Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C@@H:2]([C:6]([OH:8])=[O:7])[C@H:3]([CH3:5])[OH:4].C([O-])(O)=O.[Na+].[CH2:14]([O:22][C:23](N1C=CC=CC1=O)=[O:24])[CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>O.C1COCC1>[OH:4][C@@H:3]([CH3:5])[C@@H:2]([NH:1][C:23]([O:22][CH2:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[O:24])[C:6]([OH:8])=[O:7]
Reactant: C[C@H](O)[C@@H](N)C(=O)O
Reactant: O=C(OCCc1ccccc1)n1ccccc1=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: C[C@H](O)[C@@H](NC(=O)OCCc1ccccc1)C(=O)O
Reaction time: 15 h
Yield: 104.8 %

Procedure:
To a stirred mixture of D-threonine (0.150 g, 1.25 mmol) and NaHCO3 (0.158 g, 1.89 mmol) in H2O (3.5 mL), the crude mixture containing phenethyl-2-pyridyl-carbonate and phenethyl-2-oxopyridine 1-carboxylate (0.459 g, 1.89 mmol) in THF (3.5 mL) was added. After 15 h at rt, the crude mixture was rotary evaporated to remove the organics and subsequently extracted with Et2O (3×5 mL). The aqueous phase was acidified with 2M HCl solution to pH 2-3 and subsequently extracted with AcOEt (3×10 mL). The organic fraction was dried over Na2SO4, filtered and concentrated to dryness to afford the title compound (0.35 g, 89%) as transparent oil, which was used in the next step without further purification. MS (ESI) m/z: 268 [M−H]+; (ESI) m/z: 266 [M−H]−. 1H NMR (DMSO-d6): δ 1.09 (d, J=6.4 Hz, 3H), 2.89 (t, J=6.9 Hz, 2H), 3.94 (dd, J=3.4, 9.0 Hz, 1H), 4.04-4.11 (m, 1H), 4.13-4.24 (m, 2H), 6.75 (d, J=9.0 Hz, 1H), 7.20-7.33 (m, 5H) 11.95 (br s, 1H).
Reaction SMILES: C([NH:8][C@H:9]([C:18]([NH:20][C@@H:21]([C:26]([NH:28][CH2:29][C:30]([NH:32][C@H:33]([C:41]([CH:43]1[C:50]2([NH2:52])[CH2:51][CH:46]3[CH2:47][CH:48]([CH2:53][C:44]1([C:54]([OH:56])=[O:55])[CH2:45]3)[CH2:49]2)=[O:42])[CH2:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)=[O:31])=[O:27])[CH2:22][CH2:23][S:24][CH3:25])=[O:19])[CH2:10][C:11]1[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=1)(OC(C)(C)C)=O.[ClH:57]>O1CCOCC1>[ClH:57].[NH2:8][C@H:9]([C:18]([NH:20][C@@H:21]([C:26]([NH:28][CH2:29][C:30]([NH:32][C@H:33]([C:41]([CH:43]1[C:50]2([NH2:52])[CH2:51][CH:46]3[CH2:47][CH:48]([CH2:53][C:44]1([C:54]([OH:56])=[O:55])[CH2:45]3)[CH2:49]2)=[O:42])[CH2:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)=[O:31])=[O:27])[CH2:22][CH2:23][S:24][CH3:25])=[O:19])[CH2:10][C:11]1[CH:12]=[CH:13][C:14]([OH:17])=[CH:15][CH:16]=1
Reactant: CSCC[C@@H](NC(=O)[C@H](Cc1ccc(O)cc1)NC(=O)OC(C)(C)C)C(=O)NCC(=O)N[C@@H](Cc1ccccc1)C(=O)C1C2(N)CC3CC(C2)CC1(C(=O)O)C3
Agent: Cl
Solvent: C1COCCO1
Product: CSCC[C@@H](NC(=O)[C@@H](N)Cc1ccc(O)cc1)C(=O)NCC(=O)N[C@@H](Cc1ccccc1)C(=O)C1C2(N)CC3CC(C2)CC1(C(=O)O)C3
Reaction time: 0.5 h

