Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([NH:4][C:5]1[CH:13]=[CH:12][C:8]([C:9]([OH:11])=[O:10])=[C:7]([F:14])[CH:6]=1)(=O)C.B(F)(F)F.[CH3:19][CH2:20]OCC>C(O)C>[NH2:4][C:5]1[CH:13]=[CH:12][C:8]([C:9]([O:11][CH2:19][CH3:20])=[O:10])=[C:7]([F:14])[CH:6]=1
Reactant: CC(=O)Nc1ccc(C(=O)O)c(F)c1
Reactant: CCOCC
Agent: FB(F)F
Solvent: CCO
Product: CCOC(=O)c1ccc(N)cc1F

Procedure:
A solution of 10.0 g of 4-acetamido-2-fluorobenzoic acid, 100 ml of ethyl alcohol and 2.0 ml of boron trifluoride etherate is heated under reflux for 22 hours. The solvent is slowly removed by distillation as an equal amount of fresh ethyl alcohol is added. After 200 ml of solvent has been removed, the remainder is evaporated at reduced pressure. The residue is dissolved in ethyl acetate, washed with saturated aqueous sodium bicarbonate, dried and the solvent then evaporated to yield a solid. Recrystallization of the solid from ethanol-hexane yields ethyl 4-amino-2-fluorobenzoate.
Reaction SMILES: [NH2:1][C:2]1[C:9](I)=[CH:8][C:5]([C:6]#[N:7])=[C:4]([Cl:11])[CH:3]=1.CCN(C(C)C)C(C)C.[C:21]([Si:23]([CH3:26])([CH3:25])[CH3:24])#[CH:22]>[Cu]I>[NH2:1][C:2]1[C:9]([C:22]#[C:21][Si:23]([CH3:26])([CH3:25])[CH3:24])=[CH:8][C:5]([C:6]#[N:7])=[C:4]([Cl:11])[CH:3]=1
Reactant: N#Cc1cc(I)c(N)cc1Cl
Reactant: C#C[Si](C)(C)C
Agent: [Cu]I
Solvent: CCN(C(C)C)C(C)C
Product: C[Si](C)(C)C#Cc1cc(C#N)c(Cl)cc1N
Temperature: 70 °C
Yield: 48.2 %

Procedure:
A round bottom bottle was charged with 236 (2.78 g, 0.01 mol), CuI (95 mg, 0.5 mmol), Pd(PPh3)Cl2 (200 mg, 0.5 mmol), DIPEA (3.87 g, 0.03 mol) and ethynyltrimethylsilane (2.94 g, 0.03 mol). The mixture was heated under nitrogen atmosphere at 70° C. overnight then cooled and partitioned between EtOAc (500 mL) and H2O (100 mL). The organic layer was concentrated to dryness in vacuo. The crude was purified by SiO2 chromatography eluting with 10% EtOAc/petroleum ether to afford 1.2 g (48%) of 4-amino-2-chloro-5-((trimethylsilyl)ethynyl)benzonitrile (238) as brown solid: MS (ESI) m/z=249.1 [M+1]+
Reaction SMILES: [CH3:1][C:2]1[C:3](O)=[N:4][C:5]2[C:10]([N:11]=1)=[CH:9][CH:8]=[CH:7][CH:6]=2.[N+:13]([CH2:15][C:16]([O:18][CH:19]([CH3:21])[CH3:20])=[O:17])#[C-:14]>>[CH3:1][C:2]1[C:3]2[N:4]([CH:14]=[N:13][C:15]=2[C:16]([O:18][CH:19]([CH3:21])[CH3:20])=[O:17])[C:5]2[C:10]([N:11]=1)=[CH:9][CH:8]=[CH:7][CH:6]=2
Reactant: Cc1nc2ccccc2nc1O
Reactant: [C-]#[N+]CC(=O)OC(C)C
Product: Cc1nc2ccccc2n2cnc(C(=O)OC(C)C)c12

