Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: I[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][N:5]=[C:4]2[O:11][CH2:12][CH2:13][C:3]=12.[OH:14][C@:15]1([CH3:30])[C@@H:20]([CH3:21])[CH2:19][NH:18][CH2:17][C@H:16]1[NH:22][C:23](=[O:29])[O:24][C:25]([CH3:28])([CH3:27])[CH3:26].CCN(C(C)C)C(C)C>CCO>[OH:14][C@:15]1([CH3:30])[C@@H:20]([CH3:21])[CH2:19][N:18]([C:2]2[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][N:5]=[C:4]3[O:11][CH2:12][CH2:13][C:3]=23)[CH2:17][C@H:16]1[NH:22][C:23](=[O:29])[O:24][C:25]([CH3:28])([CH3:27])[CH3:26]
Reactant: C[C@H]1CNC[C@@H](NC(=O)OC(C)(C)C)[C@]1(C)O
Reactant: O=[N+]([O-])c1cnc2c(c1I)CCO2
Solvent: CCO
Solvent: CCN(C(C)C)C(C)C
Product: C[C@H]1CN(c2c([N+](=O)[O-])cnc3c2CCO3)C[C@@H](NC(=O)OC(C)(C)C)[C@]1(C)O
Temperature: 110 °C
Reaction time: 15 h
Yield: 65.7 %

Procedure:
To a vial containing 4-iodo-5-nitro-2,3-dihydrofuro[2,3-b]pyridine (59 mg, 0.20 mmol) and tert-butyl [(3R,4R,5S)-4-hydroxy-4,5-dimethylpiperidin-3-yl]carbamate (46 mg, 0.19 mmol) was added EtOH (2.0 mL), followed by DIPEA (100 mg, 0.772 mmol). The mixture was stirred at 110° C. for 15 h. After cooling to the room temperature, the reaction was concentrated under reduced pressure. The resulting residue was purified on silica gel (0-100% EtOAc in hexanes) to give the sub-title compound as a yellow foamy solid (51 mg, 67%). LCMS calc. for C19H29N4O6 (M+H)+: m/z=409.2. found 409.0.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][C:10]2([CH2:22][C:21](=[O:23])[C:20]3[C:15](=[CH:16][CH:17]=[C:18](/[CH:24]=[CH:25]/[C:26](O)=[O:27])[CH:19]=3)[O:14]2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1.[NH2:43][O:44][CH:45]1[CH2:50][CH2:49][CH2:48][CH2:47][O:46]1>C(Cl)Cl>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][C:10]2([CH2:22][C:21](=[O:23])[C:20]3[C:15](=[CH:16][CH:17]=[C:18](/[CH:24]=[CH:25]/[C:26]([NH:43][O:44][CH:45]4[CH2:50][CH2:49][CH2:48][CH2:47][O:46]4)=[O:27])[CH:19]=3)[O:14]2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: NOC1CCCCO1
Reactant: CC(C)(C)OC(=O)N1CCCC2(CC(=O)c3cc(/C=C/C(=O)O)ccc3O2)C1
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCCC2(CC(=O)c3cc(/C=C/C(=O)NOC4CCCCO4)ccc3O2)C1
Temperature: 0 °C
Reaction time: 2 h
Yield: 68 %

Procedure:
TEA (0.259 ml, 1.86 mmol) was added to solution of (±)-(E)-3-[1′-tert-butoxycarbonyl-4-oxo-spiro(chromane-2,3′-piperidine)-6-yl]-acrylic acid (481 mg, 1.24 mmol) in DCM (15 ml). The mixture was cooled down to 0° C., and EDC (356 mg, 1.86 mmol) and HOBt (251 mg, 1.86 mmol) were added. The mixture was stirred at 0° C. for 2 h, then NH2OTHP (174 mg, 1.49 mmol) was added and the mixture was stirred at RT overnight. The solution was washed with aqueous 5% NaHCO3 solution and brine. The organic layer was then dried over Na2SO4 and evaporated. The crude residue was purified by column chromatography (eluent: DCM/MeOH 98:2) to give (E)-3-[1′-tert-butoxycarbonyl-4-oxo-spiro(chromane-2,3′-piperidine)-6-yl]-N-(tetrahydro-pyran-2-yloxy)-acrylamide (410 mg).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7]([OH:22])=[C:8]2[CH:16]=[CH:15][N:14]([CH2:17][CH2:18][CH:19]([CH3:21])[CH3:20])[C:9]2=[C:10]([C:12]#[N:13])[N:11]=1)=[O:5])[CH3:2].[C:23](OC(=O)C)(=[O:25])[CH3:24].C(N(CC)CC)C>C(Cl)Cl>[CH2:1]([O:3][C:4]([C:6]1[C:7]([O:22][C:23](=[O:25])[CH3:24])=[C:8]2[CH:16]=[CH:15][N:14]([CH2:17][CH2:18][CH:19]([CH3:21])[CH3:20])[C:9]2=[C:10]([C:12]#[N:13])[N:11]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1nc(C#N)c2c(ccn2CCC(C)C)c1O
Reactant: CC(=O)OC(C)=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOC(=O)c1nc(C#N)c2c(ccn2CCC(C)C)c1OC(C)=O
Yield: 96.3 %

