Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.Cl.Cl.[O:4]1[C:12]2[CH:11]=[CH:10][N:9]=[C:8]([N:13]3[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][C@H:21]4[CH2:26][CH2:25][C@H:24]([NH2:27])[CH2:23][CH2:22]4)[CH2:15][CH2:14]3)[C:7]=2[CH2:6][CH2:5]1.[CH3:28][O:29][CH2:30][CH2:31][C:32](O)=[O:33]>>[O:4]1[C:12]2[CH:11]=[CH:10][N:9]=[C:8]([N:13]3[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][C@H:21]4[CH2:26][CH2:25][C@H:24]([NH:27][C:32](=[O:33])[CH2:31][CH2:30][O:29][CH3:28])[CH2:23][CH2:22]4)[CH2:15][CH2:14]3)[C:7]=2[CH2:6][CH2:5]1
Reactant: N[C@H]1CC[C@H](CCN2CCN(c3nccc4c3CCO4)CC2)CC1
Reactant: COCCC(=O)O
Agent: Cl
Product: COCCC(=O)N[C@H]1CC[C@H](CCN2CCN(c3nccc4c3CCO4)CC2)CC1

Procedure:
The title compound, off-white solid (65 mg, 62%), MS (ISP) m/z=417.4 [(M+H)+], mp 246.5° C., was prepared in accordance with the general method of example 32 from trans-4-{2-[4-(2,3-dihydrofuro[3,2-c]pyridin-4-yl)-piperazin-1-yl]-ethyl}-cyclohexanamine trihydrochloride (intermediate C) (110 mg, 0.25 mmol) and 3-methoxypropionic acid.
Reaction SMILES: [CH:1]([C:4]1[CH:8]=[C:7]([N:9]2[CH2:57][CH2:56][C:12]3[N:13]=[C:14]([C:36]4[CH:44]=[CH:43][CH:42]=[C:41]5[C:37]=4[C:38]([CH3:55])=[CH:39][N:40]5[S:45]([C:48]4[CH:54]=[CH:53][C:51]([CH3:52])=[CH:50][CH:49]=4)(=[O:47])=[O:46])[N:15]=[C:16]([N:17]4[CH2:22][CH2:21][N:20](S(C5C=CC=CC=5[N+]([O-])=O)(=O)=O)[C@H:19]([CH3:35])[CH2:18]4)[C:11]=3[CH2:10]2)[N:6]([CH3:58])[N:5]=1)([CH3:3])[CH3:2].C1CCN2C(=NCCC2)CC1.SCC(O)=O>CN(C=O)C.O.ClCCl>[CH:1]([C:4]1[CH:8]=[C:7]([N:9]2[CH2:57][CH2:56][C:12]3[N:13]=[C:14]([C:36]4[CH:44]=[CH:43][CH:42]=[C:41]5[C:37]=4[C:38]([CH3:55])=[CH:39][N:40]5[S:45]([C:48]4[CH:49]=[CH:50][C:51]([CH3:52])=[CH:53][CH:54]=4)(=[O:46])=[O:47])[N:15]=[C:16]([N:17]4[CH2:22][CH2:21][NH:20][C@H:19]([CH3:35])[CH2:18]4)[C:11]=3[CH2:10]2)[N:6]([CH3:58])[N:5]=1)([CH3:2])[CH3:3]
Reactant: Cc1ccc(S(=O)(=O)n2cc(C)c3c(-c4nc5c(c(N6CCN(S(=O)(=O)c7ccccc7[N+](=O)[O-])[C@H](C)C6)n4)CN(c4cc(C(C)C)nn4C)CC5)cccc32)cc1
Agent: O=C(O)CS
Solvent: O
Solvent: C1CCC2=NCCCN2CC1
Solvent: CN(C)C=O
Product: Cc1ccc(S(=O)(=O)n2cc(C)c3c(-c4nc5c(c(N6CCN[C@H](C)C6)n4)CN(c4cc(C(C)C)nn4C)CC5)cccc32)cc1
Reaction time: 3 h

Procedure:
To a solution of (R)-6-(3-isopropyl-1-methyl-1H-pyrazol-5-yl)-2-(3-methyl-1-tosyl-1H-indol-4-yl)-4-(3-methyl-4-((2-nitrophenyl)sulfonyl)piperazin-1-yl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidine (105 mg, 0.127 mmol) in DMF (3 mL) was added DBU (0.1 mL, 0.64 mmol) followed by 2-mercaptoacetic acid (0.018 mL, 0.255 mmol). The mixture was stirred for 3 hours and then diluted with water and dichloromethane. The layers were separated and the aqueous layer was extracted three additional times with dichloromethane. The organic layers were combined, dried over Na2SO4, filtered and concentrated. The resulting residue was purified via silica gel flash chromatography [4-25% (2 M NH3 in MeOH)/DCM] to provide (R)-6-(3-isopropyl-1-methyl-1H-pyrazol-5-yl)-2-(3-methyl-1-tosyl-1H-indol-4-yl)-4-(3-methylpiperazin-1-yl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidine. MS (ESI+) m/z 639.4 (M+H)+.