Procedure:
M.p. 182°-183° C., from 3-methyl-2-quinoxalinol and isopropyl isocyanoacetate. (Compound 5)
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[CH:2]1.Cl[C:7]1[N:8]=[C:9]([NH:20][CH2:21][C:22]2[CH:27]=[CH:26][C:25]([Cl:28])=[C:24]([Cl:29])[CH:23]=2)[C:10]2[CH:15]=[C:14]([C:16]([F:19])([F:18])[F:17])[S:13][C:11]=2[N:12]=1>>[N:1]1([C:7]2[N:8]=[C:9]([NH:20][CH2:21][C:22]3[CH:27]=[CH:26][C:25]([Cl:28])=[C:24]([Cl:29])[CH:23]=3)[C:10]3[CH:15]=[C:14]([C:16]([F:18])([F:19])[F:17])[S:13][C:11]=3[N:12]=2)[CH:5]=[CH:4][N:3]=[CH:2]1
Reactant: c1c[nH]cn1
Reactant: FC(F)(F)c1cc2c(NCc3ccc(Cl)c(Cl)c3)nc(Cl)nc2s1
Product: FC(F)(F)c1cc2c(NCc3ccc(Cl)c(Cl)c3)nc(-n3ccnc3)nc2s1

Procedure:
Following the procedure of Example 97, the reaction of imidazole with 2-chloro-6-trifluoromethyl-4-(3,4-dichlorobenzylamino)-thieno-[2,3-d]-pyrimidine gives 2-(imidazol-1-yl)-6-trifluoromethyl-4-(3,4-dichlorobenzylamino)-thieno-[2,3-d]-pyrimidine.
Reaction SMILES: [CH:1]([C:4]1[CH:11]=[CH:10][CH:9]=[C:8]([CH:12]([CH3:14])[CH3:13])[C:5]=1[CH2:6]O)([CH3:3])[CH3:2].S(Cl)([Cl:17])=O>C1(C)C=CC=CC=1>[CH:1]([C:4]1[CH:11]=[CH:10][CH:9]=[C:8]([CH:12]([CH3:14])[CH3:13])[C:5]=1[CH2:6][Cl:17])([CH3:3])[CH3:2]
Reactant: O=S(Cl)Cl
Reactant: CC(C)c1cccc(C(C)C)c1CO
Solvent: Cc1ccccc1
Product: CC(C)c1cccc(C(C)C)c1CCl
Yield: 99.3 %

Procedure:
To a solution of 1.37 g (7.12 mmol) of 2, 6-diisopropylbenzyl alcohol in 20 ml of toluene was added 0.78 ml (10.7 mmol) of thionyl chloride, and the resultant mixture was stirred at room temperature for 3.5 hours. The reaction mixture was washed with water, dried over anhydrous magnesium sulfate and the solvent evaporated in vacuo to give 1.49 g of 2, 6-diisopropylbenzyl chloride as an oil.
Reaction SMILES: C(OC([NH:8][C@H:9]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[CH:18][C:17]([N:20]3[CH2:24][C@H:23]([CH2:25][N:26]([C:35]4[CH:39]=[CH:38][O:37][N:36]=4)[C:27]([O:29][CH2:30][C:31]([Cl:34])([Cl:33])[Cl:32])=[O:28])[O:22][C:21]3=[O:40])=[CH:16][C:15]=2[F:41])[CH2:10]1)=O)(C)(C)C.Cl>ClCCl.C(O)C>[NH2:8][C@H:9]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[CH:18][C:17]([N:20]3[CH2:24][C@H:23]([CH2:25][N:26]([C:35]4[CH:39]=[CH:38][O:37][N:36]=4)[C:27]([O:29][CH2:30][C:31]([Cl:34])([Cl:32])[Cl:33])=[O:28])[O:22][C:21]3=[O:40])=[CH:16][C:15]=2[F:41])[CH2:10]1
Reactant: CC(C)(C)OC(=O)N[C@H]1CCN(c2ccc(N3C[C@H](CN(C(=O)OCC(Cl)(Cl)Cl)c4ccon4)OC3=O)cc2F)C1
Agent: Cl
Solvent: CCO
Solvent: ClCCl
Product: N[C@H]1CCN(c2ccc(N3C[C@H](CN(C(=O)OCC(Cl)(Cl)Cl)c4ccon4)OC3=O)cc2F)C1
Temperature: 25 °C
Reaction time: 5 h
Yield: 110.8 %