Procedure:
To a solution of 7-cyano-4-hydroxy-1-(3-methyl-butyl)-1H-pyrrolo[2,3-c]pyridine-5-carboxylic acid ethyl ester (0.4 g, 1.33 mmol), example 97(a), and acetic anhydride (0.25 mL, 2.65 mmol) in methylene chloride (8 mL) at ambient temperature was added triethylamine (0.37 mL, 2.65 mmol). The reaction mixture was stirred at ambient temperature for 2.5 h before 100 mL of methylene chloride was added. The organic solution was washed with 80 mL of water, dried, filtered, and concentrated. The crude product was purified by flash chromatography eluting from silica gel with a gradient of 0-50% ethyl acetate in hexanes to produce 0.44 g of a colorless oil. MS: (+) m/z 344.3 (M+1).
Reaction SMILES: [Cl:1]C1C=C(NC(NC)=O)C=CC=1Cl.O=CC(Cl)(Cl)Cl.[Cl:20][C:21]1[CH:22]=[C:23]([NH:28][C:29]([N:31]([CH:33](O)[C:34]([Cl:37])([Cl:36])[Cl:35])[CH3:32])=[O:30])[CH:24]=[CH:25][C:26]=1[Cl:27].S(Cl)(Cl)=O>S(=O)(=O)(O)O.C(OCC)C>[CH3:32][N:31]([CH:33]([Cl:1])[C:34]([Cl:37])([Cl:36])[Cl:35])[C:29]([NH:28][C:23]1[CH:24]=[CH:25][C:26]([Cl:27])=[C:21]([Cl:20])[CH:22]=1)=[O:30]
Reactant: CNC(=O)Nc1ccc(Cl)c(Cl)c1
Reactant: CN(C(=O)Nc1ccc(Cl)c(Cl)c1)C(O)C(Cl)(Cl)Cl
Agent: O=CC(Cl)(Cl)Cl
Agent: O=S(=O)(O)O
Solvent: CCOCC
Solvent: O=S(Cl)Cl
Product: CN(C(=O)Nc1ccc(Cl)c(Cl)c1)C(Cl)C(Cl)(Cl)Cl
Temperature: 65 °C

Procedure:
1-(3,4-dichlorophenyl)-3-methyl urea (15.2 g, 0.07 mol) was combined with 15.0 g (0.1 mol) of chloral and 5 drops of concentrated sulfuric acid. The mixture was heated for an hour to effect reaction, then stripped under vacuum. To the crude 1-(3,4-dichlorophenyl)-3-(1-hydroxy-2,2,2-trichloroethyl)-3-methyl urea was added an excess of thionyl chloride and the mixture was heated gradually to a maximum of 65° C. Diethyl ether was added to the crude product, and the insoluble product was collected on a filter, washed twice with diethyl ether and dried. The 15.3 g of product, which melted at 132°-140° C., analyzed as follows: %Cl, calculated 55.2, found 46.0. The product is the seventh compound tabulated in Table I.
Reaction SMILES: Cl[C:2]([O:4][CH2:5][CH3:6])=[O:3].[CH3:7][C:8]([CH:10]1[CH2:15][CH2:14][C:13]([CH2:16][NH2:17])=[CH:12][CH2:11]1)=[CH2:9].C(N(CC)CC)C.[Cl-].[Na+]>>[CH3:9][C:8]([CH:10]1[CH2:15][CH2:14][C:13]([CH2:16][NH:17][C:2](=[O:3])[O:4][CH2:5][CH3:6])=[CH:12][CH2:11]1)=[CH2:7]
Reactant: C=C(C)C1CC=C(CN)CC1
Reactant: CCOC(=O)Cl
Agent: [Cl-]
Agent: [Na+]
Solvent: CCN(CC)CC
Product: C=C(C)C1CC=C(CNC(=O)OCC)CC1

