Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1](Cl)(=[O:4])[O:2][CH3:3].[NH2:6][C@H:7]1[CH2:12][CH2:11][C@H:10]([NH:13][C:14]2[CH:15]=[C:16]([N:33]([CH:43]3[CH2:45][CH2:44]3)CC3C=CC(OC)=CC=3)[C:17]3[N:18]([C:20]([C:23]([NH:25][C:26]4[CH:31]=[CH:30][N:29]=[CH:28][C:27]=4[F:32])=[O:24])=[CH:21][N:22]=3)[N:19]=2)[CH2:9][CH2:8]1.CCN(C(C)C)C(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH:43]1([NH:33][C:16]2[C:17]3[N:18]([C:20]([C:23](=[O:24])[NH:25][C:26]4[CH:31]=[CH:30][N:29]=[CH:28][C:27]=4[F:32])=[CH:21][N:22]=3)[N:19]=[C:14]([NH:13][C@H:10]3[CH2:11][CH2:12][C@H:7]([NH:6][C:1](=[O:4])[O:2][CH3:3])[CH2:8][CH2:9]3)[CH:15]=2)[CH2:44][CH2:45]1
Reactant: COc1ccc(CN(c2cc(N[C@H]3CC[C@H](N)CC3)nn3c(C(=O)Nc4ccncc4F)cnc23)C2CC2)cc1
Reactant: COC(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)N[C@H]1CC[C@H](Nc2cc(NC3CC3)c3ncc(C(=O)Nc4ccncc4F)n3n2)CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Methyl carbonochloridate (7.81 mg, 0.083 mmol) was added to a solution of 6-((trans)-4-aminocyclohexylamino)-8-(cyclopropyl(4-methoxybenzyl)amino)-N-(3-fluoropyridin-4-yl)imidazo[1,2-b]pyridazine-3-carboxamide (30 mg, 0.055 mmol) and DIEA (0.00617 mL, 0.035 mmol) in CH2Cl2 (1 mL). The reaction mixture was stirred at room temperature for 2 hrs, concentrated and treated with TFA (0.127 mL, 1.653 mmol) at 65° C. for 1 h. The reaction mixture was concentrated and purified by preparative HPLC (Phenomenex Axia Luna 5 micron 30×100 mm) 20% B (Solvent B=90% MeOH-10% H2O-0.1% TFA) to 100% B in A (Solvent A=10% MeOH-90% H2O-0.1% TFA)). The title compound, methyl (trans-4-((8-(cyclopropylamino)-3-((3-fluoro-4-pyridinyl)carbamoyl)imidazo[1,2-b]pyridazin-6-yl)amino)cyclohexyl)carbamate, was isolated as a white solid (15 mg, 56.4%). LC/MS (Phenomenex Luna 5 micron C18 4.6×30 mm, 0 to 100 B in 2 min with 1 min hold time, Flow rate=5 mL/min, detection at 254 nm, Solvent A: 10% methanol/90% water/0.1% TFA; Solvent B: 10% water/90% methanol/0.1% TFA) Rt=1.63 (M+H=483.24). 1H NMR (400 MHz, DMSO-d6) δ ppm 11.42 (1H, s), 8.74 (1H, d, J=2.27 Hz), 8.51 (1H, t, J=6.17 Hz), 8.44 (1H, d, J=5.54 Hz), 8.01 (1H, s), 7.61 (1H, s), 7.18 (1H, d, J=8.06 Hz), 6.94 (1H, d, J=8.31 Hz), 5.98 (1H, s), 3.79 (1H, br. s.), 3.42-3.64 (4H, m), 3.30 (1H, br. s.), 2.02 (2H, d, J=9.57 Hz), 1.79 (2H, br. s.), 1.17-1.45 (4H, m), 0.70-0.82 (2H, m), 0.54-0.68 (2H, m).
Reaction SMILES: Cl.[NH:2]1[CH2:7][CH2:6][CH:5]([C:8]2[C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=3[O:10][N:9]=2)[CH2:4][CH2:3]1.[Cl:17][CH2:18][CH2:19][CH2:20][CH:21]([C:29]1[CH:34]=[CH:33][C:32]([F:35])=[CH:31][CH:30]=1)[C:22]1[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=1.C(=O)([O-])[O-].[K+].[K+].[I-].[K+]>C(OCC)C.O.CN(C)C=O>[ClH:17].[F:28][C:25]1[CH:24]=[CH:23][C:22]([CH:21]([C:29]2[CH:30]=[CH:31][C:32]([F:35])=[CH:33][CH:34]=2)[CH2:20][CH2:19][CH2:18][N:2]2[CH2:3][CH2:4][CH:5]([C:8]3[C:12]4[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=4[O:10][N:9]=3)[CH2:6][CH2:7]2)=[CH:27][CH:26]=1
Reactant: Fc1ccc(C(CCCCl)c2ccc(F)cc2)cc1
Reactant: c1ccc2c(C3CCNCC3)noc2c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [I-]
Solvent: CN(C)C=O
Solvent: CCOCC
Solvent: O
Product: Fc1ccc(C(CCCN2CCC(c3noc4ccccc34)CC2)c2ccc(F)cc2)cc1
Temperature: 25 °C
Yield: 29.7 %