Reaction SMILES: Cl.[Cl:2][C:3]1[C:4]([F:38])=[C:5]([F:37])[CH:6]=[C:7]2[C:12]=1[N:11]([C:13]1[C:18]([F:19])=[CH:17][C:16]([F:20])=[C:15]([NH:21]CC3C=CC(OC)=CC=3)[N:14]=1)[CH:10]=[C:9]([C:31]([O:33]CC)=[O:32])[C:8]2=[O:36]>C(O)(=O)C>[NH2:21][C:15]1[N:14]=[C:13]([N:11]2[C:12]3[C:7](=[CH:6][C:5]([F:37])=[C:4]([F:38])[C:3]=3[Cl:2])[C:8](=[O:36])[C:9]([C:31]([OH:33])=[O:32])=[CH:10]2)[C:18]([F:19])=[CH:17][C:16]=1[F:20]
Reactant: CCOC(=O)c1cn(-c2nc(NCc3ccc(OC)cc3)c(F)cc2F)c2c(Cl)c(F)c(F)cc2c1=O
Agent: Cl
Solvent: CC(=O)O
Product: Nc1nc(-n2cc(C(=O)O)c(=O)c3cc(F)c(F)c(Cl)c32)c(F)cc1F
Reaction time: 16 h
Yield: 57.6 %

Procedure:
To a mixed solution of 6 ml of 4N hydrochloric acid and 6 ml of acetic acid was added 3.00 g of ethyl 8-chloro-1-[3,5-difluoro-6-(p-methoxybenzylamino)pyridin-2-yl]-6,7-difluoro-4-oxo-1,4-dihydroquinoline-3-carboxylate, and the mixture was heated under reflux with stirring for 16 hours. The solution was allowed to cool and stand, and the precipitate was collected by decantation, and washed by adding a small amount of distilled water, shaking, allowing to stand, and decanting. To the precipitate was added 10 ml of ethanol, and the mixture was heated under reflux with stirring for 1 hour and allowed to cool and stand, and the precipitate was collected by decantation. To this precipitate was again added 10 ml of chloroform, and the mixture was stirred under reflux condition for 1 hour and allowed to cool, and the precipitate was collected by filtration and washed with ethanol and diisopropylether successively to obtain 1.25 g of the title compound as a pale brown powder.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(N(CC)CC)C.I[C:28]1[N:29]=[C:30]([CH3:33])[NH:31][CH:32]=1.C[Si]([C:38]#[C:39][C:40]1[CH:45]=[CH:44][N:43]=[C:42]([C:46]#[N:47])[CH:41]=1)(C)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>C1COCC1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.Cl[Pd]Cl.[Cu]I>[CH3:33][C:30]1[NH:31][CH:32]=[C:28]([C:38]#[C:39][C:40]2[CH:45]=[CH:44][N:43]=[C:42]([C:46]#[N:47])[CH:41]=2)[N:29]=1
Reactant: C[Si](C)(C)C#Cc1ccnc(C#N)c1
Reactant: Cc1nc(I)c[nH]1
Agent: Cl[Pd]Cl
Agent: [Cu]I
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: Cc1nc(C#Cc2ccnc(C#N)c2)c[nH]1
Temperature: 60 °C

Procedure:
Triphenylphosphine (126 mg, 0.48 mmol), bis(triphenylphosphine)palladium(II)chloride (1.01 g, 1.44 mmol) and triethylamine (3.65 g, 101.2 mmol) were dissolved in 40 ml of dry THF. This mixture was evacuated and backfilled with argon several times to remove oxygen from the solution. 4-iodo-2-methyl-1H-imidazole [Tetrahedron Letters 30(11), 1409 (1989)] (5.0 g, 20.8 mmol), 4-trimethylsilanylethynyl-pyridine-2-carbonitrile (4.43 g, 22.1 mmol) and copper (I) iodide (46 mg, 0.24 mmol) were added and the mixture was warmed to 60° C. A 1M solution of tetrabutylammonium fluoride (24 ml, 24.0 mmol) was added dropwise over a period of 30 min. After the addition was finished, the reaction mixture was stirred at 60° C. for another hour. The solvent was evaporated. The residue was taken up in 200 mL water and extracted three times with 200 ml of ethyl acetate. The combined organic extracts were dried with magnesium sulfate, filtered and evaporated. The crude product was purified by flash chromatography on silica gel (methanol/methylene chloride 5:95). The desired product was obtained as a light yellow solid (1.06 g, 21%). MS: m/e=208.9 (M+).