Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: COC1C=CC(CO[CH2:11][CH2:12][O:13][CH2:14][C@H:15]2[CH2:26][CH2:25][C:24]3[S:23][C:22]4[N:21]=[CH:20][N:19]=[C:18]([O:27][CH:28]5[CH2:33][CH2:32][CH:31]([N:34]([CH3:42])[C:35](=[O:41])[O:36][C:37]([CH3:40])([CH3:39])[CH3:38])[CH2:30][CH2:29]5)[C:17]=4[C:16]2=3)=CC=1.C(C1C(=O)C(Cl)=C(Cl)[C:47](=[O:48])C=1C#N)#N>ClCCl.O>[OH:48][CH2:47][CH2:11][CH2:12][O:13][CH2:14][C@H:15]1[CH2:26][CH2:25][C:24]2[S:23][C:22]3[N:21]=[CH:20][N:19]=[C:18]([O:27][CH:28]4[CH2:29][CH2:30][CH:31]([N:34]([CH3:42])[C:35](=[O:41])[O:36][C:37]([CH3:38])([CH3:39])[CH3:40])[CH2:32][CH2:33]4)[C:17]=3[C:16]1=2
Reactant: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Reactant: COc1ccc(COCCOC[C@H]2CCc3sc4ncnc(OC5CCC(N(C)C(=O)OC(C)(C)C)CC5)c4c32)cc1
Solvent: ClCCl
Solvent: O
Product: CN(C(=O)OC(C)(C)C)C1CCC(Oc2ncnc3sc4c(c23)[C@@H](COCCCO)CC4)CC1
Temperature: 25 °C
Reaction time: 14 h
Yield: 64.3 %

Procedure:
A solution of tert-butyl N-(4-[[(3S)-3-([2-[(4-methoxyphenyl)methoxy]ethoxy]methyl)-7-thia-9,11-diazatricyclo[6.4.0.0^[2,6]]dodeca-1(8),2(6),9,11-tetraen-12-yl]oxy]cyclohexyl)-N-methylcarbamate (700 mg, 1.17 mmol, 1.00 equiv) in dichloromethane (10 mL)/water (0.5 mL) was added DDQ (399 mg, 1.76 mmol, 1.50 equiv) and the resulting solution was stirred for 14 hrs at 25° C. under nitrogen. The resulting solution was diluted with water and extracted with 3×100 mL of ethyl acetate. The organic layers were combined, washed with brine, dried over sodium sulfate and concentrated in vacuo. The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (1:1) to give tert-butyl N-(4-[[(3S)-3-[(3-hydroxypropoxy)methyl]-7-thia-9,11-diazatricyclo[6.4.0.0[2,6]]dodeca-1(8),2(6),9,11-tetraen-12-yl]oxy]cyclohexyl)-N-methylcarbamate (370 mg, 64%) as a colorless oil. MS: m/z 478 (M+H)+.
Reaction SMILES: [CH2:1]([OH:4])[CH2:2][OH:3].C(OC)(OC)OC.[CH3:12][O:13][N:14]=[C:15]([C:19](=O)[CH3:20])[C:16](=[O:18])[CH3:17]>C1(C)C=CC(S(O)(=O)=O)=CC=1>[CH3:12][O:13]/[N:14]=[C:15](/[C:19]1([CH3:20])[O:4][CH2:1][CH2:2][O:3]1)\[C:16](=[O:18])[CH3:17]
Reactant: CON=C(C(C)=O)C(C)=O
Reactant: OCCO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: COC(OC)OC
Product: CO/N=C(\C(C)=O)C1(C)OCCO1
Temperature: 85 °C
Reaction time: 0.25 h
Yield: 79.4 %

Procedure:
2400 g (39 mol) of ethylene glycol, 430 g (3.62 mol) of trimethyl orthoformate, 550 g (3.9 mol) of pentane-2,3,4-trione 3-(O-methyloxime) and 9 g of p-toluene sulfonic acid (46 mmol) were heated with stirring to 85° C. over a period of 15 min. After 30 min at 85° C., the mixture was cooled to room temperature. During the reaction, volatile components were distilled off via a column head. For work-up, the mixture was washed with saturated sodium bicarbonate solution and extracted with methyl tert-butyl ether, and the combined organic phases were washed twice with water and finally dried over magnesium sulfate. Distillative removal of the solvent gave 580 g of a red-brown oil (phys. data see Tab. 1).
Reaction SMILES: [F:1][C:2]([F:16])([F:15])[CH:3]([CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[CH2:4][C:5]([OH:7])=O.C(Cl)(=O)C(Cl)=O.[Al+3].[Cl-].[Cl-].[Cl-]>C(Cl)Cl>[F:15][C:2]([F:1])([F:16])[CH:3]1[CH2:8][C:9]2[C:14](=[CH:13][CH:12]=[CH:11][CH:10]=2)[C:5](=[O:7])[CH2:4]1
Reactant: O=C(O)CC(Cc1ccccc1)C(F)(F)F
Agent: O=C(Cl)C(=O)Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: O=C1CC(C(F)(F)F)Cc2ccccc21
Yield: 82.7 %