Procedure:
To a solution of 0.94 g of Boc-L-tyrosyl-D-methionyl-glycyl-L-phenyalanyl-3-amino-1-adamantanecarboxylic acid in 20 ml of dioxane is added 10 ml of a 5.7 N solution of hydrogen chloride in dioxane. The reaction mixture is allowed to stand for 30 minutes at room temperature. The solvent is removed under vacuum and the residue is dissolved in water. The cloudy solution is stirred with a small amount of SupercelHyflo for 30 minutes then filtered and lyophilized to give a white powder. The powder is dried for 2 hours at 50° C. and 0.1 mm pressure to give L-tyrosyl-D-methionyl-glycyl-L-phenylalanyl-3-amino-1-adamantanecarboxylic acid hydrochloride which is represented by the following formula ##STR27##
Reaction SMILES: Cl[CH2:2][C:3]([C:5]1[S:25][C:8]2[CH2:9][CH2:10][CH:11]3[C:16]([C:7]=2[CH:6]=1)=[N:15][N:14]([C:17]1[CH:22]=[CH:21][C:20]([CH3:23])=[CH:19][CH:18]=1)[C:13](=[O:24])[CH2:12]3)=[O:4].[C:26]([O-:29])(=[O:28])[CH3:27].[K+]>C(O)(=O)C>[C:26]([O:29][CH2:2][C:3]([C:5]1[S:25][C:8]2[CH2:9][CH2:10][CH:11]3[C:16]([C:7]=2[CH:6]=1)=[N:15][N:14]([C:17]1[CH:22]=[CH:21][C:20]([CH3:23])=[CH:19][CH:18]=1)[C:13](=[O:24])[CH2:12]3)=[O:4])(=[O:28])[CH3:27]
Reactant: Cc1ccc(N2N=C3c4cc(C(=O)CCl)sc4CCC3CC2=O)cc1
Reactant: CC(=O)[O-]
Agent: [K+]
Solvent: CC(=O)O
Product: CC(=O)OCC(=O)c1cc2c(s1)CCC1CC(=O)N(c3ccc(C)cc3)N=C21
Reaction time: 5 h
Yield: 71.3 %

Procedure:
To a suspension of 5.8 g of 8-chloroacetyl-4,4a,5,6-tetrahydro-2-(4-methylphenyl)thieno-[2,3-h]cinnolin-3(2H)-one in 100 ml of acetic acid was added 12 g of potassium acetate and the mixture was stirred for 5 hours. The mixture was poured into ice-cold water and the precipitate was collected by filtration. The filtrate was extracted with ethyl acetate. The extract was washed with brine, dried over anhydrous magnesium sulfate and concentrated in vacuo. The residue and the precipitate were combined and chromatographed on a silica gel (SiO2 :200 g) column using chloroform as an eluent. The resulting crystals were recrystallized from a mixed solvent of chloroform and methanol to give 4.4 g of 8-acetoxyacetyl-4,4a, 5,6-tetrahydro-2-(4-methylphenyl)thieno-[2,3-h]cinnolin-3(2H)-one as a white powder, melting at 144°-145° C.
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([C:8]#[C:9][CH:10]=[N:11][OH:12])[CH:5]=[CH:6][CH:7]=1.[CH3:13]C1C=C(C#CC=O)C=CC=1>>[OH:12][N:11]=[CH:10][C:9]#[C:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([CH3:13])[CH:3]=1
Reactant: ON=CC#Cc1cccc(Cl)c1
Reactant: Cc1cccc(C#CC=O)c1
Product: Cc1cccc(C#CC=NO)c1

Procedure:
The title compound was synthesized following the procedure reported for Compound 31e but starting from Compound 91b instead of Compound 31d. The crude title compound (brownish oil) was used in the next step without further purification.
Reaction SMILES: [Br:1][C:2]1[C:3]([CH2:24][C:25]2[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[CH:27][CH:26]=2)=[CH:4][C:5]([C:11]2(OC)[C@H:16]([OH:17])[C@@H:15]([OH:18])[C@H:14]([OH:19])[C@@H:13]([CH2:20][OH:21])[O:12]2)=[C:6]2[C:10]=1[CH2:9][CH2:8][CH2:7]2.C([SiH](CC)CC)C.B(F)(F)F.CCOCC>C(Cl)Cl.CC#N>[Br:1][C:2]1[C:3]([CH2:24][C:25]2[CH:26]=[CH:27][C:28]([O:31][CH3:32])=[CH:29][CH:30]=2)=[CH:4][C:5]([C@H:11]2[C@H:16]([OH:17])[C@@H:15]([OH:18])[C@H:14]([OH:19])[C@@H:13]([CH2:20][OH:21])[O:12]2)=[C:6]2[C:10]=1[CH2:9][CH2:8][CH2:7]2
Reactant: COc1ccc(Cc2cc(C3(OC)O[C@H](CO)[C@@H](O)[C@H](O)[C@H]3O)c3c(c2Br)CCC3)cc1
Agent: CC[SiH](CC)CC
Agent: FB(F)F
Solvent: CC#N
Solvent: CCOCC
Solvent: ClCCl
Product: COc1ccc(Cc2cc([C@@H]3O[C@H](CO)[C@@H](O)[C@H](O)[C@H]3O)c3c(c2Br)CCC3)cc1
Temperature: -30 °C