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([S:8][C:9]2[CH:17]=[C:16]3[C:12]([C:13]([CH:18]=[CH:19][C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)=[N:14][NH:15]3)=[CH:11][CH:10]=2)[CH:5]=[CH:6][CH:7]=1.N1C=CC=CC=1.[C:32](OC(=O)C)(=[O:34])[CH3:33]>ClCCl.O>[C:32]([NH:1][C:2]1[CH:3]=[C:4]([S:8][C:9]2[CH:17]=[C:16]3[C:12]([C:13]([CH:18]=[CH:19][C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)=[N:14][NH:15]3)=[CH:11][CH:10]=2)[CH:5]=[CH:6][CH:7]=1)(=[O:34])[CH3:33]
Reactant: CC(=O)OC(C)=O
Reactant: Nc1cccc(Sc2ccc3c(C=Cc4ccccc4)n[nH]c3c2)c1
Solvent: ClCCl
Solvent: O
Solvent: c1ccncc1
Product: CC(=O)Nc1cccc(Sc2ccc3c(C=Cc4ccccc4)n[nH]c3c2)c1
Temperature: 23 °C
Reaction time: 0.17 h
Yield: 129.7 %

Procedure:
To a solution of 6-(3-aminophenylsulfanyl)-3-styryl-1H-indazole (43.7 mg, 0.10 mmol) in dichloromethane (0.5 mL) was added pyridine (81 μL, 1.0 mmol, 10 equiv), and acetic anhydride (47 μL, 0.5 mmol, 5 equiv). The mixture was allowed to stir for 10 min at 23° C. The mixture was diluted with water and the product was extracted with 30% hexane in ethyl acetate. The organic material was washed with 5% citric acid and saturated sodium bicarbonate. The organic material was dried over sodium sulfate, decanted and concentrated. Purification by silica gel chromatography (3:7 ethyl acetate-hexane) gave 6-(3-acetamido-phenylsulfanyl)-3-styryl-1H-indazole as an oil (50 mg, 97%): Rf sm 0.33, Rf p 0.18 (ethyl acetate-hexane 3:7); 1H NMR (300 MHz, CDCl3) δ 7.94 (d, 1H), 7.65-7.1 (m, 13H), 5.70 (s, 2H), 3.62 (t, 2H, J=8.2 Hz), 2.18 (s, 3H), 0.93 (t, 2H, J=8.2 Hz), −0.05 (s, 9H). HRMS (FAB) [M+Cs]/z Calc'd 648.1117, found 648.1098.
Reaction SMILES: [C:1]([O-:6])(=[O:5])[C:2]([CH3:4])=[CH2:3].[CH2:7]([Sn+:11]([CH2:16][CH2:17][CH2:18][CH3:19])[CH2:12][CH2:13][CH2:14][CH3:15])[CH2:8][CH2:9][CH3:10].[C:20]1([CH3:26])[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>>[C:1]([O-:6])(=[O:5])[C:2]([CH3:4])=[CH2:3].[CH2:16]([Sn+:11]([CH2:7][CH2:8][CH2:9][CH3:10])[CH2:12][CH2:13][CH2:14][CH3:15])[CH2:17][CH2:18][CH3:19].[CH2:1]=[CH:26][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: Cc1ccccc1
Agent: C=C(C)C(=O)[O-]
Agent: CCCC[Sn+](CCCC)CCCC
Product: C=Cc1ccccc1

Procedure:
S8 was prepared with the same additives as in S7. In this synthesis unequal molar quantities of tri-n-butyltin methacrylate (0.1 mole) and stryene (0.2 mole) were reacted with the azo initiator in 200 ml of toluene for 24 hours. The resultant polymer was a transparent, yellow tinted elastomer that could be cast as a film from the toluene solution. Analysis showed 20.46% Sn.