Procedure:
A mixture of 3.94 g of 3-(4-piperidyl)-1,2-benzisoxazole hydrochloride, 4.60 g of 4-chloro-1,1-bis(4-fluorophenyl)butane, 4.95 g of anhydrous potassium carbonate, a few crystals of potassium iodide and 85 ml of dimethylformamide were stirred and heated at 90° for 8 hrs and then stirred at ambient temperature over the weekend. The mixture was poured into water and extracted with ethyl acetate and saturated sodium chloride solution, dried over anhydrous magnesium sulfate and the solvent was removed in vacuo to yield an oil. The oil was dissolved in anhydrous diethyl ether and a sautrated hydrogen chloride-ether solution was added dropwise to precipitate a gum. The gum was recrystallized from ethyl acetate-ether to yield a solid. The mother liquor was concentrated to yield an additional solid. The solids were combined and recrystallized twice from ethyl acetate-ether to yield 2.35 g (29.5%) of product, mp, 156°-157°.
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([O:12]C)[CH:10]=2)[N:5]=[C:4]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:3]=1.B(Br)(Br)Br>C(Cl)Cl>[Cl:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([OH:12])[CH:10]=2)[N:5]=[C:4]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:3]=1
Reactant: COc1ccc2nc(-c3ccccc3)cc(Cl)c2c1
Agent: BrB(Br)Br
Solvent: ClCCl
Product: Oc1ccc2nc(-c3ccccc3)cc(Cl)c2c1
Temperature: 25 °C
Reaction time: 4.5 h
Yield: 39.6 %

Procedure:
To a −78° C. solution of 4-chloro-6-methoxy-2-phenyl-quinoline (1.0 g, 3.7 mmol) in CH2Cl2 (25 ml) was added dropwise BBr3 (11.1 ml, 11.1 mmol, 1M in CH2Cl2). Reaction mixture was then allowed to warm to room temperature. After 4.5 hours, mixture was cooled to −10° C. and quenched slowly with a saturated solution of NaHCO3 (70 ml). The aqueous phase was extracted with ethyl acetate (3×100 ml). Combined organic phases were dried over Na2SO4 and concentrated. The solid residue was refluxed during 1 hour in ethyl acetate (30 ml), cooled to room temperature, and filtered. Filtrate was concentrated and chromatographed over silica gel (hexane-ethyl acetate, 4:1) to provide 4-chloro-2-phenyl-quinolin-6-ol (0.375 g, 40%) as a yellow solid, m. p. 180-181° C., MS: m/e=255 (M+).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[N:6]=[CH:7][C:8](=[O:15])[NH:9][C:10]=1[NH:11][C:12](=[O:14])[CH3:13])=[O:4].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O.[F:47][CH2:48][CH2:49]O.C([O-])(O)=O.[Na+]>C1COCC1>[CH3:1][O:2][C:3]([C:5]1[C:10]([NH:11][C:12](=[O:14])[CH3:13])=[N:9][C:8]([O:15][CH2:49][CH2:48][F:47])=[CH:7][N:6]=1)=[O:4]
Reactant: COC(=O)c1ncc(=O)[nH]c1NC(C)=O
Reactant: OCCF
Agent: CCOC(=O)N=NC(=O)OCC
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Product: COC(=O)c1ncc(OCCF)nc1NC(C)=O
Temperature: -10 °C
Reaction time: 0.25 h
Yield: 205.3 %