Procedure:
4,4,4-Trifluoro-3-(phenylmethyl)butanoic acid (177) (0.97 g, 4.18 mmol) was treated with oxalyl chloride followed by AlCl3 in CH2Cl2 to give 0.74 g (82%) of the title compound (178) as an off-white solid. 1H NMR (400 MHz, CDCl3): δ 2.60-2.75 (m, 1H), 2.85-3.00 (m, 2H), 3.05-3.25 (m, 2H), 7.30 (d, J=7.7 Hz, 1H), 7.37 (t, J=7.6 Hz, 1H), 7.50-7.57 (m, 1H), 8.05 (d, J=7.7 Hz, 1H). LCMS (ESI): m/z 215 (M−H)−.
Reaction SMILES: [CH2:1]([O:5][C:6]1[CH:28]=[CH:27][C:9]([C:10]([N:12]([CH3:26])[C:13]2[CH:18]=[CH:17][C:16]([N:19]3[CH2:23][CH2:22][CH:21]([NH:24][CH3:25])[CH2:20]3)=[CH:15][CH:14]=2)=[O:11])=[CH:8][CH:7]=1)[CH2:2][CH2:3][CH3:4].[C:29](OC(=O)C)(=[O:31])[CH3:30]>N1C=CC=CC=1>[C:29]([CH2:25][NH:24][CH:21]1[CH2:22][CH2:23][N:19]([C:16]2[CH:17]=[CH:18][C:13]([N:12]([CH3:26])[C:10](=[O:11])[C:9]3[CH:27]=[CH:28][C:6]([O:5][CH2:1][CH2:2][CH2:3][CH3:4])=[CH:7][CH:8]=3)=[CH:14][CH:15]=2)[CH2:20]1)(=[O:31])[CH3:30]
Reactant: CC(=O)OC(C)=O
Reactant: CCCCOc1ccc(C(=O)N(C)c2ccc(N3CCC(NC)C3)cc2)cc1
Solvent: c1ccncc1
Product: CCCCOc1ccc(C(=O)N(C)c2ccc(N3CCC(NCC(C)=O)C3)cc2)cc1

Procedure:
4-Butoxy-N-methyl-N-[4-(3-methylaminopyrrolidin-1-yl)phenyl]benzamide was mixed with pyridine and acetic anhydride. Volatile fractions were removed after 2 hours. This resulted in the product with the molecular weight of 423.56 (C25H33N3O3); MS (ESI): 424 (M+H+).
Reaction SMILES: [CH3:1][N:2]([CH2:14][C:15]([OH:17])=O)[NH:3][C:4](=[O:13])[NH:5][CH2:6][C:7]1[CH:12]=[CH:11][N:10]=[CH:9][CH:8]=1.[NH2:18][C@@H:19]([CH3:43])[C:20]([N:22]([C@@H:34]([CH3:42])[CH:35]([O:39][CH2:40][CH3:41])[O:36][CH2:37][CH3:38])[CH2:23][C:24]1[C:33]2[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=2)[CH:27]=[CH:26][CH:25]=1)=[O:21]>>[CH2:40]([O:39][CH:35]([O:36][CH2:37][CH3:38])[C@@H:34]([N:22]([CH2:23][C:24]1[C:33]2[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=2)[CH:27]=[CH:26][CH:25]=1)[C:20](=[O:21])[C@@H:19]([NH:18][C:15](=[O:17])[CH2:14][N:2]([CH3:1])[NH:3][C:4]([NH:5][CH2:6][C:7]1[CH:8]=[CH:9][N:10]=[CH:11][CH:12]=1)=[O:13])[CH3:43])[CH3:42])[CH3:41]
Reactant: CCOC(OCC)[C@H](C)N(Cc1cccc2ccccc12)C(=O)[C@H](C)N
Reactant: CN(CC(=O)O)NC(=O)NCc1ccncc1
Product: CCOC(OCC)[C@H](C)N(Cc1cccc2ccccc12)C(=O)[C@H](C)NC(=O)CN(C)NC(=O)NCc1ccncc1