Procedure:
Ethyl chloroformate 1.1 eq, [4-(1-methylethenyl)-1-cyclohexen-1-yl]methylamine 1.0 eq, triethylamine 1.3 eq, quench with 10% sodium chloride solution, yield=37%.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[N:6][C:5]([CH2:8][CH2:9][C:10]2[N:14]3[CH:15]=[CH:16][CH:17]=[CH:18][C:13]3=[N:12][N:11]=2)=[CH:4][CH:3]=1.[Br:19][C:20]1[CH:21]=[CH:22][C:23]([NH:26][NH:27][C:28](=O)[CH:29]([C:31]2[N:32]=[N:33][C:34](Cl)=[CH:35][CH:36]=2)[CH3:30])=[N:24][CH:25]=1.P(Cl)(Cl)(Cl)=[O:40]>>[Br:19][C:20]1[CH:21]=[CH:22][C:23]2[N:24]([C:28]([CH:29]([C:31]3[CH:36]=[CH:35][C:34]4[N:33]([CH:9]=[C:10]([NH:14][C:15]([CH:16]5[CH2:17][CH2:18]5)=[O:40])[N:11]=4)[N:32]=3)[CH3:30])=[N:27][N:26]=2)[CH:25]=1.[Cl:1][C:2]1[N:7]=[N:6][C:5]([CH2:8][CH2:9][C:10]2[N:14]3[CH:15]=[CH:16][CH:17]=[CH:18][C:13]3=[N:12][N:11]=2)=[CH:4][CH:3]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: CC(C(=O)NNc1ccc(Br)cn1)c1ccc(Cl)nn1
Agent: Clc1ccc(CCc2nnc3ccccn23)nn1
Product: CC(c1ccc2nc(NC(=O)C3CC3)cn2n1)c1nnc2ccc(Br)cn12

Procedure:
6-Bromo-3-((-(6-chloropyridazin-3-yl)ethyl)-[1,2,4]triazolo[4,3-a]pyridine (48D): A solution of N′-(5-bromopyridin-2-yl)-2-(6-chloropyridazin-3-yl)propanehydrazide (13 g, 36.5 mmol) in phosphoryl trichloride (84 ml, 901 mmol) was heated in the microwave at 140° C. for 15 min. The reaction was concentrated via rotary evaporation and the resulting mixture was added drop-wise to a mixture of EtOAc:Saturated Bicarbonate (aq) (4:6, 1 L). The organic phase was separated and the aqueous phase was extracted with EtOAc (3×75 mL). The EtOAc solutions were combined and evaporated to dryness. The resulting residue was purified by MPLC (DCM:MeOH, 97:3) to provide the title compound, 6-Bromo-3-(1-(6-chloropyridazin-3-yl)ethyl)-[1,2,4]triazolo[4,3-a]pyridine (48D, 3.3 g, 26.7%). 1H NMR (400 MHz, DMSO-d6) δ ppm 1.86 (d, J=7.07 Hz, 3 H) 5.27 (d, J=7.33 Hz, 1 H) 7.49 (dd, J=9.60, 1.77 Hz, 1H) 7.78 (dd, J=9.85, 1.01 Hz, 1 H) 7.94 (s, 2 H) 8.79 (s, 1 H). ESI-MS:m/z 339.1 (M+H)+.
Reaction SMILES: [CH2:1]([C@@H:8]1[CH2:12][O:11][C:10](=[O:13])[N:9]1[C:14](=[O:23])[CH2:15][C:16]1[CH:21]=[CH:20][C:19]([Br:22])=[CH:18][CH:17]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:24][Si]([N-][Si](C)(C)C)(C)C.[Na+].CI>C1COCC1>[CH2:1]([C@@H:8]1[CH2:12][O:11][C:10](=[O:13])[N:9]1[C:14](=[O:23])[C@@H:15]([C:16]1[CH:17]=[CH:18][C:19]([Br:22])=[CH:20][CH:21]=1)[CH3:24])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C[Si](C)(C)[N-][Si](C)(C)C
Reactant: O=C(Cc1ccc(Br)cc1)N1C(=O)OC[C@H]1Cc1ccccc1
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CI
Product: C[C@@H](C(=O)N1C(=O)OC[C@H]1Cc1ccccc1)c1ccc(Br)cc1
Temperature: -78 °C
Reaction time: 3 h
Yield: 17.9 %