Procedure:
To a solution of compound 15 (0.94 g, 1.85 mmol) in CH2Cl2/CH3CN (8.9 mL/8.9 mL) were added triethylsilane (0.59 mL, 3.7 mmol) and boron trifluoride diethyl etherate (0.46 mL, 3.7 mmol) at −60° C. under nitrogen atmosphere. The mixture was warmed up to −30° C. for 2 h. The reaction mixture was quenched with saturated NaHCO3 solution (15 mL) and extracted with EtOAc (50 mL). The organic layer was washed with brine, dried over anhydrous MgSO4, filtered and concentrated in vacuo. The residue was purified by prep HPLC (reverse phase) to provide the compound E001 (0.15 g, 0.306 mmol, 17%).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[C:5](N)=[C:4]([CH3:12])[CH:3]=1.N([O-])=O.[Na+].OP=O>S(=O)(=O)(O)O.O.[Cu-]=O>[Br:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[C:4]([CH3:12])[CH:3]=1
Reactant: Cc1cc(Br)cc([N+](=O)[O-])c1N
Agent: O=[Cu-]
Agent: O=N[O-]
Agent: O=PO
Solvent: O
Product: Cc1cc(Br)cc([N+](=O)[O-])c1
Temperature: 0 °C
Yield: 82.7 %

Procedure:
A solution of 10 g of 4-bromo-2-methyl-6-nitro-phenylamine in 100 ml of concentrated sulfuric acid in an ice bath was treated dropwise with 3.58 g of sodium nitrite in 10 ml of water keeping the temperature below 10° C. The mixture was then treated simultaneously over 1 hr with 6.81 g of copper (I) oxide and 31.4 ml of hypophosphorus acid. Poured into ice water, extracted with ether, washed with water, dried over magnesium sulfate, and evaporated to dryness. The residue was purified by flash column chromatography on silica gel eluting with ethyl acetate/hexane (1:9) giving 7.73 g of 1-bromo-3-methyl-5-nitrobenzene. ##STR152##
Reaction SMILES: [CH2:1]([N:3]([CH2:27][CH3:28])[C:4](=[O:26])[NH:5][C@H:6]1[CH2:20][C@H:19]2[C@@H:9]([CH2:10][C:11]3[C:21]4[C:14](=[CH:15][CH:16]=[CH:17][C:18]2=4)[NH:13][C:12]=3[C:22](O)=O)[N:8]([CH3:25])[CH2:7]1)[CH3:2]>CO>[CH3:22][C:12]1[NH:13][C:14]2[C:21]3[C:11]=1[CH2:10][C@@H:9]1[C@@H:19]([C:18]=3[CH:17]=[CH:16][CH:15]=2)[CH2:20][C@H:6]([NH:5][C:4](=[O:26])[N:3]([CH2:27][CH3:28])[CH2:1][CH3:2])[CH2:7][N:8]1[CH3:25]
Reactant: CCN(CC)C(=O)N[C@H]1C[C@@H]2c3cccc4[nH]c(C(=O)O)c(c34)C[C@H]2N(C)C1
Solvent: CO
Product: CCN(CC)C(=O)N[C@H]1C[C@@H]2c3cccc4[nH]c(C)c(c34)C[C@H]2N(C)C1

Procedure:
8α-(3,3-diethylureido)-6-methylergoline-2-carboxylic acid, yield: 48%, [α]D =+27° (0.2% in methanol).
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[CH:5][CH:4]=[C:3]1[C:7]([NH:9][CH:10]([C:12]1[N:17]=[N:16][C:15]([NH:18][C:19]2[CH:24]=[C:23]([O:25][CH3:26])[C:22]([O:27][CH3:28])=[C:21]([O:29][CH3:30])[CH:20]=2)=[N:14][CH:13]=1)[CH3:11])=O.N1C=NC=N1.P(Cl)(Cl)(Cl)=O>N1C=CC=CC=1>[CH3:11][C:10]1[N:9]=[C:7]([C:3]2[N:2]([CH3:1])[CH:6]=[CH:5][CH:4]=2)[N:17]2[C:12]=1[CH:13]=[N:14][C:15]([NH:18][C:19]1[CH:24]=[C:23]([O:25][CH3:26])[C:22]([O:27][CH3:28])=[C:21]([O:29][CH3:30])[CH:20]=1)=[N:16]2
Reactant: COc1cc(Nc2ncc(C(C)NC(=O)c3cccn3C)nn2)cc(OC)c1OC
Agent: c1nc[nH]n1
Solvent: O=P(Cl)(Cl)Cl
Solvent: c1ccncc1
Product: COc1cc(Nc2ncc3c(C)nc(-c4cccn4C)n3n2)cc(OC)c1OC
Yield: 24.4 %