Procedure:
According to the procedure described in the synthesis method of Compound II-15, 2-(1-methyl-2-(pyridin-4-ylmethylcarbamoyl)hydrazinyl)acetic acid (Compound VI-6) 100 mg (0.42 mmol) was coupled with (S)-2-amino-N—((S)-1,1-diethoxypropan-2-yl)-N-(naphthalen-1-ylmethyl)propanamide (Compound IV-10) 100 mg (0.28 mmol) to obtain the title compound.
Reaction SMILES: [CH3:1][C:2]1([CH3:24])[O:7][C:6]2[CH:8]=[C:9]([NH:12]C(=O)OCC3C=CC=CC=3)[CH:10]=[CH:11][C:5]=2[C:4](=[O:23])[O:3]1>CO.[Pd]>[NH2:12][C:9]1[CH:10]=[CH:11][C:5]2[C:4](=[O:23])[O:3][C:2]([CH3:1])([CH3:24])[O:7][C:6]=2[CH:8]=1
Reactant: CC1(C)OC(=O)c2ccc(NC(=O)OCc3ccccc3)cc2O1
Agent: [Pd]
Solvent: CO
Product: CC1(C)OC(=O)c2ccc(N)cc2O1
Reaction time: 24 h
Yield: 77.5 %

Procedure:
To a solution of benzyl 2,2-dimethyl-4-oxo-4H-1,3-benzodioxin-7-ylcarbamate (3.5 g) in methanol (250 mL) was added Pd/C (350 mg) and hydrogenated under 2 Bars of pressure for 24 h. The reaction mixture was filtered through a bed of celite and concentrated to give the title compound (1.6 g).
Reaction SMILES: [CH:1]1[CH:2]=[CH:3][N:4]2[CH2:10][C:9]3[CH:11]=[CH:12][CH:13]=[CH:14][C:8]=3[N:7]([C:15](C3C=CC(B4OC(C)(C)C(C)(C)O4)=C(C)C=3)=[O:16])[CH2:6][C:5]=12.FC(F)(F)S(O[C:39]1[CH:44]([CH3:45])[CH2:43][CH2:42][CH2:41][CH:40]=1)(=O)=O>>[CH:1]1[CH:2]=[CH:3][N:4]2[CH2:10][C:9]3[CH:11]=[CH:12][CH:13]=[CH:14][C:8]=3[N:7]([C:15]([C:42]3[CH:41]=[CH:40][C:39]([C:8]4[CH:9]([CH3:10])[CH2:11][CH2:12][CH2:13][CH:14]=4)=[C:44]([CH3:45])[CH:43]=3)=[O:16])[CH2:6][C:5]=12
Reactant: CC1CCCC=C1OS(=O)(=O)C(F)(F)F
Reactant: Cc1cc(C(=O)N2Cc3cccn3Cc3ccccc32)ccc1B1OC(C)(C)C(C)(C)O1
Product: Cc1cc(C(=O)N2Cc3cccn3Cc3ccccc32)ccc1C1=CCCCC1C
Yield: 176.5 %

Procedure:
(10,11-Dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepin-10-yl)-[3-methyl-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-methanone of Example 2, Step B (0.428 g, 1.00 mmol) and 6-methyl-cyclohex-1-en-1-yl trifluoromethanesulfonate (0.269 g, 1.10 mmol) were reacted in the manner of Example 2, Step C. Purification by flash column chromatography on silica gel, eluting with 20% ethyl acetate in hexane, followed by recrystallization from petroleum ether afforded the title compound (0.350 g) as white crystals, m.p. 132–133° C.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[CH:4][N:3]=1.CC[N:14](C(C)C)C(C)C>>[NH2:14][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[CH:4][N:3]=1
Reactant: Clc1ncnc2ccccc12
Reactant: CCN(C(C)C)C(C)C
Product: Nc1ncnc2ccccc12

Procedure:
4-Chloro quinazoline derivative 3a was reacted with the primary amine 2d in the presence of Hunig's base to provide the 4-amino quinazoline intermediate 3b. Ammonolysis of the ester group with 7N ammonia/methanol solution afforded carboxamide 3c. When R4 is a protecting Nosyl group, deprotection with cesium carbonate in the presence of thiophenol provides 3d.
Reaction SMILES: C([O:3][C:4](=[O:14])[C:5]([C:7]1[CH:11]=[C:10]([Br:12])[S:9][C:8]=1[Br:13])=[O:6])C.Cl>CC(C)=O.O>[Br:13][C:8]1[S:9][C:10]([Br:12])=[CH:11][C:7]=1[C:5](=[O:6])[C:4]([OH:14])=[O:3]
Reactant: CCOC(=O)C(=O)c1cc(Br)sc1Br
Agent: Cl
Solvent: CC(C)=O
Solvent: O
Product: O=C(O)C(=O)c1cc(Br)sc1Br