Procedure:
To a solution of 76A (380 mg, 1.01 mmol) in THF (5 mL) at −78° C., was added NaHMDS (1.3 mL, 1.0M, 1.3 mmol), dropwise. The solution was stirred at −78° C. for 3 h. A solution of MeI (0.62 mL, 10 mmol) in 2 mL THF was added. The solution was stirred −78° C. for 3 h, and −40° C. for 1 h. The reaction was quenched with sat. NH4Cl and extracted with EtOAc (3×20 mL). The organic layer washed with brine, dried (Na2SO4), and concentrated. Purification via flash chromatography (0-30% EtOAc in hexanes) gives 76B (70 mg, 18%). MS (ESI) m/z 388.3 (M+H)+.
Reaction SMILES: [C:1]1([C:7]2[CH:8]=[CH:9][C:10]3[N:11]([C:13]([CH2:16][NH:17][C:18]4[CH:23]=[CH:22][N:21]=[CH:20][C:19]=4[NH2:24])=[N:14][N:15]=3)[N:12]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[N:25]([O-])=O.[Na+]>CC(O)=O.O>[C:1]1([C:7]2[CH:8]=[CH:9][C:10]3[N:11]([C:13]([CH2:16][N:17]4[C:18]5[CH:23]=[CH:22][N:21]=[CH:20][C:19]=5[N:24]=[N:25]4)=[N:14][N:15]=3)[N:12]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: Nc1cnccc1NCc1nnc2ccc(-c3ccccc3)nn12
Reactant: O=N[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: c1ccc(-c2ccc3nnc(Cn4nnc5cnccc54)n3n2)cc1
Reaction time: 1 h

Procedure:
To a solution of N4-((6-phenyl-[1,2,4]triazolo[4,3-b]pyridazin-3-yl)methyl)pyridine-3,4-diamine (0.0640 g, 0.202 mmol) in HOAc (5 mL) was added sodium nitrite (0.0153 g, 0.222 mmol) in water (2 mL). Stirred for 1 h. Concentrated. Took up in DMSO and purified on RPHPLC. Took fractions containing product and made basic with 9% sodium carbonate and removed volatiles in vacuo. Product crashed out and was isolated by filtration. MS m/z=329.2 [M+1]+. Calc'd for C17H12N8: 328.3.
Reaction SMILES: CS[C:3]1[N:8]=[C:7]([NH:9][CH2:10][C:11]2[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[C:13]([Cl:19])[CH:12]=2)[C:6]([C:20](=[O:29])[NH:21][CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][N:24]=2)=[CH:5][N:4]=1.ClC1C=CC=C(C(OO)=O)C=1.[NH:41]1[CH2:46][CH2:45][NH:44][CH2:43][CH2:42]1.C(OCC)(=O)C>C(Cl)(Cl)Cl>[N:41]1([C:3]2[N:8]=[C:7]([NH:9][CH2:10][C:11]3[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[C:13]([Cl:19])[CH:12]=3)[C:6]([C:20](=[O:29])[NH:21][CH2:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][N:24]=3)=[CH:5][N:4]=2)[CH2:46][CH2:45][NH:44][CH2:43][CH2:42]1
Reactant: C1CNCCN1
Reactant: COc1ccc(CNc2nc(SC)ncc2C(=O)NCc2ccccn2)cc1Cl
Agent: O=C(OO)c1cccc(Cl)c1
Solvent: ClC(Cl)Cl
Solvent: CCOC(C)=O
Product: COc1ccc(CNc2nc(N3CCNCC3)ncc2C(=O)NCc2ccccn2)cc1Cl
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 2-methylthio-4-(3-chloro-4-methoxybenzylamino)-5-[N-(2-pyridylmethyl)carbamoyl]pyrimidine (prepared in Example 80) 150.0 mg in chloroform 5.0 ml is treated with m-chloroperbenzoic acid (80%) 85.6 mg at 0° C. for 30 minites. Piperazine 0.263 g is added thereto and the mixture is stirred at room temperature overnight. To the reaction mixture is added ethyl acetate and an aqueous saturated sodium hydrogen carbonate solution, and the organic layer is separated. The organic layer is washed with an aqueous saturated sodium hydrogen carbonate solution, water and a saturated brine, dried over anhydrous sodium sulfate, filtered and then concentrated in vacuo. The residue is purified with silica gel chromatography (solvent; ethyl acetate) to give 2-(1-pyperazinyl)-4-(3-chloro-4-methoxybenzylamino)-5-[N-(2-pyridylmethyl)carbamoyl]pyrimidine as a colorless amorphous solid, 128.4 mg.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:13](=[CH:14][CH:15]=1)[C:12]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[N:6]([S:16]([C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([O:25]C)[CH:20]=1)(=[O:18])=[O:17])[CH:5]2[CH3:27].C1CCCCC=1.B(Br)(Br)Br.ClCCl>>[F:1][C:2]1[CH:3]=[C:4]2[C:13](=[CH:14][CH:15]=1)[C:12]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[N:6]([S:16]([C:19]1[CH:20]=[C:21]([OH:25])[CH:22]=[CH:23][CH:24]=1)(=[O:18])=[O:17])[CH:5]2[CH3:27]
Reactant: COc1cccc(S(=O)(=O)N2c3ccccc3-c3ccc(F)cc3C2C)c1
Agent: BrB(Br)Br
Solvent: ClCCl
Solvent: C1=CCCCC1
Product: CC1c2cc(F)ccc2-c2ccccc2N1S(=O)(=O)c1cccc(O)c1
Yield: 77 %