Procedure:
To a solution of 3-acetylamino-5-oxo-4,5-dihydro-pyrazine-2-carboxylic acid methyl ester (300 mg, 1.136 mmol, 80% purity) in dry THF (8 ml) under argon were added triphenylphosphine (119 mg, 0.455 mmol) and diethyl azodicarboxylate (DEAD, 0.072 ml, 0.455 mmol) at −10° C. The reaction was stirred at −10° C. for 15 min and then 2-fluoro-ethanol (0.033 ml, 0.568 mmol) was added. The reaction was stirred at rt for 15 min. To complete the reaction, more triphenylphosphine (119 mg, 0.455 mmol) and DEAD (0.072 ml, 0.455 mmol) were added at −10° C. and the resulting mixture was stirred at −10° C. for 15 min before the addition of 2-fluoro-ethanol (0.033 ml, 0.568 mmol). The reaction was stirred for 100 min. More triphenylphosphine (119 mg, 0.455 mmol) and DEAD (0.072 ml, 0.455 mmol) were added at −10° C. and the resulting mixture was stirred at −10° C. for 15 min before the addition of 2-fluoroethanol (0.033 ml, 0.568 mmol). The reaction was stirred for another 2 h. Saturated aq. NaHCO3 was added and the mixture was extracted with EtOAc, the combined organic layers were washed with aq. sodium chloride, filtered and dried with Na2SO4 and evaporated. The residue was purified by chromatography on silica gel (DCM to DCM/EtOAc 9:1) to provide the title compound as yellow oil (300 mg).
Reaction SMILES: [CH3:1][C@H:2]1[CH2:6][CH2:5][CH2:4][N:3]1[C@H:7]1[CH2:11][CH2:10][N:9]([C:12]2[CH:13]=[C:14]3[C:19](=[CH:20][CH:21]=2)[CH2:18][NH:17][CH2:16][CH2:15]3)[CH2:8]1.[CH3:22][O:23][C:24]1[CH:32]=[CH:31][C:27]([C:28](Cl)=[O:29])=[CH:26][CH:25]=1.C(N(CC)CC)C>C(Cl)Cl>[CH3:22][O:23][C:24]1[CH:32]=[CH:31][C:27]([C:28]([N:17]2[CH2:16][CH2:15][C:14]3[C:19](=[CH:20][CH:21]=[C:12]([N:9]4[CH2:10][CH2:11][C@H:7]([N:3]5[CH2:4][CH2:5][CH2:6][C@@H:2]5[CH3:1])[CH2:8]4)[CH:13]=3)[CH2:18]2)=[O:29])=[CH:26][CH:25]=1
Reactant: C[C@H]1CCCN1[C@H]1CCN(c2ccc3c(c2)CCNC3)C1
Reactant: COc1ccc(C(=O)Cl)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1ccc(C(=O)N2CCc3cc(N4CC[C@H](N5CCC[C@@H]5C)C4)ccc3C2)cc1

Procedure:
To a solution of 6-((2S,3′S)-2-Methyl-[1,3′]bipyrrolidinyl-1′-yl)-1,2,3,4-tetrahydro-isoquinoline in DCM (7 mL) was added 4-Methoxy-benzoyl chloride in DCM, followed by triethylamine. The reaction was quenched with aq. NaHCO3 and DCM work up. The crude product was purified on a silica gel column to obtain the title compound.
Reaction SMILES: BrBr.[Cl:3][C:4]1[CH:24]=[CH:23][C:7]2[CH2:8][CH2:9][CH:10]3[C:15]([C:6]=2[CH:5]=1)=[N:14][N:13]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C:12](=[O:22])[CH2:11]3>C(O)(=O)C>[Cl:3][C:4]1[CH:24]=[CH:23][C:7]2[CH2:8][CH2:9][C:10]3[C:15]([C:6]=2[CH:5]=1)=[N:14][N:13]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C:12](=[O:22])[CH:11]=3
Reactant: O=C1CC2CCc3ccc(Cl)cc3C2=NN1c1ccccc1
Agent: BrBr
Solvent: CC(=O)O
Product: O=c1cc2c(nn1-c1ccccc1)-c1cc(Cl)ccc1CC2
Temperature: 25 °C
Yield: 54.4 %