Procedure:
(2,5-Dibromothiophen-3-yl)-oxo-acetic acid ethyl ester (1.71 g, 5.0 mmol) was dissolved in 15 ml acetone and 2 ml water, then treated with 15 ml concentrated HCl at reflux for 2 hours. The reaction mixture was then poured into 100 ml water, and extracted into 100 ml of dichloromethane. The organic layer was dried over Na2SO4 and concentrated under vacuum to yield crude (2,5-dibromothiophen-3-yl)-oxo-acetic acid which was used without further purification.
Reaction SMILES: [I:1][C:2]1[NH:6][C:5]([C:7]2([CH3:11])[CH2:10]OC2)=[N:4][C:3]=1[C:12]([F:15])([F:14])[F:13].[O:16]1[CH2:21]CC(C=O)C[CH2:17]1>>[I:1][C:2]1[NH:6][C:5]([CH:7]2[CH2:10][CH2:21][O:16][CH2:17][CH2:11]2)=[N:4][C:3]=1[C:12]([F:13])([F:14])[F:15]
Reactant: O=CC1CCOCC1
Reactant: CC1(c2nc(C(F)(F)F)c(I)[nH]2)COC1
Product: FC(F)(F)c1nc(C2CCOCC2)[nH]c1I

Procedure:
The title compound was prepared using standard chemical manipulations and procedures similar to those used for the preparation of compound 202.2, except tetrahydro-2H-pyran-4-carbaldehyde was used instead of 3-methyloxetane-3-carbaldehyde.
Reaction SMILES: [C:1]1([CH:7]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:8](Cl)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH2:17][CH2:18][CH2:19][CH2:20][N:21]1[CH2:26][CH2:25][CH:24]([C:27]2[CH:28]=[C:29]([NH:33][C:34](=[O:43])[O:35][CH2:36][C:37]3[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=3)[CH:30]=[CH:31][CH:32]=2)[CH2:23][CH2:22]1>>[C:1]1([CH:7]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:8]([NH:17][CH2:18][CH2:19][CH2:20][N:21]2[CH2:26][CH2:25][CH:24]([C:27]3[CH:28]=[C:29]([NH:33][C:34](=[O:43])[O:35][CH2:36][C:37]4[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=4)[CH:30]=[CH:31][CH:32]=3)[CH2:23][CH2:22]2)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: NCCCN1CCC(c2cccc(NC(=O)OCc3ccccc3)c2)CC1
Reactant: O=C(Cl)C(c1ccccc1)c1ccccc1
Product: O=C(Nc1cccc(C2CCN(CCCNC(=O)C(c3ccccc3)c3ccccc3)CC2)c1)OCc1ccccc1

Procedure:
Example 140 was prepared from diphenylacetyl chloride and benzyl 3-[1-(3-aminopropyl)-4-piperidinyl]phenylcarbamate according to the procedures described in Scheme 8: ESMS m/e: 562.5 (M+H)+.
Reaction SMILES: Cl.[NH:2]1[CH2:8][CH2:7][CH2:6][CH:5]([OH:9])[CH2:4][CH2:3]1.F[C:11]1[CH:18]=[CH:17][C:14]([C:15]#[N:16])=[CH:13][CH:12]=1.C(=O)([O-])[O-].[K+].[K+]>CS(C)=O>[OH:9][CH:5]1[CH2:6][CH2:7][CH2:8][N:2]([C:11]2[CH:18]=[CH:17][C:14]([C:15]#[N:16])=[CH:13][CH:12]=2)[CH2:3][CH2:4]1
Reactant: OC1CCCNCC1
Reactant: N#Cc1ccc(F)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: N#Cc1ccc(N2CCCC(O)CC2)cc1
Temperature: 120 °C
Reaction time: 6 h
Yield: 71.2 %