Reaction SMILES: C(C1NC=CN=1)(C1NC=CN=1)=O.[C:13]([O:17][C:18]([NH:20][C:21]1([C:25]([OH:27])=O)[CH2:24][O:23][CH2:22]1)=[O:19])([CH3:16])([CH3:15])[CH3:14].O[N:29]=[C:30]([C:32]1[CH:33]=[CH:34][C:35]([CH3:50])=[C:36]([NH:38][C:39]([C:41]2[N:45]3[CH:46]=[CH:47][CH:48]=[CH:49][C:44]3=[N:43][CH:42]=2)=[O:40])[CH:37]=1)[NH2:31]>CN1C(=O)CCC1>[N:43]1[CH:42]=[C:41]([C:39]([NH:38][C:36]2[CH:37]=[C:32]([C:30]3[N:29]=[C:25]([C:21]4([NH:20][C:18](=[O:19])[O:17][C:13]([CH3:14])([CH3:15])[CH3:16])[CH2:22][O:23][CH2:24]4)[O:27][N:31]=3)[CH:33]=[CH:34][C:35]=2[CH3:50])=[O:40])[N:45]2[CH:46]=[CH:47][CH:48]=[CH:49][C:44]=12
Reactant: CC(C)(C)OC(=O)NC1(C(=O)O)COC1
Reactant: Cc1ccc(C(N)=NO)cc1NC(=O)c1cnc2ccccn12
Agent: O=C(c1ncc[nH]1)c1ncc[nH]1
Solvent: CN1CCCC1=O
Product: Cc1ccc(-c2noc(C3(NC(=O)OC(C)(C)C)COC3)n2)cc1NC(=O)c1cnc2ccccn12
Temperature: 125 °C
Reaction time: 0.33 h
Yield: 64.8 %

Procedure:
Carbonyl diimidazole (CDI) (162.2 mg, 1.0 mmol) was added to a stirred solution of 3-((tert-butoxycarbonyl)amino)oxetane-3-carboxylic acid (45) (217.1 mg, 1.0 mmol)) in NMP (1.0 mL). After 20 minutes, N-(5-(N′-hydroxycarbamimidoyl)-2-methylphenyl)imidazo[1,2-a]pyridine-3-carboxamide (9) (150.0 mg, 0.5 mmol) was added in one portion and the resulting solution was stirred for 1 hour before it was heated at 125° C. for 15 minutes in a microwave reactor. The reaction solution was subjected to standard aqueous work up to afford a residue which was purified by silica chromatography to yield tert-butyl (3-(3-(3-(imidazo[1,2-a]pyridine-3-carboxamido)-4-methylphenyl)-1,2,4-oxadiazol-5-yl)oxetan-3-yl)carbamate (46) (159 mg, 65% yield). MS m/z 491.2 (M+1)+.