Procedure:
About half volume of 10 ml of solution of 3.9 g of bromine in acetic acid is added dropwise to a solution of 5 g of 9-chloro-2-phenyl-4,4a,5,6-tetrahydrobenzo[h]cinnolin-3(2H)-one in 150 ml of acetic acid with stirring at room temperature. After the mixture is heated up to 50° C. on a water bath, the remaining solution is added dropwise. After stirring under heating at 50° C. for 2 hours, the precipitated crystals are collected by filtration, washed with water and recrystallized from ethanol to give 2.7 g of 9-chloro-2-phenyl-5,6-dihydrobenzo[h]cinnolin-3(2H)-one as yellow leaflets, melting at 184°-186° C.
Reaction SMILES: Br[C:2]1[C:3]([C:13]([O:15][CH3:16])=[O:14])=[N:4][O:5][C:6]=1[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.C([Sn](CCCC)(CCCC)[C:22]([O:24]CC)=[CH2:23])CCC.Cl.[F-].[K+]>O1CCOCC1.C(OCC)(=O)C.O>[C:22]([C:2]1[C:3]([C:13]([O:15][CH3:16])=[O:14])=[N:4][O:5][C:6]=1[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)(=[O:24])[CH3:23]
Reactant: C=C(OCC)[Sn](CCCC)(CCCC)CCCC
Reactant: COC(=O)c1noc(-c2ccccc2)c1Br
Agent: Cl
Agent: [F-]
Agent: [K+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: COC(=O)c1noc(-c2ccccc2)c1C(C)=O
Temperature: 100 °C
Reaction time: 1 h

Procedure:
A solution of methyl 4-bromo-5-phenylisoxazole-3-carboxylate (358 mg, 1.269 mmol, prepared in a similar manner as described in step 9-B) and tributyl(1-ethoxyvinyl)tin (0.858 mL, 2.54 mmol) in dioxane (5 mL) was heated at 100° C. for 24 h. To the reaction mixture was added 1N aqueous hydrochloric acid (2.54 mL, 2.54 mmol), and the mixture was stirred at room temperature for 1 h. The reaction mixture was diluted with ethyl acetate (100 mL), washed with water (30 mL), washed with a saturated aqueous solution of sodium bicarbonate (30 mL), and washed with brine (30 mL). The mixture was concentrated to ˜5 mL, and potassium fluoride (0.059 mL, 2.54 mmol) in 2 mL of water was added, and the mixture was stirred for 10 minutes. The solid was filtered and washed with ethyl acetate, and the filtrate was washed with water (10 mL), washed with brine (10 mL), and dried over anhydrous sodium sulfate. Concentration followed by purification by silica gel chromatography with hexanes/ethyl acetate (10/1) afforded methyl 4-acetyl-5-phenylisoxazole-3-carboxylate (105 mg). The compound had an HPLC ret. time=2.69 min.−Column: YMC S5 COMBISCREEN® 4.6×50 mm; Gradient time: 4 min; Flow rate=4 ml/min; Solvent A=10% MeOH−90% Water−0.2% H3PO4; Solvent B=90% MeOH−10% water−0.2% H3PO4; Start % B=0; Final % B=100. LC-MS: M+1=246+.
Reaction SMILES: CCN(C(C)C)C(C)C.[Cl:10][C:11]1[CH:19]=[CH:18][C:14]([C:15]([OH:17])=O)=[CH:13][CH:12]=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.[CH:42]1([C@@H:46]([NH:53][CH3:54])[CH2:47][N:48]2[CH2:51][CH:50]([OH:52])[CH2:49]2)[CH2:45][CH2:44][CH2:43]1>C(Cl)Cl.CN1C(=O)CCC1>[Cl:10][C:11]1[CH:12]=[CH:13][C:14]([C:15]([N:53]([C@H:46]([CH:42]2[CH2:45][CH2:44][CH2:43]2)[CH2:47][N:48]2[CH2:49][CH:50]([OH:52])[CH2:51]2)[CH3:54])=[O:17])=[CH:18][CH:19]=1
Reactant: O=C(O)c1ccc(Cl)cc1
Reactant: CN[C@@H](CN1CC(O)C1)C1CCC1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN1CCCC1=O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CN(C(=O)c1ccc(Cl)cc1)[C@@H](CN1CC(O)C1)C1CCC1
Temperature: 25 °C
Yield: 52.4 %