Procedure:
3-(4-(3(S)-(t-Butoxycarbonyl)aminopyrrolidin-1-yl)-3-fluorophenyl)-5(R)-(N-(2,2,2-trichloroethyloxycarbonyl)isoxazol-3-ylaminomethyl)oxazolidin-2-one (1.03 g, 1.62 mM) was dissolved in dichloromethane (5 ml) under nitrogen and treated with a solution of hydrogen chloride in ethanol (3.8 M, 25 ml). After stirring 5 hours at ambient temperature, solvent was removed, and the residue evaporated repeatedly with portions of dichloromethane to give the hydrochloride salt of the desired product as a white foam (962 mg).
Reaction SMILES: [OH:1][CH2:2][C@@H:3]([NH:10][C:11](=[O:17])[O:12][C:13]([CH3:16])([CH3:15])[CH3:14])[C:4]([N:6]([O:8][CH3:9])[CH3:7])=[O:5].CN(C=O)C.[CH3:23][C:24]([Si:27](Cl)([CH3:29])[CH3:28])([CH3:26])[CH3:25].N1C=CN=C1>CCOC(C)=O>[Si:27]([O:1][CH2:2][C@@H:3]([NH:10][C:11](=[O:17])[O:12][C:13]([CH3:14])([CH3:16])[CH3:15])[C:4]([N:6]([O:8][CH3:9])[CH3:7])=[O:5])([C:24]([CH3:26])([CH3:25])[CH3:23])([CH3:29])[CH3:28]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: CON(C)C(=O)[C@@H](CO)NC(=O)OC(C)(C)C
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CON(C)C(=O)[C@@H](CO[Si](C)(C)C(C)(C)C)NC(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 1 h
Yield: 93 %

Procedure:
(R)-tert-butyl 3-hydroxy-1-(methoxy(methyl)amino)-1-oxopropan-2-ylcarbamate (21) (4.4 g, 17.5 mmol, 1.0 equiv.) was added to a 100 mL RBF followed by DMF (35 mL) and cooled to 0° C. via an ice bath. Next, TBDMSCl (2.9 g, 19.3 mmol, 1.1 equiv.) and imidazole (2.4 g, 35.1 mmol, 2.0 equiv.) were added to the reaction flask. The solution was stirred at 0° C. for 1 h and then allowed to warm to rt, stirring an additional 2 h. The reaction solution was transferred to a 500 mL separatory funnel with EtOAc (150 mL). The mixture was washed with 1% HCl (3×40 mL), sat. NaHCO3 (1×40 mL), and sat. NaCl (2×40 mL). The organic layer was separated and dried over Na2SO4. The solution was concentrated on a rotary evaporator and dried under vacuum to give 5.9 g (93%) of 22 as a colorless oil. Rf=0.54 (50% EtOAc/hexanes); [α]D23.5=+3.55 (c 1.22, MeOH); IR (film) 3437, 3324, 2953, 2929, 2884, 2856, 1715, 1666, 1496, 1471, 1365, 1253, 1171, 1114 cm−1; 1H NMR (500 MHz, CDCl3) δ 5.34 (br d, J=8.5 Hz, 1H, carbamate-NH), 4.73 (br s, 1H, Boc-NH—CH), 3.83 (m, 1H, CH—CH2), 3.77 (m, 1H, CH—CH2), 3.73 (s, 3H, N—OCH3), 3.19 (s, 3H, NCH3), 1.41 (s, 9H, Boc-t-butyl-CH3), 0.84 (s, 9H, Si-t-butyl-CH3), 0.00 (s, 6H, Si—(CH3)2); 13C NMR (125 MHz, CDCl3) δ 170.9, 155.5, 79.7, 63.6, 61.6, 52.6, 32.3, 28.5, 25.9, 18.4, −5.4; LRMS (ESI-MS m/z): Mass calcd for C16H34N2O5Si [M]+, 362.54. Found 363. Anal. calcd for C16H34N2O5Si: C, 53.01; H, 9.45; N, 7.73. Found: C, 53.26; H, 9.63; N, 7.68.
Reaction SMILES: C1([C:7]2[CH:8]=[C:9](OC)[C:10]([N+:15]([O-:17])=[O:16])=[C:11]([CH:14]=2)[C:12]#[N:13])C=CC=CC=1.B(Br)(Br)Br.C(OCC)(=[O:26])C>ClCCl>[C:12]([C:11]1[CH:14]=[C:7]([OH:26])[CH:8]=[CH:9][C:10]=1[N+:15]([O-:17])=[O:16])#[N:13]
Reactant: CCOC(C)=O
Reactant: COc1cc(-c2ccccc2)cc(C#N)c1[N+](=O)[O-]
Agent: BrB(Br)Br
Solvent: ClCCl
Product: N#Cc1cc(O)ccc1[N+](=O)[O-]
Reaction time: 3 h
Yield: 96 %