Reaction SMILES: F[C:2](F)(F)C([O-])=O.[Cl:8][C:9]1[CH:10]=[CH:11][C:12]([S:15][C:16]2[N:20]([CH3:21])[CH:19]=[NH+:18][C:17]=2[C:22]2[CH:27]=[CH:26][C:25]([C@H:28]3[CH2:30][C@@H:29]3[C:31]3[N:32]=[N:33][NH:34][N:35]=3)=[CH:24][CH:23]=2)=[N:13][CH:14]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.IC>[Cl:8][C:9]1[CH:10]=[CH:11][C:12]([S:15][C:16]2[N:20]([CH3:21])[CH:19]=[N:18][C:17]=2[C:22]2[CH:23]=[CH:24][C:25]([C@H:28]3[CH2:30][C@@H:29]3[C:31]3[N:32]=[N:33][N:34]([CH3:2])[N:35]=3)=[CH:26][CH:27]=2)=[N:13][CH:14]=1
Reactant: Cn1c[nH+]c(-c2ccc([C@H]3C[C@@H]3c3nn[nH]n3)cc2)c1Sc1ccc(Cl)cn1
Reactant: O=C([O-])C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: CN(C)C=O
Product: Cn1nnc([C@H]2C[C@@H]2c2ccc(-c3ncn(C)c3Sc3ccc(Cl)cn3)cc2)n1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of Example 37 (10 mg, 0.024 mmol) and excess potassium carbonate in DMF (0.5 mL) was added 3 drops of iodomethane. The reaction was stirred at rt for 1 h, before filtering and subjecting to purification via reverse phase HPLC. The fractions containing the major product were collected, diluted with ethyl acetate, and washed with aqueous sodium bicarbonate, water, and brine. The organic layer was dried (MgSO4), filtered, and concentrated to afford the title compound. 1H NMR (500 MHz), [CD3OD]: 8.38 (s, 1H), 7.78 (d, 2H), 7.76 (br, 3H), 7.30 (br, 3H), 3.83 (s, 3H), 3.66 (s, 3H), 2.66 (m, 1H), 2.45 (m, 1H), 1.85-1.72 (br, 2H). LCMS: [M+1]+=424. Human FAAH lysate assay: IC50=37 nM
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:7][N:8]([CH2:16][C:17]1[C:22]2[N:23]=[C:24]([C:26]3[CH:31]=[C:30]([O:32][CH3:33])[CH:29]=[CH:28][C:27]=3[O:34][CH2:35]OC)[O:25][C:21]=2[CH:20]=[CH:19][CH:18]=1)[CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][N:11]=1.BrCC1C2N=C(C3C=C(OC)C=CC=3OC)OC=2C=CC=1>>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:7][N:8]([CH2:16][C:17]1[C:22]2[N:23]=[C:24]([C:26]3[CH:31]=[C:30]([O:32][CH3:33])[CH:29]=[CH:28][C:27]=3[O:34][CH3:35])[O:25][C:21]=2[CH:20]=[CH:19][CH:18]=1)[CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][N:11]=1
Reactant: COCOc1ccc(OC)cc1-c1nc2c(CN(Cc3ccccn3)Cc3ccccn3)cccc2o1
Agent: COc1ccc(OC)c(-c2nc3c(CBr)cccc3o2)c1
Product: COc1ccc(OC)c(-c2nc3c(CN(Cc4ccccn4)Cc4ccccn4)cccc3o2)c1

Procedure:
4-bis(2-pyridylmethyl)aminomethyl-2-(2,5-dimethoxyphenyl)benzoxazole (F22) was prepared in a similar manner for the preparation of 4-bis(2-pyridylmethyl)aminomethyl-2-(5-methoxy-2-methoxymethoxyphenyl)benzoxazole (F18) using 4-bromomethyl-2-(2,5-dimethoxyphenyl)benzoxazole (F14) (522 mg, 1.5 mmol) instead of 4-bromomethyl-2-(5-methoxy-2-methoxymethoxyphenyl)benzoxazole (F12) in 91% (640 mg); 1H-NMR (400 MHz, CDCl3) δ3.88 (s, 4H), 3.95 (s, 6H), 4.23 (s, 2H), 7.01-7.07 (m, 2H), 7.13 (dd, 2H, J=8.0, 5.0 Hz), 7.34 (t, 1H, J=7.5 Hz), 7.49 (d, 1H, J=7.5 Hz), 7.57 (d, 1H, J=7.5 Hz), 7.64-7.68 (m, 3H), 7.80 (d, 2H, J=8.0 Hz), 8.52 (d, 2H, J=5.0 Hz).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:12])[C:5]1[CH:10]=[CH:9][CH:8]=[C:7](Br)[CH:6]=1)[CH3:2].[OH:13][CH2:14][C:15]1[CH:16]=[C:17](B(O)O)[CH:18]=[CH:19][CH:20]=1.C([O-])([O-])=O.[K+].[K+].CO>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.C1(C)C=CC=CC=1>[OH:13][CH2:14][C:15]1[CH:20]=[C:19]([C:7]2[CH:8]=[CH:9][CH:10]=[C:5]([C:4]([O:3][CH2:1][CH3:2])=[O:12])[CH:6]=2)[CH:18]=[CH:17][CH:16]=1