Procedure:
DIPEA (0.275 mL, 1.57 mmol) was added to a suspension of 4-chlorobenzoic acid (82 mg, 0.52 mmol) and TBTU (168 mg, 0.52 mmol) in DCM (1 mL) at rt. The reaction mixture was stirred for 45 min before a solution of (R)-1-(2-cyclobutyl-2-(methylamino)ethyl)azetidin-3-ol (Compound G2.6) (184 mg, 0.52 mmol) in NMP (1.000 mL) was added. The reaction mixture was stirred at rt over the weekend. The reaction mixture was washed with NaHCO3 (8% aq.2 mL). The organic layer was passed through a phase separator and the solvent was removed in vacuo. The residue was purified by preparative HPLC to give the title compound (88 mg, 52%). 1H NMR (600 MHz, DMSO-d6) δ 1.38-1.52, 1.55-1.62, 1.64-1.95, 2.00-2.06, 2.21-2.25, 2.27-2.33, 2.36-2.43, 2.55-2.62, 2.64-2.68, 2.70-2.72, 2.73-2.79, 3.23-3.26, 3.40-3.44, 3.54-3.57, 4.11-4.18, 4.43-4.51, 5.20-5.27, 7.29-7.35, 7.47-7.54. HRMS (M+H)+: calculated 323.1526. found 323.1535
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:8][C:9](=[O:23])[C:10]2[CH:15]=[CH:14][CH:13]=[N:12][C:11]=2[NH:16][C@H:17]2[CH2:22][CH2:21][CH2:20][NH:19][CH2:18]2)[CH:5]=[CH:6][CH:7]=1.ClC1C=C(N[C:32](=[O:50])[C:33]2C=CC=NC=2NC2CC(C)(C)NC(C)(C)C2)C=CC=1>>[Cl:1][C:2]1[CH:3]=[C:4]([NH:8][C:9](=[O:23])[C:10]2[CH:15]=[CH:14][CH:13]=[N:12][C:11]=2[NH:16][C@H:17]2[CH2:22][CH2:21][CH2:20][N:19]([CH2:33][CH2:32][OH:50])[CH2:18]2)[CH:5]=[CH:6][CH:7]=1
Reactant: O=C(Nc1cccc(Cl)c1)c1cccnc1N[C@H]1CCCNC1
Reactant: CC1(C)CC(Nc2ncccc2C(=O)Nc2cccc(Cl)c2)CC(C)(C)N1
Product: O=C(Nc1cccc(Cl)c1)c1cccnc1N[C@H]1CCCN(CCO)C1
Yield: 60.8 %