Procedure:
The title compound was prepared from 8-fluoro-5-[(3-methoxyphenyl)sulfonyl]-6-methyl-5,6-dihydrophenanthridine (0.50 g, 1.3 mmol), cyclohexene (2.4 mL, 24 mmol), and 1 M boron tribromide in dichloromethane (7.8 mL, 7.8 mmol) according to the procedure and in the same manner as described in Example 47, Step b. The crude product was purified by flash column chromatography on silica gel, eluting with a mixture of ethyl acetate-hexane (1:4), followed by trituration from hexane, to yield 3-[(8-fluoro-6-methylphenanthridin-5(6H)-yl)sulfonyl]phenol as a homogeneous solid (0.37 g, 71%), m.p. 161° C.;
Reaction SMILES: O[CH2:2][CH2:3][N:4]([CH:38]([CH3:40])[CH3:39])[C:5]([C:7]1[C:12]([O:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[C:11]([OH:21])[N:10]=[C:9]([CH2:22][C:23]2(C3C=CC4C(=CC=CC=4)C=3)[CH2:27][CH2:26][CH2:25][CH2:24]2)[N:8]=1)=[O:6].C(OC1C(=O)N=C(C[C:57]2([C:62]3[CH:67]=[C:66](Cl)[CH:65]=[CH:64][C:63]=3Cl)[CH2:61][CH2:60][CH2:59]C2)N2CCN(C(C)C)C(=O)C=12)C1C=CC=CC=1>>[CH2:14]([O:13][C:12]1[C:11](=[O:21])[N:10]=[C:9]([CH2:22][C:23]2([C:61]3[CH:60]=[CH:59][C:63]4[C:62](=[CH:67][CH:66]=[CH:65][CH:64]=4)[CH:57]=3)[CH2:27][CH2:26][CH2:25][CH2:24]2)[N:8]2[CH2:2][CH2:3][N:4]([CH:38]([CH3:40])[CH3:39])[C:5](=[O:6])[C:7]=12)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: CC(C)N1CCn2c(CC3(c4cc(Cl)ccc4Cl)CCCC3)nc(=O)c(OCc3ccccc3)c2C1=O
Reactant: CC(C)N(CCO)C(=O)c1nc(CC2(c3ccc4ccccc4c3)CCCC2)nc(O)c1OCc1ccccc1
Product: CC(C)N1CCn2c(CC3(c4ccc5ccccc5c4)CCCC3)nc(=O)c(OCc3ccccc3)c2C1=O
Yield: 41.33 %

Procedure:
9-Benzyloxy-2-isopropyl-6-(1-naphthalen-2-yl-cyclopentylmethyl)-3,4-dihydro-2H-pyrazino[1,2-c]pyrimidine-1,8-dione (221) (90.0 mg, 41.33%) was synthesized as a white solid from 5-benzyloxy-6-hydroxy-2-(1-naphthalen-2-yl-cyclopentylmethyl)-pyrimidine-4-carboxylic acid (2-hydroxyethyl)-isopropylamide (220) (225.0 mg, 0.417 mmol) following the procedure described for 9-benzyloxy-6-[1-(2,5-dichlorophenyl)-cyclopentylmethyl]-2-isopropyl-3,4-dihydro-2H-pyrazino[1,2-c]pyrimidine-1,8-dione (208).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:19]=[CH:20][C:21]=1[Cl:22])[CH2:5][N:6]1[CH2:11][CH2:10][N:9]([CH2:12][CH:13]([CH3:18])[C:14]([O:16]C)=[O:15])[CH2:8][CH2:7]1.O.[OH-].[Li+].CO>O>[Cl:1][C:2]1[CH:3]=[C:4]([CH:19]=[CH:20][C:21]=1[Cl:22])[CH2:5][N:6]1[CH2:11][CH2:10][N:9]([CH2:12][CH:13]([CH3:18])[C:14]([OH:16])=[O:15])[CH2:8][CH2:7]1
Reactant: COC(=O)C(C)CN1CCN(Cc2ccc(Cl)c(Cl)c2)CC1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CC(CN1CCN(Cc2ccc(Cl)c(Cl)c2)CC1)C(=O)O
Reaction time: 21 h
Yield: 98.6 %