Procedure:
In a similar manner as described for Example 9, 1-methyl-N-(1-{3-[(3,4,5-trimethoxyphenyl)amino]-1,2,4-triazin-6-yl}ethyl)-1H-pyrrole-2-carboxamide (Intermediate 35) (222 mg, 0.54 mmol), and 1,2,4-triazole (220 mg, 3.2 mmol) in pyridine (10 mL) and phosphorous oxychloride (0.15 mL, 1.6 mmol) gave 5-methyl-7-(1-methyl-1H-pyrrol-2-yl)-N-(3,4,5-trimethoxyphenyl)imidazo[5,1-f][1,2,4]triazin-2-amine (52 mg, 25%) as a yellow solid. 1H NMR (DMSO-d6): δ9.54 (s, 1H), 9.18 (s, 1H), 7.19 (d, J=2.01 Hz, 1H), 7.16 (s, 2H), 6.98 (s, 1H), 6.14 (t, J=3.02 Hz, 1H), 3.96 (s, 3H), 3.74 (s, 6H), 3.61 (s, 3H), 2.51 (s, 3H). MS m/z 394 (M+1).
Reaction SMILES: [N:1]1[NH:2][C:3]([C:10]([OH:12])=O)=[C:4]2[CH2:9][O:8][CH2:7][CH2:6][C:5]=12.[NH2:13][C@@H:14]([CH3:30])[CH2:15][N:16]1[CH:20]=[CH:19][C:18]([C:21]2[CH:28]=[CH:27][C:24]([C:25]#[N:26])=[C:23]([Cl:29])[CH:22]=2)=[N:17]1>>[Cl:29][C:23]1[CH:22]=[C:21]([C:18]2[CH:19]=[CH:20][N:16]([CH2:15][C@@H:14]([NH:13][C:10]([C:3]3[NH:2][N:1]=[C:5]4[CH2:6][CH2:7][O:8][CH2:9][C:4]=34)=[O:12])[CH3:30])[N:17]=2)[CH:28]=[CH:27][C:24]=1[C:25]#[N:26]
Reactant: C[C@H](N)Cn1ccc(-c2ccc(C#N)c(Cl)c2)n1
Reactant: O=C(O)c1[nH]nc2c1COCC2
Product: C[C@@H](Cn1ccc(-c2ccc(C#N)c(Cl)c2)n1)NC(=O)c1[nH]nc2c1COCC2
Yield: 65.7 %