Procedure:
The title compound was prepared in the same manner as in Example 21, with the exception that (S)—N-(3-chlorophenyl)-2-(3-piperidylamino)nicotinamide of Example 20-B, instead of N-(3-chlorophenyl)-2-(2,2,6,6-tetramethylpiperidin-4-ylamino)nicotinamide, was used in the same molar amount (Yield: 60.8%). 1H NMR (CDCl3) δ 8.50 (br, 1H), 8.22 (d, 1H), 7.97 (s, 1H), 7.73 (d, 1H), 7.61 (s, 1H), 7.45 (d, 1H), 7.25 (t, 1H), 7.09 (d, 1H), 6.53-6.47 (m, 1H), 4.33 (br, 1H), 3.61 (t, 2H), 2.76-2.45 (m, 6H), 1.85-1.58 (m, 4H) ppm.
Reaction SMILES: [CH2:1]([OH:4])[C:2]#[CH:3].[F:5][C:6]1[C:7]([NH:17][C:18]2[CH:23]=[CH:22][C:21](I)=[CH:20][C:19]=2[F:25])=[C:8]([CH:13]=[CH:14][C:15]=1[F:16])[C:9]([O:11][CH3:12])=[O:10]>>[F:5][C:6]1[C:7]([NH:17][C:18]2[CH:23]=[CH:22][C:21]([C:3]#[C:2][CH2:1][OH:4])=[CH:20][C:19]=2[F:25])=[C:8]([CH:13]=[CH:14][C:15]=1[F:16])[C:9]([O:11][CH3:12])=[O:10]
Reactant: COC(=O)c1ccc(F)c(F)c1Nc1ccc(I)cc1F
Reactant: C#CCO
Product: COC(=O)c1ccc(F)c(F)c1Nc1ccc(C#CCO)cc1F
Yield: 94 %

Procedure:
The title compound was prepared by Sonogashira reaction of propargyl alcohol and methyl 3,4-difluoro-2-(2-fluoro-4-iodoanilino)benzoate by the general procedure of Example 1, Step A. The oil resulting from workup was purified by chromatography on silica gel (20% EtOAc/PE as eluant), to give methyl 3,4-difluoro-2-[2-fluoro-4-(3-hydroxy-1-propynyl)anilino]benzoate as a pale yellow solid (94%); m.p. (Et2O/hexane) 116-120° C. 1H NMR [400 MHz, (CD3)2SO] δ 8.79 (s, 1 H), 7.79 (ddd, J=8.3, 5.9, 2.0 Hz, 1 H), 7.30 (dd, J=12.2, 1.8 Hz, 1 H), 7.26-7.17 (m, 1 H), 7.15 (dd, J=8.5, 1.6 Hz, 1 H), 6.92 (ddd, J=8.8,8.8,4.7 Hz, 1 H), 5.31 (br s, 1 H), 4.28 (s, 2 H), 3.81 (s, 3 H). Anal. calcd. for C17H12F3NO3: C, 60.9; H, 3.6; N, 4.2. Found C, 61.4; H, 3.9; N, 4.7. Step B: Preparation of Methyl 3,4-difluoro-2-[2-fluoro-4-(3-hydroxypropyl)anilino]benzoate
Reaction SMILES: [Br:1][C:2]1[C:3]2[CH:4]3[CH2:13][CH:5]3[C:6](=O)[NH:7][C:8]=2[CH:9]=[CH:10][CH:11]=1.Cl>CO>[Br:1][C:2]1[C:3]2[CH:4]3[CH2:13][CH:5]3[CH2:6][NH:7][C:8]=2[CH:9]=[CH:10][CH:11]=1
Reactant: O=C1Nc2cccc(Br)c2C2CC12
Agent: Cl
Solvent: CO
Product: Brc1cccc2c1C1CC1CN2
Temperature: 80 °C
Yield: 82.9 %

Procedure:
The mixture of 7-bromo-3,7b-dihydro-1H-cyclopropa[c]quinolin-2(1aH)-one (100 mg, 0.420 mmol) and borane tetrahydrofuran complex (5 mL, 5.00 mmol) was heated at 80° C. for 4 h. After this time, MeOH (5 mL) was added slowly to the reaction mixture, followed by 3 mL of conc. HCl. The resulting mixture was heated at 100° C. for 1 h, and then cooled to room temperature. After removing most of the solvent, the mixture was adjusted to a pH of 8-9 by using saturated Na2CO3. The aqueous solution was extracted with EtOAc (2×10 mL). The combined organic layers were concentrated and purified by flash chromatography (0 to 30% ethyl acetate:hexanes) to afford the title compound (78 mg, 83% yield) as an oil. LCMS, [M+H]+=223.9. 1H NMR (400 MHz, CDCl3) δ 8.15 (s, 1H), 7.24 (d, J=7.7 Hz, 1H), 7.00 (t, J=7.7 Hz, 1H), 6.69 (d, J=7.7 Hz, 1H), 2.84 (td, J=8.1, 5.2 Hz, 1H), 2.22-2.13 (m, 1H), 1.76 (td, J=9.2, 4.7 Hz, 1H), 0.75 (dd, J=10.0, 5.0 Hz, 1H).
Reaction SMILES: [Si:1]([O:8][CH2:9][CH2:10][C:11](=[O:13])[CH3:12])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[C:14]1([Mg]Br)[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.CCOCC>C1COCC1>[Si:1]([O:8][CH2:9][CH2:10][C:11]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([OH:13])[CH3:12])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: Br[Mg]c1ccccc1
Reactant: CC(=O)CCO[Si](C)(C)C(C)(C)C
Solvent: CCOCC
Solvent: C1CCOC1
Product: CC(O)(CCO[Si](C)(C)C(C)(C)C)c1ccccc1
Reaction time: 1 h

