydroxypropan-2-yl)-5,6,7,8-tetrahydroquinoline-6-carboxylic acid (66 mg, 0.28 mmol) and N,N-diisopropylethylamine (290 μL, 1.7 mmol) in N-methylpyrrolidinone (850 μL) was added and the mixture stirred at room temperature for 1 hour. The reaction was quenched with water (100 μL), filtered and purified by reverse-phase HPLC (10-75% MeCN in 10 mM Et2NH/H2O) to afford the amide as a light yellow solid (70 mg, 54%). Additional purification by silica chromatography was performed (0-100% EtOAc in hexanes) to obtain a white solid (45 mg, 35%). m/z=464.6 (M+H)+. 1H NMR (400 MHz, DMSO-d6) δ 9.19 (br s, 1H), 8.41 (app dd J=7.8 Hz, J=11.0 Hz, 1H), 7.45 (app dd, J=3.0 Hz, J=8.0 Hz, 1H), 7.36 (app dd, J=1.5 Hz, J=8.0 Hz, 1H), 7.23 (d, J=8.5 Hz, 1H), 7.07 (d, J=11.5 Hz, 1H), 5.17-5.04 (m, 2H) 3.02 (s, 3H), 2.92-2.73 (m, 4H), 2.68-2.57 (m, 1H), 2.26 (s, 3H), 2.09-1.96 (m, 1H), 1.88-1.66 (m, 1H), 1.39 (s, 3H), 1.39 (s, 3H), 1.35 (d, J=7.0 Hz, 3H).
Reaction SMILES: [C:1]([O:5][CH:6]([C:11]1[N:16]([CH3:17])[C:15](=[O:18])[C:14]2[NH:19][CH:20]=[CH:21][C:13]=2[C:12]=1[C:22]1[C:23]([CH3:32])=[C:24]2[C:29](=[CH:30][CH:31]=1)[O:28][CH2:27][CH2:26][CH2:25]2)[C:7]([O:9]C)=[O:8])([CH3:4])([CH3:3])[CH3:2].Br[CH2:34][CH:35]1[CH2:40][CH2:39][CH2:38][CH2:37][CH2:36]1>>[C:1]([O:5][CH:6]([C:11]1[N:16]([CH3:17])[C:15](=[O:18])[C:14]2[N:19]([CH2:34][CH:35]3[CH2:40][CH2:39][CH2:38][CH2:37][CH2:36]3)[CH:20]=[CH:21][C:13]=2[C:12]=1[C:22]1[C:23]([CH3:32])=[C:24]2[C:29](=[CH:30][CH:31]=1)[O:28][CH2:27][CH2:26][CH2:25]2)[C:7]([OH:9])=[O:8])([CH3:4])([CH3:3])[CH3:2]
Reactant: BrCC1CCCCC1
Reactant: COC(=O)C(OC(C)(C)C)c1c(-c2ccc3c(c2C)CCCO3)c2cc[nH]c2c(=O)n1C
Product: Cc1c(-c2c(C(OC(C)(C)C)C(=O)O)n(C)c(=O)c3c2ccn3CC2CCCCC2)ccc2c1CCCO2

Procedure:
The title compound was prepared in a manner similar to that described in Example 49 step D from methyl 2-(tert-butoxy)-2-(6-methyl-4-(5-methylchroman-6-yl)-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-5-yl)acetate and (bromomethyl)cyclohexane, and was isolated as white solid after reverse phase chromatography (45%): 1H NMR (400 MHz, CHLOROFORM-d) ppm 7.35-7.28 (m, 0.4H), 6.99 (d, J=8.4 Hz, 0.6H), 6.90 (t, J=2.5 Hz, 1H), 6.78-6.67 (m, 1H), 5.73 (d, J=2.7 Hz, 0.4H), 5.67 (d, J=2.7 Hz, 0.6H), 5.40 (s, 0.4H), 5.15 (d, J=2.1 Hz, 0.6H), 4.48-4.34 (m, 1H), 4.34-4.23 (m, 1H), 4.23-4.12 (m, 2H), 3.73-3.61 (m, 3H), 2.79-2.57 (m, 2H), 2.16-2.05 (m, 2H), 2.05-1.98 (m, 2H), 1.98-1.83 (m, 2H), 1.75-1.55 (m, 5H), 1.40-0.91 (m, 14H); LCMS (m/z) ES+=521 (M+1).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[N:7]([CH3:19])[N:8]=[C:9]([C:11]2[C:16]([F:17])=[CH:15][C:14]([Cl:18])=[CH:13][N:12]=2)[CH:10]=1)=[O:5])[CH3:2].C([O-])(=O)C.[Na+].[Cl:25]Cl>C(O)(=O)C>[CH2:1]([O:3][C:4]([C:6]1[N:7]([CH3:19])[N:8]=[C:9]([C:11]2[C:16]([F:17])=[CH:15][C:14]([Cl:18])=[CH:13][N:12]=2)[C:10]=1[Cl:25])=[O:5])[CH3:2]
Reactant: CCOC(=O)c1cc(-c2ncc(Cl)cc2F)nn1C
Reactant: ClCl
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)O
Product: CCOC(=O)c1c(Cl)c(-c2ncc(Cl)cc2F)nn1C
Temperature: 0 °C
Yield: 95 %