Procedure:
The title compound was prepared using the method of Example 34(d) starting from 2,4,6,7-tetrahydropyrano[4,3-c]pyrazole-3-carboxylic acid (0.168 g, 0.997 mmol) and (S)-4-(1-(2-aminopropyl)-1H-pyrazol-3-yl)-2-chlorobenzonitrile (0.2 g, 0.767 mmol). The product was triturated twice with acetonitrile. Yield 65.7%. 1H-NMR (400 MHz; d6-DMSO): δ 1.11 (d, 3H), 2.70 (t, 2H), 3.72-3.80 (m, 2H), 4.23-4.46 (m, 3H), 4.56-4.68 (m, 2H), 6.94 (d, 1H), 7.82 (d, 1H), 7.97-8.00 (m, 2H), 8.07-8.09 (m, 1H), 8.21 (d, 1H). 12.98 (s, 1H).
Reaction SMILES: Cl.[C:2]1([CH:8]([O:15][C:16]([C:18]2[N:23]3[C:24](=[O:27])[C@@H:25]([NH2:26])[C@H:22]3[S:21][CH2:20][C:19]=2[O:28][S:29]([CH3:32])(=[O:31])=[O:30])=[O:17])[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:33]([O:37][C:38]([NH:40][C:41]1[S:42][CH:43]=[C:44](/[C:46](=[N:50]/[O:51][C:52]([C:65]2[CH:70]=[CH:69][CH:68]=[CH:67][CH:66]=2)([C:59]2[CH:64]=[CH:63][CH:62]=[CH:61][CH:60]=2)[C:53]2[CH:58]=[CH:57][CH:56]=[CH:55][CH:54]=2)/[C:47](O)=[O:48])[N:45]=1)=[O:39])([CH3:36])([CH3:35])[CH3:34].CN1CCOCC1.P(Cl)(Cl)(OC1C=CC=CC=1)=O>ClCCl.Cl.O>[C:2]1([CH:8]([O:15][C:16]([C:18]2[N:23]3[C:24](=[O:27])[C@@H:25]([NH:26][C:47](=[O:48])/[C:46](/[C:44]4[N:45]=[C:41]([NH:40][C:38]([O:37][C:33]([CH3:35])([CH3:34])[CH3:36])=[O:39])[S:42][CH:43]=4)=[N:50]\[O:51][C:52]([C:59]4[CH:64]=[CH:63][CH:62]=[CH:61][CH:60]=4)([C:53]4[CH:58]=[CH:57][CH:56]=[CH:55][CH:54]=4)[C:65]4[CH:70]=[CH:69][CH:68]=[CH:67][CH:66]=4)[C@H:22]3[S:21][CH2:20][C:19]=2[O:28][S:29]([CH3:32])(=[O:31])=[O:30])=[O:17])[C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)Nc1nc(/C(=N/OC(c2ccccc2)(c2ccccc2)c2ccccc2)C(=O)O)cs1
Reactant: CS(=O)(=O)OC1=C(C(=O)OC(c2ccccc2)c2ccccc2)N2C(=O)[C@@H](N)[C@H]2SC1
Agent: Cl
Agent: O=P(Cl)(Cl)Oc1ccccc1
Solvent: O
Solvent: ClCCl
Solvent: CN1CCOCC1
Product: CC(C)(C)OC(=O)Nc1nc(/C(=N/OC(c2ccccc2)(c2ccccc2)c2ccccc2)C(=O)N[C@@H]2C(=O)N3C(C(=O)OC(c4ccccc4)c4ccccc4)=C(OS(C)(=O)=O)CS[C@H]23)cs1
Reaction time: 0.07 h
Yield: 91.9 %

Procedure:
To a suspension of 7β-amino-3-methanesulfonyloxy-3-cephem-4-carboxylic acid diphenylmethyl ester hydrochloride (37.27 g: 75 mMol.) and (Z)-2-(2-t-butoxycarbonylaminothiazol-4-yl)-2-trityloxyiminoacetic acid (45.63 g; 86 mMol.) in dichloromethane (600 ml) is added at -30° C. N-methylmorpholine (27.2 ml: 0.25 Mol.) over 3 minutes. After 4 minutes, phenyl dichlorophosphate (12.3 ml: 82 mMol.) is added to the mixture. After stirring over 3 hours, the mixture is diluted with 10% hydrochloric acid (40 ml) and water and extracted with ethyl acetate. The extract is washed with water, aqueous sodium hydrogen carbonate, dilute hydrochloric acid, and water, dried over sodium sulfate, and concentrated under reduced pressure. The residue is dissolved in isopropanol (2 liters) by warming and cooled to give 7β-[(Z)-2-(2-t-butoxycarbonylaminothiazol-4-yl)-2-trityloxyiminoacetamido]-3-methanesulfonyloxy-3-cephem-4-carboxylic acid diphenylmethyl ester (67 g). Colorless powder. Yield: 92%.
Reaction SMILES: [N:1]([C@@H:4]1[CH2:8][N:7]([C:9]([O:11][CH2:12][C:13]2[CH:18]=[CH:17][C:16]([N+:19]([O-:21])=[O:20])=[CH:15][CH:14]=2)=[O:10])[C@H:6]([C:22]([C:24]2[N:25]=[CH:26][N:27]3[CH:31]=[CH:30][S:29][C:28]=23)=[O:23])[CH2:5]1)=[N+:2]=[N-:3].[CH2:32]([Sn:36](Cl)([CH2:41][CH2:42][CH2:43][CH3:44])[CH2:37][CH2:38][CH2:39][CH3:40])[CH2:33][CH2:34][CH3:35].C[Si]([N-][Si](C)(C)C)(C)C.[Li+].C1COCC1>>[N:1]([C@@H:4]1[CH2:8][N:7]([C:9]([O:11][CH2:12][C:13]2[CH:18]=[CH:17][C:16]([N+:19]([O-:21])=[O:20])=[CH:15][CH:14]=2)=[O:10])[C@H:6]([C:22]([C:24]2[N:25]=[CH:26][N:27]3[CH:31]=[C:30]([Sn:36]([CH2:37][CH2:38][CH2:39][CH3:40])([CH2:41][CH2:42][CH2:43][CH3:44])[CH2:32][CH2:33][CH2:34][CH3:35])[S:29][C:28]=23)=[O:23])[CH2:5]1)=[N+:2]=[N-:3]
Reactant: CCCC[Sn](Cl)(CCCC)CCCC
Reactant: [N-]=[N+]=N[C@H]1C[C@@H](C(=O)c2ncn3ccsc23)N(C(=O)OCc2ccc([N+](=O)[O-])cc2)C1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: CCCC[Sn](CCCC)(CCCC)c1cn2cnc(C(=O)[C@@H]3C[C@H](N=[N+]=[N-])CN3C(=O)OCc3ccc([N+](=O)[O-])cc3)c2s1