Procedure:
To a 0° C. solution of 578 mg (2.28 mmol) 5-phenyl-methoxy-2-nitrobenzonitrile, prepared according to the procedure of E. Elslager, et. al., J. Heterocyclic Chem. 1972, 9, 759-773, in 5 mL of dichloromethane at 0° C. was added 2.6 mL (2.62 mmol, 1.15 equiv) of a 1.0 M solution of boron tribromide in dichloromethane. After the reaction mixture was stirred for 3 h, it was diluted with ethyl acetate, washed sequentially with 1N aqueous sodium hydrogen sulfate solution and saturated aqueous sodium chloride solution, dried over magnesium sulfate and concentrated to give 357 mg (96%) of the title compound which was used without further purification: 1H NMR (400 MHz, CD3OD) δ8.17 (d, 1H, J=9.2 Hz), 7.03 (d, 1H, J=2.7 Hz), 6.92 (dd, 1H, J=2.7, 9.3 Hz).
Reaction SMILES: Br[CH2:2][C:3]([N:5]1[CH2:10][CH2:9][N:8]([C:11]2[CH:16]=[CH:15][C:14]([C:17]([O:26]COC)([C:22]([F:25])([F:24])[F:23])[C:18]([F:21])([F:20])[F:19])=[CH:13][C:12]=2[CH2:30][CH2:31][CH3:32])[CH2:7][C@@H:6]1[CH3:33])=[O:4].CC(O[C:38]1[CH:39]=[C:40]([C:44]2([CH3:51])[NH:48][C:47](=[O:49])[NH:46][C:45]2=[O:50])[CH:41]=[CH:42][CH:43]=1)C>>[F:20][C:18]([F:19])([F:21])[C:17]([C:14]1[CH:15]=[CH:16][C:11]([N:8]2[CH2:9][CH2:10][N:5]([C:3](=[O:4])[CH2:2][N:46]3[C:45](=[O:50])[C:44]([C:40]4[CH:39]=[CH:38][C:43]([O:26][CH:17]([CH3:18])[CH3:14])=[CH:42][CH:41]=4)([CH3:51])[NH:48][C:47]3=[O:49])[C@@H:6]([CH3:33])[CH2:7]2)=[C:12]([CH2:30][CH2:31][CH3:32])[CH:13]=1)([OH:26])[C:22]([F:23])([F:25])[F:24]
Reactant: CC(C)Oc1cccc(C2(C)NC(=O)NC2=O)c1
Reactant: CCCc1cc(C(OCOC)(C(F)(F)F)C(F)(F)F)ccc1N1CCN(C(=O)CBr)[C@@H](C)C1
Product: CCCc1cc(C(O)(C(F)(F)F)C(F)(F)F)ccc1N1CCN(C(=O)CN2C(=O)NC(C)(c3ccc(OC(C)C)cc3)C2=O)[C@@H](C)C1

Procedure:
(S)-2-bromo-1-(4-{4-[1,1,1,3,3,3-hexafluoro-2-(methoxymethoxy)propan-2-yl]-2-propylphenyl}-2-methylpiperazin-1-yl)ethanone and 5-(3-(1-methylethoxy)phenyl)-5-methylimidazolidine-2,4-dione were used for a similar reaction and treatment as Examples 14-1 and 15-1, and the title compound was obtained as a yellow oil.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]2[C:13]3[N:22]([CH2:23][CH2:24][O:25][C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=4)[CH:21]=[N:20][C:14]=3[CH:15]=[N+:16]([O-])[C:17]=2[CH:18]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.ClC(Cl)(Cl)C([N:36]=C=O)=O.C[O-].[Na+]>C(Cl)(Cl)Cl>[CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]2[C:13]3[N:22]([CH2:23][CH2:24][O:25][C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=4)[CH:21]=[N:20][C:14]=3[C:15]([NH2:36])=[N:16][C:17]=2[CH:18]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: [O-][n+]1cc2ncn(CCOc3ccccc3)c2c2ccc(OCc3ccccc3)cc21
Reactant: O=C=NC(=O)C(Cl)(Cl)Cl
Agent: C[O-]
Agent: [Na+]
Solvent: ClC(Cl)Cl
Product: Nc1nc2cc(OCc3ccccc3)ccc2c2c1ncn2CCOc1ccccc1
Reaction time: 4.5 h
Yield: 59.3 %