Reactant: CCOC(=O)c1cccc(Br)c1
Reactant: OCc1cccc(B(O)O)c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: CO
Product: CCOC(=O)c1cccc(-c2cccc(CO)c2)c1
Temperature: 80 °C

Procedure:
A mixture of ethyl-3-bromobenzoate (3.0 g, 13 mmol), [3-(hydroxymethyl)-phenyl]boronic acid (3.0 g, 20 mmol), PdCl2(PPh3)2 (0.46 g, 0.66 mmol), K2CO3 (3.6 g, 26 mmol), methanol (4 mL), and toluene (36 mL) was heated at 80° C. for 18 h under N2 and then allowed to cool to rt. The reaction mixture was filtered through Celite and then poured into a mixture of ethyl acetate and brine. The two layers were separated and the aqueous layer was extracted with ethyl acetate (×3). The organic extracts were dried (Na2SO4), filtered, concentrated and purified by silica gel chromatography to give ethyl 3′-(hydroxymethyl)biphenyl-3-carboxylate as an orange oil. A solution of CBr4 (5.8 g, 17 mmol) and CH2Cl2 (20 mL) was added dropwise to a solution of the above alcohol, PPh3 (4.6 g, 18 mmol), and CH2Cl2 (50 mL) at 0° C. under N2. The reaction was allowed to warm to rt, maintained for 2 h, concentrated, and purified by silica gel chromatography to give ethyl 3′-(bromomethyl)biphenyl-3-carboxylate as a clear oil. Ethyl 3′-(bromomethyl)biphenyl-3-carboxylate was used to alkylate 1-(2,2-dimethylpropyl)-4-propyl-1H-indol-5-ol following the procedure outlined in example 1. A mixture of the above indole (0.66 g, 1.4 mmol), 1 N LiOH (8 mL), and THF (8 mL) was heated at 40° C. for 2 d and then cooled to 0° C.—acetone can used in place of THF if faster reaction rates are desired. The reaction was acidified to pH=1 with conc. HCl and extracted with ethyl acetate (×3). The organic extracts were dried (Na2SO4), filtered, concentrated and purified by silica gel chromatography to give a yellow oil. 1H NMR (CDCl3, 500 MHz) δ 8.39 (s, 1H), 8.11 (d, 1H), 7.85 (d, 1H), 7.76 (s, 1H), 7.59-7.48 (m, 4H), 7.12 (d, 1H), 7.05 (d, 1H), 6.96 (d, 1H), 6.46 (d, 1H), 5.16 (s, 2H), 3.84 (s, 2H), 2.95 (t, 2H), 1.76 (m, 2H), 1.01 (t, 3H), 0.99 (s, 9H). MS (ESI): 456 (M+H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[C:6]3[N:14]=[C:13](Cl)[N:12]=[C:11]([O:16][CH2:17][CH3:18])[C:7]=3[NH:8][C:9]=2[CH:10]=1.[NH:19]1[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]1>C1(C)C=C(C)C=C(C)C=1>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[C:6]3[N:14]=[C:13]([N:19]4[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]4)[N:12]=[C:11]([O:16][CH2:17][CH3:18])[C:7]=3[NH:8][C:9]=2[CH:10]=1
Reactant: CCOc1nc(Cl)nc2c1[nH]c1cc(Br)ccc12
Reactant: C1CNCCN1
Solvent: Cc1cc(C)cc(C)c1
Product: CCOc1nc(N2CCNCC2)nc2c1[nH]c1cc(Br)ccc12

Procedure:
5.1 g (15.6 mmol) 7-bromo-2-chloro-4-ethoxy-5H-pyrimido[5,4-b]indole and 13.4 g (155.8 mmol) piperazine were heated in 80 ml mesitylene to 150° C. for 7.5 h. Then, the solvent was removed and the residue was suspended in water and sucked off. 5.8 g (99%) of the title substance was obtained. ESI-MS [m/z]: 376, 378 [M+H]+