Procedure:
The title compound (321 mg) was prepared in substantially the same manner as in step c) of Synthesis Example 1, except that 585 mg of 7-[(2S,4S)-4-azido-1-(4-nitrobenzyloxycarbonyl)pyrrolidin-2-yl]carbonylimidazo[5,1-b]thiazole, 0.396 ml of tri-n-butylstannyl chloride, and 2.8 ml of a 1.0 N lithium bis(trimethylsilyl)amide/THF solution were used as the starting materials.
Reaction SMILES: [CH3:1][C:2]([NH2:9])([CH2:5][CH:6]([CH3:8])[CH3:7])[CH2:3][NH2:4].[Cl:10][C:11]1[CH:12]=[C:13]([O:24][CH2:25][C:26]2[C:31]([F:32])=[CH:30][CH:29]=[CH:28][C:27]=2[F:33])[C:14]2[N:15]([C:17]([C:21](O)=[O:22])=[C:18]([CH3:20])[N:19]=2)[CH:16]=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.CN1CCOCC1>CN(C=O)C.O.C(O)(C(F)(F)F)=O>[NH2:9][C:2]([CH3:1])([CH2:5][CH:6]([CH3:8])[CH3:7])[CH2:3][NH:4][C:21]([C:17]1[N:15]2[CH:16]=[C:11]([Cl:10])[CH:12]=[C:13]([O:24][CH2:25][C:26]3[C:27]([F:33])=[CH:28][CH:29]=[CH:30][C:31]=3[F:32])[C:14]2=[N:19][C:18]=1[CH3:20])=[O:22]
Reactant: CC(C)CC(C)(N)CN
Reactant: Cc1nc2c(OCc3c(F)cccc3F)cc(Cl)cn2c1C(=O)O
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: O=C(O)C(F)(F)F
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Product: Cc1nc2c(OCc3c(F)cccc3F)cc(Cl)cn2c1C(=O)NCC(C)(N)CC(C)C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
61 mg (0.47 mmol) of rac-2,4-dimethylpentane-1,2-diamine were added to 150 mg (0.43 mmol) of 6-chloro-8-[(2,6-difluorobenzyl)oxy]-2-methylimidazo[1,2-a]pyridine-3-carboxylic acid Example 16A, 143 mg (0.45 mmol) of TBTU and 0.19 ml (1.70 mmol) of 4-methylmorpholine in DMF (1.5 ml), and the reaction mixture was stirred at RT overnight. The mixture was diluted with water/TFA and purified by prep. RP-HPLC (acetonitrile/water gradient with addition of 0.1% TFA). The product fraction was concentrated. Saturated aqueous sodium bicarbonate solution was added to the residue, and the mixture was extracted three times with dichloromethane. The combined organic phases were dried over sodium sulphate, filtered off and concentrated. This gave 162 mg (79% of theory, purity 96%) of the target compound.
Reaction SMILES: [OH:1][C:2]1[C:3]2[O:21][N:20]=[C:19]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[C:4]=2[C:5]([C:13]#[C:14][Si](C)(C)C)=[N:6][C:7]=1[C:8]([O:10][CH2:11][CH3:12])=[O:9].C(=O)([O-])[O-].[Cs+].[Cs+]>CCO.C(Cl)Cl>[C:13]([C:5]1[C:4]2[C:19]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)=[N:20][O:21][C:3]=2[C:2]([OH:1])=[C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[N:6]=1)#[CH:14]
Reactant: CCOC(=O)c1nc(C#C[Si](C)(C)C)c2c(-c3ccccc3)noc2c1O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: ClCCl
Solvent: CCO
Product: C#Cc1nc(C(=O)OCC)c(O)c2onc(-c3ccccc3)c12
Temperature: 25 °C
Reaction time: 14 h
Yield: 111.1 %