Procedure:
Methyl 2-[4-(3,4-dichlorobenzyl)piperazin-1-ylmethyl]propionate (470 mg, 1.36 mmol) and lithium hydroxide monohydrate (185 mg, 4.41 mmol) were dissolved in water (5 ml) and methanol (15 ml) and stirred at room temperature. After 21 h, the solvents were removed under reduced pressure. The resulting residue was taken up in a mixture of methylene chloride and water, and the aqueous layer was made acidic (pH 4) with 1M HCl. The layers were separated and the aqueous phase was extracted with several portions of methylene chloride. The combined organic layers were dried over sodium sulfate and concentrated under reduced pressure to afford 2-(RS)-[4-(3,4-dichloro-benzyl)piperazin-1-ylmethyl]propionic acid (444 mg) as a pale-yellow foam.
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][C:9]2[CH2:8][CH2:7][N:6]3[C:12]4[CH:13]=[CH:14][CH:15]=[C:16]([F:19])[C:17]=4[CH:18]=[C:5]3[C:4]=2[N:3]=1.[F:20][C:21]1[CH:26]=[CH:25][C:24]([C:27]2[O:28][C:29]3[CH:39]=[C:38]([N:40]([CH3:45])[S:41]([CH3:44])(=[O:43])=[O:42])[C:37](B4OC(C)(C)C(C)(C)O4)=[CH:36][C:30]=3[C:31]=2[C:32]([NH:34][CH3:35])=[O:33])=[CH:23][CH:22]=1>O1CCOCC1.O.[Pd](Cl)Cl.C(P(C(C)(C)C)[C-]1C=CC=C1)(C)(C)C.[C-]1(P(C(C)(C)C)C(C)(C)C)C=CC=C1.[Fe+2]>[F:19][C:16]1[C:17]2[CH:18]=[C:5]3[C:4]4[N:3]=[C:2]([C:37]5[C:38]([N:40]([CH3:45])[S:41]([CH3:44])(=[O:43])=[O:42])=[CH:39][C:29]6[O:28][C:27]([C:24]7[CH:25]=[CH:26][C:21]([F:20])=[CH:22][CH:23]=7)=[C:31]([C:32]([NH:34][CH3:35])=[O:33])[C:30]=6[CH:36]=5)[CH:11]=[CH:10][C:9]=4[CH2:8][CH2:7][N:6]3[C:12]=2[CH:13]=[CH:14][CH:15]=1
Reactant: CNC(=O)c1c(-c2ccc(F)cc2)oc2cc(N(C)S(C)(=O)=O)c(B3OC(C)(C)C(C)(C)O3)cc12
Reactant: Fc1cccc2c1cc1n2CCc2ccc(Cl)nc2-1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: CC(C)(C)P([c-]1cccc1)C(C)(C)C
Solvent: C1COCCO1
Solvent: O
Product: CNC(=O)c1c(-c2ccc(F)cc2)oc2cc(N(C)S(C)(=O)=O)c(-c3ccc4c(n3)-c3cc5c(F)cccc5n3CC4)cc12
Temperature: 90 °C
Reaction time: 4 h
Yield: 81.6 %

Procedure:
To a degassed solution of 2-chloro-11-fluoro-5,6-dihydroindolo[1,2-h][1,7]naphthyridine (50 mg, 0.18 mmol) and 2-(4-fluorophenyl)-N-methyl-6-(N-methylmethylsulfonamido)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzofuran-3-carboxamide (120 mg, 0.24 mmol) in 1,4-dioxane (8 mL) and water (200 μl) was added CS2CO3 (119 mg, 0.37 mmol) and 1,1′-bis(di-tert-butylphosphino)ferrocene palladium chloride (20 mg, 0.03 mmol) under N2 protection. The resulting mixture was heated to 90° C. and stirred for 4 hours. The reaction was cooled, filtered through a pad of the celite and washed with ethyl acetate. The combined filtrate was evaporated in vacuo. Preparative TLC (eluted with 30% EtOAc/DCM) provide 5-(11-fluoro-5,6-dihydroindolo[1,2-h][1,7]naphthyridin-2-yl)-2-(4-fluorophenyl)-N-methyl-6-(N-methylmethylsulfonamido)benzofuran-3-carboxamide (90 mg, yield: 80%) MS (M+H)+: 613.
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([C:9]([N:11]2[C:19]3[CH:18]=[CH:17][N:16]=[CH:15][C:14]=3[CH:13]=[CH:12]2)=[O:10])=[C:4]([Cl:20])[CH:3]=1.[N-:21]=[N+]=[N-].[Na+].CNCCNC>C(O)C.O.[Cu](I)I>[NH2:21][C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([C:9]([N:11]2[C:19]3[CH:18]=[CH:17][N:16]=[CH:15][C:14]=3[CH:13]=[CH:12]2)=[O:10])=[C:4]([Cl:20])[CH:3]=1
Reactant: [N-]=[N+]=[N-]
Reactant: O=C(c1c(Cl)cc(Br)cc1Cl)n1ccc2cnccc21
Agent: I[Cu]I
Agent: CNCCNC
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: Nc1cc(Cl)c(C(=O)n2ccc3cnccc32)c(Cl)c1
Temperature: 90 °C
Yield: 45.4 %