Procedure:
To a mixture of azepan-4-ol hydrochloride (300 mg, 1.98 mmol) and 4-fluorobenzonitrile (311 mg, 2.57 mmol) in dimethyl sulfoxide (3.00 ml) was added potassium carbonate (821 mg, 5.94 mmol). The mixture was stirred at 120° C. for 6 hours. The mixture was partitioned between water and ethyl acetate. The organic layer was washed with water (three times), dried over sodium sulfate, and concentrated in vacuo. The residue was purified by silica gel column chromatography (eluent; hexane/ethyl acetate=1/4) to afford 4-(4-hydroxyazepan-1-yl)benzonitrile as a yellow solid (306 mg, 1.41 mmol, 71%).
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[C:5]([N:7]2[C:19]3[C:18]4[CH:17]=[C:16](B5OC(C)(C)C(C)(C)O5)[CH:15]=[CH:14][C:13]=4[N:12]=[CH:11][C:10]=3[N:9]([CH3:29])[C:8]2=[O:30])[C:4]([CH3:31])=[N:3]1.Br[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][N:34]=1>>[CH3:1][N:2]1[CH:6]=[C:5]([N:7]2[C:19]3[C:18]4[CH:17]=[C:16]([C:33]5[CH:38]=[CH:37][CH:36]=[CH:35][N:34]=5)[CH:15]=[CH:14][C:13]=4[N:12]=[CH:11][C:10]=3[N:9]([CH3:29])[C:8]2=[O:30])[C:4]([CH3:31])=[N:3]1
Reactant: Cc1nn(C)cc1-n1c(=O)n(C)c2cnc3ccc(B4OC(C)(C)C(C)(C)O4)cc3c21
Reactant: Brc1ccccn1
Product: Cc1nn(C)cc1-n1c(=O)n(C)c2cnc3ccc(-c4ccccn4)cc3c21

Procedure:
The title compound was synthesized in a similar manner as described in Example 112 using 1-(1,3-dimethyl-1H-pyrazol-4-yl)-3-methyl-8-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1,3-dihydro-imidazo[4,5-c]quinolin-2-one (Stage 114.1.1, 34.5 mg, 0.082 mmol) and 2-bromopyridine (Aldrich, Buchs, Switzerland, 0.011 ml, 0.114 mmol) to give the title compound as a white solid. (HPLC: tR 2.25 min (Method A); M+H=371 MS-ES; 1H-NMR (d6-DMSO, 400 MHz) 8.98 (s, 1H), 8.67-8.61 (m, 1H), 8.30-8.24 (m, 1H), 8.17-8.06 (m, 3H), 7.94-7.86 (m, 1H), 7.67-7.61 (m, 1H), 7.39-7.32 (m, 1H), 3.95 (s, 3H), 3.57 (s, 3H), 1.95 (s, 3H))
Reaction SMILES: [CH3:1][C@@H:2]1[N:7]([CH2:8][CH2:9][CH2:10][NH2:11])[CH2:6][CH2:5][N:4]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[N+:18]([O-:20])=[O:19])[CH2:3]1.[N+](C1C=CC([O:30][C:31]([N:33]2[CH:37]([C:38]3[CH:43]=[CH:42][C:41]([F:44])=[C:40]([F:45])[CH:39]=3)[CH2:36][O:35][C:34]2=[O:46])=O)=CC=1)([O-])=O>C1COCC1>[CH3:1][CH:2]1[CH2:3][N:4]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[N+:18]([O-:20])=[O:19])[CH2:5][CH2:6][N:7]1[CH2:8][CH2:9][CH2:10][NH:11][C:31]([N:33]1[CH:37]([C:38]2[CH:43]=[CH:42][C:41]([F:44])=[C:40]([F:45])[CH:39]=2)[CH2:36][O:35][C:34]1=[O:46])=[O:30]
Reactant: C[C@H]1CN(c2ccccc2[N+](=O)[O-])CCN1CCCN
Reactant: O=C1OCC(c2ccc(F)c(F)c2)N1C(=O)Oc1ccc([N+](=O)[O-])cc1
Solvent: C1CCOC1
Product: CC1CN(c2ccccc2[N+](=O)[O-])CCN1CCCNC(=O)N1C(=O)OCC1c1ccc(F)c(F)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 86.7 %

Procedure:
To a solution of (S)-(+)-3-methyl-1-(2-nitrophenyl)-4-(3-aminopropyl)-piperazine (35 mg, 0.126 mmol) in 10 mL of THF, 4-(3,4-difluorophenyl)-2-oxo-oxazolidine-3-carboxylic acid-4-nitro-phenyl ester (50 mg, 0.137 mmol) was added and the resulting yellow solution was stirred under argon atmosphere for 2 h at room temperature. The solvent was removed in vacuo and the residue was purified by column chromatography over silica gel with 1:1 hexane/EtOAc followed by MeOH:EtOAc=1:9 (Rf =0.58, MeOH:EtOAc=1:3) to obtain 4-(3,4-Difluoro-phenyl)-2-oxo-oxazolidine-3-carboxylic acid {3-[2-methyl-4-(2-nitro-phenyl)-piperazin-1-yl)-propyl}-amide (55 mg, 87%) The compound was dissolved in CH2Cl2 (3 mL) and was treated with 1N HCl in ether (1 mL). The solvent was removed in vacuo to give the corresponding hydrochloride salt as a pale yellow solid. M. P. 115-119° C.; [α]D =+38.3, (c=0.22, CH2Cl2); Anal. Calcd. For C24H28N5O5F2Cl.0.72 C6H12 : C, 56.50; H, 6.38; N, 11.63. Found: C, 56.63; H, 6.35; N, 10.08.
Reaction SMILES: [N:1]([CH2:4][C@@H:5]([OH:22])[CH2:6][N:7]1[CH2:12][CH2:11][CH:10]([O:13][C:14]2[CH:19]=[CH:18][C:17]([Cl:20])=[C:16]([Cl:21])[CH:15]=2)[CH2:9][CH2:8]1)=[N+]=[N-].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>O1CCCC1>[NH2:1][CH2:4][C@@H:5]([OH:22])[CH2:6][N:7]1[CH2:12][CH2:11][CH:10]([O:13][C:14]2[CH:19]=[CH:18][C:17]([Cl:20])=[C:16]([Cl:21])[CH:15]=2)[CH2:9][CH2:8]1
Reactant: [N-]=[N+]=NC[C@@H](O)CN1CCC(Oc2ccc(Cl)c(Cl)c2)CC1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: NC[C@@H](O)CN1CCC(Oc2ccc(Cl)c(Cl)c2)CC1
Temperature: 60 °C
Reaction time: 4 h