Procedure:
Ethyl 7-hydroxy-3-phenyl-4-((trimethylsilyl)ethynyl)isoxazolo[4,5-c]pyridine-6-carboxylate (205 mg, 0.54 mmol) was dissolved in a 1:1 mixture of EtOH/CH2Cl2 (6 mL). Cesium carbonate (211 mg, 0.65 mmol) was added and the resulting slurry was stirred at room temperature for 14 h. The solvent was evaporated and the residue was partitioned between EtOAc (25 mL) and 1 M hydrochloric acid (25 mL). The aqueous layer was extracted with CH2Cl2 and the combined organic layer was dried over MgSO4 and concentrated to give 185 mg of the title compound. MS: (+) m/z 309.29 (M+1).
Reaction SMILES: [C:1]([C:4]1[N:9]=[N:8][C:7]([NH:10][C@@H:11]2[CH2:16][CH2:15][O:14][CH2:13][C@@H:12]2[NH:17]C(=O)OC(C)(C)C)=[CH:6][C:5]=1[NH:25][C:26]1[CH:31]=[CH:30][CH:29]=[C:28]([CH3:32])[N:27]=1)(=[O:3])[NH2:2].FC(F)(F)C(O)=O>ClCCl>[NH2:17][C@@H:12]1[C@H:11]([NH:10][C:7]2[N:8]=[N:9][C:4]([C:1]([NH2:2])=[O:3])=[C:5]([NH:25][C:26]3[CH:31]=[CH:30][CH:29]=[C:28]([CH3:32])[N:27]=3)[CH:6]=2)[CH2:16][CH2:15][O:14][CH2:13]1
Reactant: Cc1cccc(Nc2cc(N[C@@H]3CCOC[C@@H]3NC(=O)OC(C)(C)C)nnc2C(N)=O)n1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1cccc(Nc2cc(N[C@@H]3CCOC[C@@H]3N)nnc2C(N)=O)n1
Temperature: 0 °C
Reaction time: 3 h
Yield: 28.6 %

Procedure:
tert-butyl (3R,4R)-4-(6-carbamoyl-5-(6-methylpyridin-2-ylamino)pyridazin-3-ylamino)tetrahydro-2H-pyran-3-ylcarbamate (60 mg, 83% pure, 0.112 mmol) was dissolved in dichloromethane (0.85 mL) and cooled to 0° C. Trifluoroacetic acid (0.35 mL, 4.49 mmol) was added drop-wise, then the mixture was warmed to room temperature. After 3 h, the mixture was concentrated in vacuo then water, sodium bicarbonate solution and ethyl acetate were added. The aqueous phase was extracted with ethyl acetate. Sodium chloride was added to the aqueous layer and it was further extracted with ethyl acetate. The combined organic extracts were washed with saturated aqueous sodium chloride solution, dried over sodium sulfate, filtered, and concentrated in vacuo. Purification by chromatography (silica, 0-10% methanol in dichloromethane) gave 6-((3R,4R)-3-amino-tetrahydropyran-4-ylamino)-4-(6-methyl-pyridin-2-ylamino)-pyridazine-3-carboxylic acid amide (11 mg, 28%) as an off-white solid. 1H NMR (300 MHz, DMSO-d6) δ ppm 11.61 (s, 1H) 8.39 (br. s., 1H) 8.12 (s, 1H) 7.65 (br. s., 1H) 7.60 (t, J=7.7 Hz, 1H) 6.95 (d, J=7.2 Hz, 1H) 6.85 (d, J=7.6 Hz, 1H) 6.75 (d, J=8.3 Hz, 1H) 4.10 (br. s., 1H) 3.79-3.89 (m, 1H) 3.66-3.75 (m, 1H) 3.49-3.57 (m, 1H) 3.37-3.47 (m, 1H) 3.00-3.08 (m, 1H) 1.94-2.12 (m, 1H) 1.76-1.92 (m, 1H) 1.63-1.73 (m, 1H). MS (EI/CI) m/z: 344 [M+H].
Reaction SMILES: F[C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=1.[NH:10]1[CH2:15][CH2:14][CH2:13][CH2:12][CH:11]1[CH2:16][OH:17].C([O-])(O)=O.[Na+].O>CN(C=O)C>[OH:17][CH2:16][CH:11]1[CH2:12][CH2:13][CH2:14][CH2:15][N:10]1[C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=1
Reactant: N#Cc1ccc(F)cc1
Reactant: OCC1CCCCN1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: N#Cc1ccc(N2CCCCC2CO)cc1
Temperature: 120 °C
Yield: 9.2 %