Reaction SMILES: [OH:1][C:2]1[C:11](=[O:12])[N:10]2[C:5]([C:6]([CH3:14])([CH3:13])[O:7][CH2:8][CH2:9]2)=[N:4][C:3]=1[C:15]([O:17][CH2:18][CH3:19])=[O:16].[CH2:20](Br)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.CCOCC>[CH2:20]([O:1][C:2]1[C:11](=[O:12])[N:10]2[C:5]([C:6]([CH3:13])([CH3:14])[O:7][CH2:8][CH2:9]2)=[N:4][C:3]=1[C:15]([O:17][CH2:18][CH3:19])=[O:16])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: BrCc1ccccc1
Reactant: CCOC(=O)c1nc2n(c(=O)c1O)CCOC2(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOCC
Product: CCOC(=O)c1nc2n(c(=O)c1OCc1ccccc1)CCOC2(C)C
Temperature: 25 °C
Reaction time: 48 h
Yield: 77.8 %

Procedure:
To a stirred solution of intermediate 25, ethyl 3-hydroxy-9,9-dimethyl-4-oxo-4,6,7,9-tetrahydropyrimido[2,1-c][1,4]oxazine-2-carboxylate, (2.68 g, 10 mmol) and benzyl bromide (1.43 mL, 12 mmol) in DMF (40 mL) was added K2CO3 (2.07 g, 20 mmol). After stirring 48 h at ambient temperature, the reaction mixture was diluted with ether (100 mL), then washed with water (3×30 mL) and brine (20 mL). The organic layer was dried (Na2SO4/activated carbon), filtered and concentrated to give a yellow solid. Trituration with hexanes/ether (9:1) afforded the title compound as an off-white solid (2.79 g, 78% yield). 1H NMR (500 MHz, CDCl3) δ ppm: 7.48–7.45 (2H, m), 7.37–7.30 (3H, m), 5.25 (2H, s), 4.33 (2H, q, J=7.3 Hz), 4.05–3.99 (4H, m), 1.62 (6H, s), 1.29 (3H, t, J=7.3 Hz). HRMS (M+H) calcd for C19H23N2O5: 359.1607; found: 359.1611. Anal calcd for C19H22N2O5: C, 63.67; H, 6.18; N, 7.81; found: C, 63.63; H, 6.16; N, 7.78.
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][NH2:7])=[CH:4][CH:3]=1.Cl[C:11]1[C:12]2[C:25]([Cl:26])=[C:24]([CH3:27])[S:23][C:13]=2[N:14]=[C:15]([C:17]2[CH:22]=[CH:21][N:20]=[CH:19][CH:18]=2)[N:16]=1>>[N:20]1[CH:19]=[CH:18][C:17]([C:15]2[N:16]=[C:11]([NH:7][CH2:6][C:5]3[CH:8]=[CH:9][C:2]([F:1])=[CH:3][CH:4]=3)[C:12]3[C:25]([Cl:26])=[C:24]([CH3:27])[S:23][C:13]=3[N:14]=2)=[CH:22][CH:21]=1
Reactant: Cc1sc2nc(-c3ccncc3)nc(Cl)c2c1Cl
Reactant: NCc1ccc(F)cc1
Product: Cc1sc2nc(-c3ccncc3)nc(NCc3ccc(F)cc3)c2c1Cl

Procedure:
With the procedure of Example 1, the reaction of 4-fluorobenzylamine with 4-chloro-2-(pyridin-4-yl)-5-chloro-6-methyl-thieno-[2,3-d]-pyrimidine yields 2-(pyridin-4-yl)-4-(4-fluorobenzylamino)-5-chloro-6-methyl-thieno-[2,3-d]-pyrimidine.
Reaction SMILES: S(=O)(=O)(O)O.[O:6]1[CH:11]=[CH:10][CH:9]=[CH:8][NH:7]1.[N+:12]([O-])([OH:14])=[O:13].[OH-].[Na+]>>[N+:12]([C:8]1[NH:7][O:6][CH:11]=[CH:10][CH:9]=1)([O-:14])=[O:13]
Reactant: C1=CNOC=C1
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Product: O=[N+]([O-])C1=CC=CON1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To concentrated sulfuric acid (13 ml) was added portionwise the oxazine IX (3.0 mmol) at 22° C., the solution obtained was cooled to 0° C. and treated with red fuming HNO3 (0.19 ml) over 20 min and stirring was continued at 0° C. for 1 h. The reaction mixture was slowly added to crushed ice (60 g), the pH was adjusted to 10 using NaOH, the aqueous layer was extracted with AcOEt, the organic layer was dried, evaporated and the residue was chromatographed on silica gel using a mixture of heptane/AcOEt 3:1 to afford the pure nitro-oxazine X.