Procedure:
A mixture of (4-bromo-2,6-dichlorophenyl)(1H-pyrrolo[3,2-c]pyridin-1-yl)methanone (200 mg, 0.54 mmol), sodium azide (105 mg, 1.62 mmol), copper (II) iodide (30 mg, 0.16) and N,N′-dimethylethane-1,2-diamine (26 mg, 0.32 moles) in ethanol (2 mL) and water (0.5 mL) was heated in a sealed vial at 90° C. for 16 hours. The reaction mixture was concentrated to remove ethanol and the residue was diluted with water (50 mL) and extracted with ethyl acetate (2×50 mL). The combined organic portion was dried over anhydrous sodium sulphate and concentrated under vacuum to give the crude product which was purified by silica gel column chromatography using ethyl acetate and hexane as eluent to yield (4-amino-2,6-dichlorophenyl)(1H-pyrrolo[3,2-c]pyridin-1-yl)methanone (75 mg, 45%).
Reaction SMILES: [NH2:1][C:2]1[C:7]([CH3:8])=[C:6]([Cl:9])[CH:5]=[CH:4][CH:3]=1.Cl.Cl[CH2:12][CH2:13][NH:14][CH2:15][CH2:16]Cl>ClC1C=CC=CC=1>[ClH:9].[Cl:9][C:6]1[C:7]([CH3:8])=[C:2]([N:1]2[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]2)[CH:3]=[CH:4][CH:5]=1
Reactant: ClCCNCCCl
Reactant: Cc1c(N)cccc1Cl
Agent: Cl
Solvent: Clc1ccccc1
Product: Cc1c(Cl)cccc1N1CCNCC1
Yield: 176.4 %

Procedure:
A mixture of 6-amino-2-chlorotoluene (158.66 g) and bis-(2-chloroethyl)amine hydrochloride (200.0 g) in chlorobenzene (800 mL) was allowed to reflux for 3 days. After cooling, the reaction mixture was filtered and then washed with ether to give the titled compound (244.3 g) as a white powder: 1H NMR (400 MHz, DMSO-d6) δ 2.29 (s, 3H), 3.06 (m, 4H), 3.22 (m, 4H), 7.05 (dd, J=2.0, 6.8 Hz, 1H), 7.17-7.23 (m, 2H), and 9.40 (br s, 2H).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:12]2[NH:13][C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][C:19]=3[C:11]=2[CH2:10][CH:9]([C:20](O)=[O:21])[NH:8][CH:7]=1)=[O:5])[CH3:2].C1N=CN(C(N2C=NC=C2)=O)C=1.[NH:35]1[CH2:40][CH2:39][CH2:38][CH2:37][CH2:36]1>C(Cl)Cl>[N:35]1([C:20]([CH:9]2[NH:8][CH:7]=[C:6]([C:4]([O:3][CH2:1][CH3:2])=[O:5])[C:12]3[NH:13][C:14]4[CH:15]=[CH:16][CH:17]=[CH:18][C:19]=4[C:11]=3[CH2:10]2)=[O:21])[CH2:40][CH2:39][CH2:38][CH2:37][CH2:36]1
Reactant: CCOC(=O)C1=CNC(C(=O)O)Cc2c1[nH]c1ccccc21
Reactant: C1CCNCC1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: ClCCl
Product: CCOC(=O)C1=CNC(C(=O)N2CCCCC2)Cc2c1[nH]c1ccccc21
Temperature: 20 °C
Reaction time: 1 h