Procedure:
The product of Example 457A (2.0 g, 9.88 mmol) in anhydrous THF (50ml) under at 0 C under nitrogen was reacted with phenylmagnesium bromide as a 3.0M solution in ether (5.0 ml, 15 mmol) dropwise via syringe then stirred for one hour. The reaction was quenched by the drop wise addition of a saturated solution of ammonium chloride and the reaction was partitioned with ether and water. The combined organics were dried over magnesium sulfate and concentrated in vacuo to give the desired compound as a clear oil (2.71 g, quantitative).
Reaction SMILES: [CH2:1]([C:3]1[N:8]=[C:7]([CH:9]=[O:10])[CH:6]=[CH:5][CH:4]=1)[CH3:2].[CH3:11]C1N=C(C=O)C=CC=1>>[CH:1]([C:3]1[N:8]=[C:7]([CH:9]=[O:10])[CH:6]=[CH:5][CH:4]=1)([CH3:11])[CH3:2]
Reactant: Cc1cccc(C=O)n1
Reactant: CCc1cccc(C=O)n1
Product: CC(C)c1cccc(C=O)n1

Procedure:
The alkylation of 6-ethyl-2-pyridinecarboxaldehyde from Step 1 was performed as described above for 6-methyl,2-pyridinecarboxaldehyde.
Reaction SMILES: CC([N:5]([C@H:9]1[CH2:14][CH2:13][C@@H:12]([CH3:15])[N:11]([C:16]2[CH:21]=[C:20]([C:22]3[CH:27]=[CH:26][C:25]([C:28]#[N:29])=[C:24]([F:30])[CH:23]=3)[N:19]=[C:18]([NH2:31])[N:17]=2)[CH2:10]1)[C:6](=O)[O-:7])(C)C.Cl.C(O)(=O)[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1.C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1.CN1CCOCC1>O1CCOCC1.CN(C=O)C.O>[NH2:31][C:18]1[N:17]=[C:16]([N:11]2[C@H:12]([CH3:15])[CH2:13][CH2:14][C@H:9]([NH:5][C:6](=[O:7])[C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)[CH2:10]2)[CH:21]=[C:20]([C:22]2[CH:27]=[CH:26][C:25]([C:28]#[N:29])=[C:24]([F:30])[CH:23]=2)[N:19]=1
Reactant: O=C(O)c1ccccc1
Reactant: C[C@@H]1CC[C@H](N(C(=O)[O-])C(C)(C)C)CN1c1cc(-c2ccc(C#N)c(F)c2)nc(N)n1
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: O
Solvent: CN(C)C=O
Product: C[C@@H]1CC[C@H](NC(=O)c2ccccc2)CN1c1cc(-c2ccc(C#N)c(F)c2)nc(N)n1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 29.8 %