Procedure:
A modification of the general method described in Part C of Example 3 was used to treat 7-benzyloxy-5-oxido-1-(2-phenoxyethyl)-1H-imidazo[4,5-c]quinoline (1.59 g, 3.86 mmol). Chloroform (10 mL) was added to help keep the starting material in solution. The reaction with trichloroacetyl isocyanate (0.6 mL, 5 mmol) was stirred for 4.5 hours. Following the reaction with sodium methoxide, a tan precipitate formed, which was isolated by filtration, washed with hexanes, and dried overnight in a vacuum oven. The solid was then stirred with water overnight, isolated by filtration, and dried in a vacuum oven to provide 0.94 g of 7-benzyloxy-1-(2-phenoxyethyl)-1H-imidazo[4,5-c]quinolin-4-amine as a tan powder, mp 200.3-200.9° C.
Reaction SMILES: [OH:1][CH:2]1[CH:7]([C:8]2[CH:13]=[CH:12][C:11]([OH:14])=[CH:10][CH:9]=2)[CH2:6][CH2:5][N:4]([C:15]([O:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[O:16])[CH2:3]1.Br[CH2:26][CH2:27][CH2:28][O:29][C:30]1[CH:35]=[C:34]([F:36])[CH:33]=[CH:32][C:31]=1[F:37]>>[F:37][C:31]1[CH:32]=[CH:33][C:34]([F:36])=[CH:35][C:30]=1[O:29][CH2:28][CH2:27][CH2:26][O:14][C:11]1[CH:10]=[CH:9][C:8]([CH:7]2[CH2:6][CH2:5][N:4]([C:15]([O:17][CH2:18][C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=3)=[O:16])[CH2:3][CH:2]2[OH:1])=[CH:13][CH:12]=1
Reactant: O=C(OCc1ccccc1)N1CCC(c2ccc(O)cc2)C(O)C1
Reactant: Fc1ccc(F)c(OCCCBr)c1
Product: O=C(OCc1ccccc1)N1CCC(c2ccc(OCCCOc3cc(F)ccc3F)cc2)C(O)C1

Procedure:
Analogously to Method I, 1.20 g of benzyl 3-hydroxy-4-(4-hydroxyphenyl)piperidine-1-carboxylate and 1.00 g of 2-(3-bromopropoxy)-1,4-difluorobenzene (Example 142d) are reacted. The title compound is obtained as a colourless oil. Rf=0.24 (1:1 EtOAc-heptane). Rt=3.29.
Reaction SMILES: [CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:3]=1[CH2:13][O:14][C:15]1[CH:23]=[CH:22][C:18]([C:19]([OH:21])=O)=[CH:17][N:16]=1.Cl.[CH3:25][C:26]1([NH2:29])[CH2:28][CH2:27]1>>[CH3:25][C:26]1([NH:29][C:19](=[O:21])[C:18]2[CH:22]=[CH:23][C:15]([O:14][CH2:13][C:3]3[C:4]([C:7]4[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=4)=[N:5][O:6][C:2]=3[CH3:1])=[N:16][CH:17]=2)[CH2:28][CH2:27]1
Reactant: Cc1onc(-c2ccccc2)c1COc1ccc(C(=O)O)cn1
Reactant: CC1(N)CC1
Agent: Cl
Product: Cc1onc(-c2ccccc2)c1COc1ccc(C(=O)NC2(C)CC2)cn1
Yield: 83 %