Procedure:
To a suspension of 1,2,3,6-tetrahydroazepino[4,5-b]indole-2,5-dicarboxylic acid 5-ethyl ester (45 mg, 0.15 mmol) in DCM (3 mL) was added CDI (27 mg, 1.1 equiv.). After stirring for 1 hour at 20° C., piperidine (23 μL, 1.5 equiv.) was added. The mixture was stirred overnight at 20° C. and a clear solution was obtained. Evaporation of solvent gave a crude product, which was purified by trituration with MeOH to afford the title compound (22 mg); 1H-NMR (CDCl3): δ 10.44 (1H, br s), 7.95 (1H, d), 7.38 (2H, d), 7.05-7.13 (2H, m), 6.69 (1H, d), 4.29 (2H, q), 3.98 (1H, dd), 3.65-3.73 (2H, m), 3.46 (1H, m), 3.31 (1H, m), 2.71 (1H, dd), 1.58-1.76 (6H, m), 1.36 (3H, t); MS (ES): 368 (MH+).
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]1[CH:9]=[C:8]([F:10])[C:7]([NH:11][S:12]([CH3:15])(=[O:14])=[O:13])=[C:6]([C:16]#[CH:17])[CH:5]=1.[C:18]([C:22]1[N:27]=[CH:26][C:25]([O:28][CH2:29][C:30](O)=[O:31])=[CH:24][CH:23]=1)([CH3:21])([CH3:20])[CH3:19].CN1C(=O)CCC1>C1COCC1>[C:18]([C:22]1[N:27]=[CH:26][C:25]([O:28][CH2:29][C:30]([NH:2][CH2:3][C:4]2[CH:9]=[C:8]([F:10])[C:7]([NH:11][S:12]([CH3:15])(=[O:14])=[O:13])=[C:6]([C:16]#[CH:17])[CH:5]=2)=[O:31])=[CH:24][CH:23]=1)([CH3:21])([CH3:19])[CH3:20]
Reactant: C#Cc1cc(CN)cc(F)c1NS(C)(=O)=O
Reactant: CC(C)(C)c1ccc(OCC(=O)O)cn1
Agent: Cl
Solvent: CN1CCCC1=O
Solvent: C1CCOC1
Product: C#Cc1cc(CNC(=O)COc2ccc(C(C)(C)C)nc2)cc(F)c1NS(C)(=O)=O
Yield: 33.3 %

Procedure:
N-(4-Aminomethyl-2-ethynyl-6-fluoro-phenyl)-methanesulfonamide HCl salt (120 mg, 0.43 mmol) was reacted with (6-tert-butyl-pyridin-3-yloxy)-acetic acid (90 mg) DMTMM (1.1 eq, 131 mg) and NMP (1.2 eq, 60 μl) in THF to give the title compound (62 mg, 33.3%) after purification by column chromatography (Hex EtOAc=2/3).
Reaction SMILES: [CH:1]1([N:4]([CH:25]2[CH2:27][CH2:26]2)[C:5]([C:7]2[N:22]([CH2:23][CH3:24])[C:10]3=[N:11][C:12]([N:19]=[C:20]=[S:21])=[C:13]4[N:17]=[CH:16][N:15]([CH3:18])[C:14]4=[C:9]3[CH:8]=2)=[O:6])[CH2:3][CH2:2]1.C1COCC1.[NH2:33][C:34]1[N:38]([CH3:39])[N:37]=[C:36]([CH3:40])[CH:35]=1.[H-].[Na+]>C(OCC)(=O)C>[CH:25]1([N:4]([CH:1]2[CH2:2][CH2:3]2)[C:5]([C:7]2[N:22]([CH2:23][CH3:24])[C:10]3=[N:11][C:12]([NH:19][C:20]([NH:33][C:34]4[N:38]([CH3:39])[N:37]=[C:36]([CH3:40])[CH:35]=4)=[S:21])=[C:13]4[N:17]=[CH:16][N:15]([CH3:18])[C:14]4=[C:9]3[CH:8]=2)=[O:6])[CH2:26][CH2:27]1
Reactant: CCn1c(C(=O)N(C2CC2)C2CC2)cc2c3c(ncn3C)c(N=C=S)nc21
Reactant: Cc1cc(N)n(C)n1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCn1c(C(=O)N(C2CC2)C2CC2)cc2c3c(ncn3C)c(NC(=S)Nc3cc(C)nn3C)nc21
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a flask charged with N,N-dicyclopropyl-6-ethyl-4-isothiocyanato-1-methyl-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridine-7-carboxamide (example 41A, 0.0342 g, 0.090 mmol) was added THF (0.449 mL). 5-Amino-1,3-dimethylpyrazole (0.012 g, 0.108 mmol) was added followed by sodium hydride (3.60 mg, 0.090 mmol). The reaction mixture was stirred at room temperature for 16 h. The reaction mixture was diluted with ethyl acetate and quenched with saturated aqueous sodium bicarbonate. The aqueous layer was extracted with ethyl acetate. The combined organics were dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The crude material was used without further purification.