Procedure:
The resulting oil from Step 2 was dissolved in wet tetrahydrofuran (225 ml) and was treated with triphenylphosphine (53.3 g, 203 mmol). The reaction was heated at 60° C. and stirred for 4 h. The solvent was removed under vacuum, the residue re-dissolved into 2N hydrochloric acid (1000 ml) and the aqueous layer was extracted with ethyl acetate (3 times 700 ml). The aqueous phase was basified with a 2N sodium hydroxide solution and extracted with dichloromethane (3 times 1000 ml). The combined organic layers were washed with brine, dried over sodium sulfate, filtered and concentrated under vacuum. The crude material was purified by chromatography (8% 7N ammonia in methanol/DCM) to give the title compound as a yellow oil (17 g).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[NH:9][NH:10][C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12].[CH3:18][O:19][C:20]1[CH:21]=[C:22]([CH:28]=[CH:29][C:30]=1[N+:31]([O-:33])=[O:32])[C:23]([N:25]=[C:26]=[O:27])=[O:24]>C(Cl)Cl>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[N:9]([C:26](=[O:27])[NH:25][C:23](=[O:24])[C:22]1[CH:28]=[CH:29][C:30]([N+:31]([O-:33])=[O:32])=[C:20]([O:19][CH3:18])[CH:21]=1)[NH:10][C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12]
Reactant: COc1cc(C(=O)N=C=O)ccc1[N+](=O)[O-]
Reactant: CC(C)(C)OC(=O)NNc1c(Cl)cccc1Cl
Solvent: ClCCl
Product: COc1cc(C(=O)NC(=O)N(NC(=O)OC(C)(C)C)c2c(Cl)cccc2Cl)ccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 2 h
Yield: 66.8 %

Procedure:
To a solution of tert-butyl 2-(2,6-dichlorophenyl)hydrazinecarboxylate (Intermediate-44, 1.2 g, 4.5 mmol) in DCM (20 mL) was added 3-methoxy-4-nitrobenzoyl isocyanate (1.0 g, 4.5 mmol). The reaction mass was stirred at RT for 2 h. Excess of solvent was removed under vacuum to afford 1.5 g of desired product. 1H NMR (300 MHz, DMSO d6): δ 1.35 (s, 9H), 3.97 (s, 3H), 7.89 (m, 1H), 7.27-7.35 (m, 2H), 7.55 (d, 1H), 7.62-7.75 (m, 1H), 7.94 (d, 1H), 8.26 (s, 1H), 9.03 (s, 1H); MS (m/z): 496.78 (M−H)−.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4](Cl)[C:5]2[CH2:10][CH2:9][CH:8]([C:11]3[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=3)[C:6]=2[N:7]=1.[CH2:19]([CH:21]1[CH2:25][CH2:24][CH2:23][NH:22]1)[CH3:20]>>[Cl:1][C:2]1[N:3]=[C:4]([N:22]2[CH2:23][CH2:24][CH2:25][CH:21]2[CH2:19][CH3:20])[C:5]2[CH2:10][CH2:9][CH:8]([C:11]3[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=3)[C:6]=2[N:7]=1
Reactant: CCC1CCCN1
Reactant: Fc1ccc(C2CCc3c(Cl)nc(Cl)nc32)cc1
Product: CCC1CCCN1c1nc(Cl)nc2c1CCC2c1ccc(F)cc1
Yield: 32 %