Procedure:
In a screw cap pressure tube, 4-fluorobenzonitrile (354.0 mg, 3.15 mmol), piperidin-2-ylmethanol (363.4 mg, 3.15 mmol) and NaHCO3 were suspended in DMF (2.0 ml). The tube was sealed and the mixture heated to 120° C. for 3 days. The mixture was allowed to cool. H2O was added and the product extracted with EtOAc. The combined organic extracts were washed with H2O, dried (MgSO4), filtered and concentrated. The crude product was purified by flash chromatography (CH2Cl2/MeOH 98:2→96:4) affording 63 mg (9%) of the title compound.
Reaction SMILES: C[O:2][C:3]1[N:8]=[CH:7][C:6]([C:9]2[CH:18]=[CH:17][C:12]([C:13]([O:15][CH3:16])=[O:14])=[CH:11][CH:10]=2)=[CH:5][CH:4]=1.B(Br)(Br)Br>ClCCl>[OH:2][C:3]1[N:8]=[CH:7][C:6]([C:9]2[CH:18]=[CH:17][C:12]([C:13]([O:15][CH3:16])=[O:14])=[CH:11][CH:10]=2)=[CH:5][CH:4]=1
Reactant: COC(=O)c1ccc(-c2ccc(OC)nc2)cc1
Agent: BrB(Br)Br
Solvent: ClCCl
Product: COC(=O)c1ccc(-c2ccc(O)nc2)cc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A solution of Example 252D (0.5 g, 2.2 mmol) in dichloromethane at −78° C. was treated with 1M BBr3 in dichloromethane (15 mL), warm to room temperature, and stirred for 18 hours. The reaction was quenched with methanol (5 mL), diluted with dichloromethane (100 mL), washed with water (30 mL), brine (30 mL), dried (Na2SO4), filtered, and concentrated. The concentrate was purified by flash column chromatography on silica gel with 2:1 hexanes/ethyl acetate to provide the desired product. MS (ESI) m/e 228, 230 (M−H)−, (M+H)+.
Reaction SMILES: Br[CH2:2][C:3]1[CH:4]=[C:5]([C:13]([O:15][CH3:16])=[O:14])[C:6](=[CH:11][CH:12]=1)[C:7]([O:9][CH3:10])=[O:8].[P:17]([O:24]CC)([O:21][CH2:22][CH3:23])[O:18][CH2:19][CH3:20]>>[CH2:19]([O:18][P:17]([CH2:2][C:3]1[CH:4]=[C:5]([C:13]([O:15][CH3:16])=[O:14])[C:6](=[CH:11][CH:12]=1)[C:7]([O:9][CH3:10])=[O:8])([O:21][CH2:22][CH3:23])=[O:24])[CH3:20]
Reactant: CCOP(OCC)OCC
Reactant: COC(=O)c1ccc(CBr)cc1C(=O)OC
Product: CCOP(=O)(Cc1ccc(C(=O)OC)c(C(=O)OC)c1)OCC
Yield: 77 %

Procedure:
65.7 g (229 mmol) of dimethyl 4-bromomethylphthalate are placed in 100 ml (583 mmol) of triethyl phosphite in a round-bottomed flask. The mixture is refluxed for 4 hours. The medium is then distilled to remove the triethyl phosphite. 60.7 g (77%) of the expected product are obtained in the form of a yellow oil.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH2:7]([N:9]1[C:18]2[C:13](=[CH:14][C:15]([F:20])=[C:16](F)[CH:17]=2)[C:12](=[O:21])[N:11]([OH:22])[C:10]1=[O:23])[CH3:8].C(N(CC)CC)C>C(#N)C>[CH2:7]([N:9]1[C:18]2[C:13](=[CH:14][C:15]([F:20])=[C:16]([N:1]3[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]3)[CH:17]=2)[C:12](=[O:21])[N:11]([OH:22])[C:10]1=[O:23])[CH3:8]
Reactant: C1CCNCC1
Reactant: CCn1c(=O)n(O)c(=O)c2cc(F)c(F)cc21
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CCn1c(=O)n(O)c(=O)c2cc(F)c(N3CCCCC3)cc21
Yield: 48.8 %

Procedure:
Piperidine (0.025 mL, 0.22 mmol) was added to a solution of 1-ethyl-6,7-difluoro-3-hydroxy-1H-quinazoline-2,4-dione (Example D, 0.05 g, 0.2 mmol) and triethylamine (0.06 mL, 0.4 mmol) in 20 mL of acetonitrile. The solution was heated to reflux for 23 hours, cooled, and concentrated to a solid. The solid was dissolved in chloroform washed with 1N HCl, water, brine, and dried over magnesium sulfate. The solution was concentrated to give 0.03 g of the title compound as a solid, mp 173-175° C.