Reaction SMILES: [CH2:1](/[N:5]=[CH:6]/[C:7]1[C:12](F)=[CH:11][CH:10]=[CH:9][C:8]=1[Cl:14])[CH2:2][CH2:3][CH3:4].[CH3:15][Mg]Cl>O1CCCC1.[Cl-].[Mn+2].[Cl-]>[CH2:1](/[N:5]=[CH:6]/[C:7]1[C:12]([CH3:15])=[CH:11][CH:10]=[CH:9][C:8]=1[Cl:14])[CH2:2][CH2:3][CH3:4]
Reactant: CCCC/N=C/c1c(F)cccc1Cl
Reactant: C[Mg]Cl
Agent: [Mn+2]
Agent: [Cl-]
Solvent: C1CCOC1
Product: CCCC/N=C/c1c(C)cccc1Cl
Temperature: 7.5 °C
Reaction time: 0.5 h
Yield: 100 %

Procedure:
This compound was prepared using methodology described in Synthesis 1999, 2138-2144. To a solution of 7.00 g (32.8 mmol) butyl-[1-(2-chloro-6-fluoro-phenyl)-meth-(E)-ylidene]-amine in 70 ml tetrahydrofuran at 0° C. was added 0.41 g (3.28 mmol) manganese(II) chloride. 21.8 ml (65.5 mmol) of a 3 M solution of methylmagnesium chloride in tetrahydrofuran was then added dropwise while the temperature of the reaction mixture was maintained at 5-10° C. After the addition was complete, the reaction mixture was stirred for a further 30 minutes, during which time the temperature rose to 40° C. (exotherm). The reaction mixture was then quenched by dropwise addition of water and stirred for a further 30 minutes before being diluted with toluene. The mixture was then filtered and the organic phase of the filtrate was then washed with saturated brine. The phases were separated and the organic phase was dried over Na2SO4, filtered and concentrated in vacuo. The residue was resuspended in carbon tetrachloride and concentrated in vacuo again to afford 6.90 g (100%) of the title compound as a yellow oil which was used in the next step without further purification. MS (ISP): 212.1 ([{37Cl}M+H]+), 210.1 ([{35Cl}M+H]+).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]([NH:8][C@H:9]([C:11]2[N:16]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:15](=[O:23])[C:14]3=[C:24]([CH3:27])[CH:25]=[CH:26][N:13]3[N:12]=2)[CH3:10])[C:3]=1Br.[OH:29][C:30]1[CH:31]=[C:32](B(O)O)[CH:33]=[C:34]([O:36][C:37]([F:40])([F:39])[F:38])[CH:35]=1.C(=O)([O-])[O-].[Na+].[Na+]>>[NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]([NH:8][C@H:9]([C:11]2[N:16]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:15](=[O:23])[C:14]3=[C:24]([CH3:27])[CH:25]=[CH:26][N:13]3[N:12]=2)[CH3:10])[C:3]=1[C:32]1[CH:33]=[C:34]([O:36][C:37]([F:40])([F:38])[F:39])[CH:35]=[C:30]([OH:29])[CH:31]=1
Reactant: OB(O)c1cc(O)cc(OC(F)(F)F)c1
Reactant: Cc1ccn2nc([C@H](C)Nc3ncnc(N)c3Br)n(-c3ccccc3)c(=O)c12
Agent: O=C([O-])[O-]
Agent: [Na+]
Product: Cc1ccn2nc([C@H](C)Nc3ncnc(N)c3-c3cc(O)cc(OC(F)(F)F)c3)n(-c3ccccc3)c(=O)c12
Yield: 50.9 %

Procedure:
(S)-2-(1-((6-Amino-5-bromopyrimidin-4-yl)amino)ethyl)-5-methyl-3-phenylpyrrolo[2,1-f][1,2,4]triazin-4(3H)-one (82 mg, 0.19 mmol) was treated with 3-hydroxy-5-(trifluoromethoxy)phenylboronic acid (124 mg, 0.56 mmol), sodium carbonate (2M, 375 μl, 0.75 mmol) and 1,1′-bis(diphenylphosphino)ferrocene-palladium(II)dichloride dichloromethane complex (15 mg, 0.02 mmol) according to the method described in Example 3 to give 52 mg (51% yield) of the title compound. Purity 98%.