Procedure:
2,4-dichloro-7-(4-fluorophenyl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine (Preparation H) (200 mg, 0.706 mmol) and 2-ethylpyrrolidine (84 mg, 0.848 mmol) were combined and purified as per Preparation Hd to give two pairs of racemic diasteriomers 2-chloro-4-(2-ethylpyrrolidin-1-yl)-7-(4-fluorophenyl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine. (Hf1, Diastereomer 1, racemic, first to elute) (77 mg, 0.223 mmol, 32% yield) LC-MS (M+H)+=346. (Hf1, Diastereomer 2, racemic, second to elute) (80 mg, 0.232 mmol, 33% yield); LC-MS (M+H)+=346.2. The relative stereochemistry for Hf1 and Hf2 was not determined
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:18])[CH2:5][C:6]1[N:7]([CH3:17])[C:8]([C:12]([O:14][CH2:15][CH3:16])=[O:13])=[C:9]([CH3:11])[CH:10]=1)[CH3:2].C(N(CC)CC)C.[Se](=O)=[O:27]>N1C=CC=CC=1>[CH3:17][N:7]1[C:8]([C:12]([O:14][CH2:15][CH3:16])=[O:13])=[C:9]([CH3:11])[CH:10]=[C:6]1[C:5](=[O:27])[C:4]([O:3][CH2:1][CH3:2])=[O:18]
Reactant: CCOC(=O)Cc1cc(C)c(C(=O)OCC)n1C
Reactant: O=[Se]=O
Solvent: CCN(CC)CC
Solvent: c1ccncc1
Product: CCOC(=O)C(=O)c1cc(C)c(C(=O)OCC)n1C
Yield: 52.2 %

Procedure:
Ethyl-1,4 dimethyl-5-ethoxycarbonylpyrrole-2-acetate (26.3 g, 0.104 mol) is mixed with triethylamine (7.2 ml, 0.052 mol), pyridine (165 ml, dried over 4 A sieves) and selenium dioxide (12.9 g, 0.115 mol) under nitrogen. The mixture is stirred mechanically and is heated to 95°-100° for 6.5 hours. The reaction is then allowed to cool and the heterogeneous mixture is filtered through a bed of Celite and washed with ether until no further color comes through. The organic solution is then washed with 2 N HCl (4×200 ml), and the combined acid washes are backwashed with ether (150 ml). The combined ether layers are washed with saturated aqueous sodium bicarbonate (100 ml) and saturated brine (150 ml). The ether solution is dried over sodium sulfate and the solvent is removed to give a brown oil which crystallizes on standing. The product is purified by preparative HPLC (4/1 hexanes/ether) to give 14.5 g of ethyl 1,4-dimethyl-5-ethoxycarbonyl-α -oxopyrrole-2-acetate.
Reaction SMILES: [Br:1][C:2]1[C:3]([F:22])=[CH:4][C:5]2[CH:11]3[CH2:12][CH:9]([CH2:10]3)[N:8]3[C:13]([CH:19]=O)=[C:14]([C:16]([NH2:18])=[O:17])[N:15]=[C:7]3[C:6]=2[CH:21]=1.[NH:23]1[CH2:27][CH2:26][CH2:25][CH2:24]1>>[Br:1][C:2]1[C:3]([F:22])=[CH:4][C:5]2[CH:11]3[CH2:10][CH:9]([CH2:12]3)[N:8]3[C:13]([CH2:19][N:23]4[CH2:27][CH2:26][CH2:25][CH2:24]4)=[C:14]([C:16]([NH2:18])=[O:17])[N:15]=[C:7]3[C:6]=2[CH:21]=1
Reactant: NC(=O)c1nc2n(c1C=O)C1CC(C1)c1cc(F)c(Br)cc1-2
Reactant: C1CCNC1
Product: NC(=O)c1nc2n(c1CN1CCCC1)C1CC(C1)c1cc(F)c(Br)cc1-2