Procedure:
As described for example 8b, 6-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-nicotinic acid (100 mg, 0.32 mmol) was converted, using 1-methylcyclopropylamine hydrochloride instead of methylamine, to the title compound (97 mg, 83%) which was obtained as a white solid. MS: m/e=362.5 [M−H]−.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[N:13]=[C:12]2[O:14][C:15]([C:24]([N:26]([CH2:29][CH3:30])[CH2:27][CH3:28])=[O:25])=[C:16]([NH:17]C(=O)C(F)(F)F)[C:11]2=[CH:10][C:9]=1[C:31]1[CH:36]=[CH:35][C:34]([Cl:37])=[CH:33][CH:32]=1.C(=O)([O-])[O-].[K+].[K+].O>CO>[NH2:17][C:16]1[C:11]2[C:12](=[N:13][C:8]([C:3]3[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=3[Cl:1])=[C:9]([C:31]3[CH:36]=[CH:35][C:34]([Cl:37])=[CH:33][CH:32]=3)[CH:10]=2)[O:14][C:15]=1[C:24]([N:26]([CH2:29][CH3:30])[CH2:27][CH3:28])=[O:25]
Reactant: CCN(CC)C(=O)c1oc2nc(-c3ccccc3Cl)c(-c3ccc(Cl)cc3)cc2c1NC(=O)C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: O
Product: CCN(CC)C(=O)c1oc2nc(-c3ccccc3Cl)c(-c3ccc(Cl)cc3)cc2c1N
Temperature: 60 °C
Reaction time: 3 h

Procedure:
To a magnetically stirred solution of 0.273 g (0.50 mmol) of the product of Example 182 in 5 mL MeOH was added 0.343 g (0.248 mmol) of potassium carbonate and 0.5 mL water. The reaction mixture was stirred at 60° C. for 3 h then cooled to room temperature and partitioned between EtOAc and 10% aq. NaHSO4. The organic extracts were separated, washed with water and brine, dried (Na2SO4), filtered and evaporated. The residue was purified on a silica gel flash chromatography column eluted with 0–20% EtOAc-hexane. Evaporation of the purified fractions and drying in vacuo afforded the titled compound. HPLC/MS: 453.9 (M+1), 455.8 (M+3); Rt=4.15 min.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:35]=[CH:36][CH:37]=1)[CH2:7][N:8]1[C:12](=[O:13])[C:11]2([CH2:18][CH2:17][N:16]([C:19]([O:21][CH2:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)=[O:20])[CH2:15][CH2:14]2)[N:10]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[CH2:9]1)([O-])=O.[Cl-].[NH4+]>[Fe].C(O)C.O>[NH2:1][C:4]1[CH:5]=[C:6]([CH:35]=[CH:36][CH:37]=1)[CH2:7][N:8]1[C:12](=[O:13])[C:11]2([CH2:18][CH2:17][N:16]([C:19]([O:21][CH2:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)=[O:20])[CH2:15][CH2:14]2)[N:10]([C:29]2[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=2)[CH2:9]1
Reactant: O=C(OCc1ccccc1)N1CCC2(CC1)C(=O)N(Cc1cccc([N+](=O)[O-])c1)CN2c1ccccc1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCO
Solvent: O
Product: Nc1cccc(CN2CN(c3ccccc3)C3(CCN(C(=O)OCc4ccccc4)CC3)C2=O)c1
Yield: 111.1 %

Procedure:
To a refluxing solution of benzyl 3-(3-nitrobenzyl)-4-oxo-1-phenyl-1,3,8-triazaspiro[4.5]decane-8-carboxylate (0.77 g, 1.53 mmol) and ammonium chloride (0.96 g, 18.0 mmol) in 2:1 mixture of ethanol/water (18 mL), was added iron powder (0.3 g, 5.4 mmol) over a period of 45 minutes. After refluxing for another hour, the reaction mixture was extracted with dichloromethane, washed the organic extracts with water and brine. The organic phase was dried over MgSO4 and concentrated to obtain benzyl 3-(3-aminobenzyl)-4-oxo-1-phenyl-1,3,8-triazaspiro[4.5]decane-8-carboxylate (0.80 g, 95%).
Reaction SMILES: C(OC(=O)[NH:7][C@@H:8]([C:19]1[NH:20][CH:21]=[C:22]([C:24]2[CH:29]=[CH:28][N:27]=[CH:26][CH:25]=2)[N:23]=1)[CH2:9][C:10]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[NH:12][CH:11]=1)(C)(C)C.[ClH:31]>C(O)(=O)C>[ClH:31].[ClH:31].[NH:12]1[C:13]2[C:18](=[CH:17][CH:16]=[CH:15][CH:14]=2)[C:10]([CH2:9][C@@H:8]([NH2:7])[C:19]2[NH:20][CH:21]=[C:22]([C:24]3[CH:29]=[CH:28][N:27]=[CH:26][CH:25]=3)[N:23]=2)=[CH:11]1
Reactant: CC(C)(C)OC(=O)N[C@H](Cc1c[nH]c2ccccc12)c1nc(-c2ccncc2)c[nH]1
Agent: Cl
Solvent: CC(=O)O
Product: N[C@H](Cc1c[nH]c2ccccc12)c1nc(-c2ccncc2)c[nH]1
Temperature: 25 °C
Reaction time: 1 h
Yield: 94 %