Procedure:
To 1,1-dimethylethyl{(3S,6R)-1-[2-amino-6-(4-cyano-3-fluorophenyl)-4-pyrimidinyl]-6-methyl-3-piperidinyl}carbamate (100 mg, 0.234 mmol) in a 20 mL vial was added 2 mL of 4M HCl in 1,4-dioxane, and the solution was stirred at room temperature for 30 minutes. The reaction was then concentrated. To the resulting whitish solid was added a premixed solution of benzoic acid (34.4 mg, 0.281 mmol), EDC (67.4 mg, 0.352 mmol), HOBT (71.8 mg, 0.469 mmol), and N-methylmorpholine (0.129 mL, 1.172 mmol) in DMF (2 mL), and the resulting solution was stirred at room temperature overnight. The reaction was diluted with water (10 mL), then extracted with EtOAc (3×10 mL). The organics were combined, washed with brine, then dried over MgSO4, filtered and concentrated to afford the crude title compound (30 mg) as a yellow oil. LC-MS (ES) m/z=431 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]3[O:15][C:14]4[CH:16]=[CH:17][C:18]([Cl:20])=[CH:19][C:13]=4[C:7]=3[N:8]=[C:9]2O)=[CH:4][CH:3]=1.[Cl:21]C1C=C2C(C3OC4C=CC=CC=4C=3N=C2O)=CC=1>>[Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]3[O:15][C:14]4[CH:16]=[CH:17][C:18]([Cl:20])=[CH:19][C:13]=4[C:7]=3[N:8]=[C:9]2[Cl:21])=[CH:4][CH:3]=1
Reactant: Oc1nc2c3ccccc3oc2c2ccc(Cl)cc12
Reactant: Oc1nc2c3cc(Cl)ccc3oc2c2ccc(Cl)cc12
Product: Clc1ccc2c(c1)c(Cl)nc1c3cc(Cl)ccc3oc21

Procedure:
The procedure was similar to step S19C, while the starting material was 27B in stead of 19B.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][C:12]2[CH:13]=[CH:14][CH:15]=[C:16]3[C:21]=2[N:20]=[CH:19][CH:18]=[CH:17]3)(=[O:10])=[O:9])=[C:4]([N+:22]([O-])=O)[CH:3]=1.[Sn](Cl)Cl.Cl>>[NH2:22][C:4]1[CH:3]=[C:2]([CH3:1])[CH:7]=[CH:6][C:5]=1[S:8]([NH:11][C:12]1[CH:13]=[CH:14][CH:15]=[C:16]2[C:21]=1[N:20]=[CH:19][CH:18]=[CH:17]2)(=[O:10])=[O:9]
Reactant: Cc1ccc(S(=O)(=O)Nc2cccc3cccnc23)c([N+](=O)[O-])c1
Agent: Cl
Agent: Cl[Sn]Cl
Product: Cc1ccc(S(=O)(=O)Nc2cccc3cccnc23)c(N)c1
Yield: 17.2 %

Procedure:
In the similar fashion using route 1 general procedure 4, 4-methyl-2-nitro-N-quinolin-8-yl-benzenesulfonamide (Intermediate 151) (3.2 g, 9.3 mmol), tin (II) chloride (5.3 g, 2.79 mmol) and 6N HCl (2 ml) gave the title compound (500 mg, 17%).
Reaction SMILES: [F:1][C:2]1[CH:12]=[CH:11][C:5]([CH2:6][O:7][CH2:8][CH2:9][OH:10])=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH3:20][S:21](Cl)(=[O:23])=[O:22]>C(Cl)Cl>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][O:7][CH2:8][CH2:9][O:10][S:21]([CH3:20])(=[O:23])=[O:22])=[CH:11][CH:12]=1
Reactant: OCCOCc1ccc(F)cc1
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CS(=O)(=O)OCCOCc1ccc(F)cc1
Temperature: -5 °C
Reaction time: 2 h
Yield: 96.1 %

Procedure:
A solution of 2-(4-fluorobenzyloxy)-ethanol (5.11 g, 30.0 mmol, from step (i) above) in methylene chloride (60 mL) was cooled to −10° C. Triethylamine (5.0 mL, 36 mmol) was added followed by methanesulfonyl chloride (3.78 g, 33.0 mmol) and the reaction mixture was stirred at −5° C. for 2 h. The reaction mixture was diluted with methylene chloride (200 mL) and the organic phase was washed with water (2×75 mL) and brine (75 mL), dried over MgSO4, and concentrated in vacuo to give 7.16 g (96%) of the title compound as a yellow oil.