Procedure:
10-bromo-9-fluoro-3-formyl-6,7-dihydro-5H-5,7-methanobenzo[c]imidazo[1,2-a]azepine-2-carboxamide (75 mg) was reacted with pyrrolidine similarly to as described in the synthesis of 9-fluoro-10-(3-hydroxy-3-methyl-but-1-ynyl)-3-[(4-methylpiperazin-1-yl)methyl]-5,6,7,12-tetrahydro-5,7-methanobenzo[c]imidazo[1,2-a]azepine-2-carboxamide to afford 10-bromo-9-fluoro-3-(pyrrolidin-1-ylmethyl)-6,7-dihydro-5H-5,7-methanobenzo[c]imidazo[1,2-a]azepine-2-carboxamide which was directly reacted with 2-Methyl-3-butyne-ol via General Procedure E to afford 15 mg (17%) of 9-fluoro-10-(3-hydroxy-3-methyl-but-1-ynyl)-3-(pyrrolidin-1-ylmethyl)-5,6,7,12-tetrahydro-5,7-methanobenzo[c]imidazo[1,2-a]azepine-2-carboxamide. M+1=423.
Reaction SMILES: C1O[C:4]2([CH2:9][CH2:8][C@@H:7]([CH2:10][CH2:11][CH2:12][OH:13])[C@H:6]([C:14]3[CH:19]=[CH:18][C:17]([C:20]([CH3:28])([CH3:27])[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])=[CH:16][C:15]=3[OH:29])[CH2:5]2)[O:3]C1.Cl.O1CCCC1.[Cl-].[Na+]>CCOCC>[CH3:28][C:20]([C:17]1[CH:18]=[CH:19][C:14]([C@H:6]2[C@H:7]([CH2:10][CH2:11][CH2:12][OH:13])[CH2:8][CH2:9][C:4](=[O:3])[CH2:5]2)=[C:15]([OH:29])[CH:16]=1)([CH3:27])[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26]
Reactant: CCCCCCC(C)(C)c1ccc([C@@H]2CC3(CC[C@H]2CCCO)OCCO3)c(O)c1
Agent: Cl
Agent: [Cl-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOCC
Product: CCCCCCC(C)(C)c1ccc([C@@H]2CC(=O)CC[C@H]2CCCO)c(O)c1
Yield: 82 %

Procedure:
A mixture of 4.0 g. (9.56 mmoles) of trans-3-[4-(1,1-dimethylheptyl)-2-hydroxyphenyl]-4-(3-hydroxypropyl)-cyclohexanone ethylene ketal, 50 ml. of 2N hydrochloric acid and 100 ml. of tetrahydrofuran was heated at reflux for 2 hours. The reaction was cooled and added to 500 ml. saturated sodium chloride and 250 ml. ether. The ether extract was separated and washed once with 500 ml. saturated sodium chloride, once with 500 ml. saturated sodium bicarbonate, dried over magnesium sulfate and evaporated (aspirator) to an oil. The crude oil was purified via column chromatography on 200 g. of silica gel eluted with 80% ether-hexane to yield 2.93 g. (82%) of the title compound as an oil.
Reaction SMILES: [C:1]([NH:5][S:6]([C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([C:15]2[N:23]3[C:18]([CH:19]=[N:20][C:21](S(C)=O)=[N:22]3)=[CH:17][CH:16]=2)[CH:10]=1)(=[O:8])=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH2:27][C:28]1[CH:39]=[CH:38][C:31]2[N:32]([CH3:37])[C:33](=[O:36])[CH2:34][O:35][C:30]=2[CH:29]=1>>[C:1]([NH:5][S:6]([C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([C:15]2[N:23]3[C:18]([CH:19]=[N:20][C:21]([NH:27][C:28]4[CH:39]=[CH:38][C:31]5[N:32]([CH3:37])[C:33](=[O:36])[CH2:34][O:35][C:30]=5[CH:29]=4)=[N:22]3)=[CH:17][CH:16]=2)[CH:10]=1)(=[O:8])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CS(=O)c1ncc2ccc(-c3cccc(S(=O)(=O)NC(C)(C)C)c3)n2n1
Reactant: CN1C(=O)COc2cc(N)ccc21
Product: CN1C(=O)COc2cc(Nc3ncc4ccc(-c5cccc(S(=O)(=O)NC(C)(C)C)c5)n4n3)ccc21
Yield: 35.7 %

Procedure:
The titled compound was prepared in analogous fashion as Example 113 using N-tert-butyl-3-(2-methanesulfinyl-pyrrolo[2,1-f][1,2,4]triazin-7-yl)-benzenesulfonamide and 7-amino-4-methyl-4H-benzo[1,4]oxazin-3-one to give N-tert-butyl-3-[2-(4-methyl-3-oxo-3,4-dihydro-2H-benzo[1,4]oxazin-7-ylamino)-pyrrolo[2,1-f][1,2,4]triazin-7-yl]-benzenesulfonamide as a light tan solid (51.6 mg, 35.7% yield). M.p=242-246° C. LCMS (E/I+) 507 (M+H). 1H NMR (400 MHz, CDCl3) δ 8.68 (d, 2H, J=6.8 Hz), 8.20 (d, 1H, J=8 Hz), 7.84 (d, 1H, J=8.1 Hz), 7.49 (t, 1H, J=7.9 Hz), 7.21 (m, 2H), 7.10 (s, 1H), 6.99 (m, 2H), 6.82 (d, 1H, J=4.8 Hz), 5.13 (s, 1H), 4.59 (s, 2H), 3.17 (s, 3H), 1.24 (s, 9H).