Procedure:
22.9 g of 5-(5-chloro-3-fluoro-2-pyridyl)-2-methyl-[2H]-pyrazole-3-carboxylic acid ethyl ester (Example P19) are introduced together with 19.9 g of sodium acetate into 300 ml of glacial acetic acid at a temperature of 65° C. With stirring, 6.3 g of chlorine gas are passed over the solution at that temperature in the course of 1 hour. The reaction mixture is then poured into 2.5 liters of ice-water and subsequently stirred for 20 minutes. The resulting precipitate is filtered off, washed with ice-water and then dried in vacuo at 50° C. 24.4 g of the desired title compound are obtained in the form of a yellow solid having a melting point of 77-79° C.
Reaction SMILES: Br[CH2:2][CH:3]1[O:7][CH2:6][CH2:5][O:4]1.[CH2:8]([NH2:11])[CH2:9][CH3:10].[OH-].[Na+]>O>[CH2:8]([NH:11][CH2:2][CH:3]1[O:7][CH2:6][CH2:5][O:4]1)[CH2:9][CH3:10]
Reactant: BrCC1OCCO1
Reactant: CCCN
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CCCNCC1OCCO1
Temperature: 100 °C
Reaction time: 0.5 h

Procedure:
2-Bromomethyl-1,3-dioxolane (20 grams) and n-propylamine (100 ml) were charged into a glass reaction vessel equipped with a mechanical stirrer, thermometer and reflux condenser. The reaction mixture was heated at a temperature of about 100° C. for a period of about 3 hours. After this time sodium hydroxide (10 grams) dissolved in water (100 ml) was added and the resulting mixture was stirred for a period of about 30 minutes. The reaction mixture was then extracted with ether and the ether solution separated and dried over magnesium sulfate. The dried solution was filtered and stripped of solvent to yield the desired product N-n-propyl-N-(1,3-dioxolan-2-ylmethyl)amine an an oil.
Reaction SMILES: FC(F)(F)[C:3](O)=[O:4].[CH2:8]([O:11][C:12]([N:14]1[C@H:18]([C:19]2[N:20]=[C:21]([CH2:24][NH:25]OC(C)(C)C)[S:22][CH:23]=2)[CH2:17][C@@H:16]([O:31][S:32]([CH3:35])(=[O:34])=[O:33])[CH2:15]1)=[O:13])[CH:9]=[CH2:10]>>[CH2:8]([O:11][C:12]([N:14]1[C@H:18]([C:19]2[N:20]=[C:21]([CH2:24][NH:25][CH:3]=[O:4])[S:22][CH:23]=2)[CH2:17][C@@H:16]([O:31][S:32]([CH3:35])(=[O:33])=[O:34])[CH2:15]1)=[O:13])[CH:9]=[CH2:10]
Reactant: O=C(O)C(F)(F)F
Reactant: C=CCOC(=O)N1C[C@H](OS(C)(=O)=O)C[C@H]1c1csc(CNOC(C)(C)C)n1
Product: C=CCOC(=O)N1C[C@H](OS(C)(=O)=O)C[C@H]1c1csc(CNC=O)n1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Trifluoroacetic acid (4 ml) is added to 1.26 g of (3R,5S)-1-allyloxycarbonyl-5-[2-(t-butoxyaminomethyl)thiazol-4-yl]-3-methanesulfonyloxypyrrolidine, and the mixture is stirred at room temperature for one hr. The reaction mixture is concentrated under reduced pressure. A saturated aqueous sodium hydrogencarbonate solution (30 ml) and 20 ml of dichloromethane are added to the residue, a mixed acid anhydride prepared from 1.0 ml of formic acid and 0.75 ml of acetic acid are added dropwise thereto, and the mixture is stirred at room temperature for one hr. The reaction mixture is subjected to separation, and the organic layer is washed with saturated saline and dried over anhydrous magnesium sulfate. The solvent is removed by evaporation under reduced pressure. The residue is purified by column chromatography on silica gel (methanol:ethyl acetate=5:95) to give 0.81 g of (3R,5S)-1-allyloxycarbonyl-5-(2-formylaminomethylthiazol-4-yl)-3-methanesulfonyloxypyrrolidine.