Procedure:
[(R)-2-(1H-indol-3-yl)-1-(4-pyridin-4-yl-1H-imidazol-2-yl)-ethyl]-carbamic acid tert-butyl ester (3.46 g, 8.58 mmol) is dissolved in a mixture of glacial acetic acid (99.5%, 25 ml) and conc. aq. HCl (37%, 2.5 ml) and the solution is stirred under argon at room temperature for 1 h. The resulting precipitate is filtered, washed with acetone and dried to give 3.04 g (94%) of (R)-2-(1H-indol-3-yl)-1-(4-pyridin-4-yl-1H-imidazol-2-yl)-ethylamine dihydrochloride (TLC: silica gel, toluene:ethanol:AcOH 4:4:1, Rf=0.18).
Reaction SMILES: [O:1]=[C:2]1[NH:7][C:6](=[O:8])[C:5](C#N)=[CH:4][N:3]1[C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([C:17]([F:20])([F:19])[F:18])[CH:12]=1.O.N>Br>[F:20][C:17]([F:18])([F:19])[C:13]1[CH:12]=[C:11]([N:3]2[CH:4]=[CH:5][C:6](=[O:8])[NH:7][C:2]2=[O:1])[CH:16]=[CH:15][CH:14]=1
Reactant: N#Cc1cn(-c2cccc(C(F)(F)F)c2)c(=O)[nH]c1=O
Agent: Br
Agent: N
Solvent: O
Product: O=c1ccn(-c2cccc(C(F)(F)F)c2)c(=O)[nH]1
Temperature: 0 °C
Yield: 86.1 %

Procedure:
2,4-Dioxo-1-(3-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydropyrimidin-5-carbonitrile (prepared in Reference Example 112) (22.7 g) was suspended in hydrobromic acid (48%, 220 ml) and the resulting mixture was stirred with heating under reflux for ten hours. The resulting mixture was cooled to 0° C. and to the reaction solutions was then added 28% ammonia water (145 ml) dropwise, and the precipitated solids were collected by filtration and washed with water to afford 1-(3-(trifluoromethyl)phenyl)pyrimidin-2,4(1H,3H)-dione (17.8 g).
Reaction SMILES: [OH:1][CH:2]([CH:6]([NH:16][C:17](=[O:35])[C:18]1[CH:23]=[CH:22][CH:21]=[N:20][C:19]=1[N:24]1[CH:28]=[CH:27][C:26]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)=[N:25]1)[CH2:7][C:8]1[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[CH:10][CH:9]=1)[C:3]([OH:5])=O.Cl.[CH3:37][O:38][NH2:39]>>[OH:1][CH:2]([C:3]([NH:39][O:38][CH3:37])=[O:5])[CH:6]([NH:16][C:17](=[O:35])[C:18]1[CH:23]=[CH:22][CH:21]=[N:20][C:19]=1[N:24]1[CH:28]=[CH:27][C:26]([C:29]2[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=2)=[N:25]1)[CH2:7][C:8]1[CH:9]=[CH:10][C:11]([O:14][CH3:15])=[CH:12][CH:13]=1
Reactant: COc1ccc(CC(NC(=O)c2cccnc2-n2ccc(-c3ccccc3)n2)C(O)C(=O)O)cc1
Reactant: CON
Agent: Cl
Product: CONC(=O)C(O)C(Cc1ccc(OC)cc1)NC(=O)c1cccnc1-n1ccc(-c2ccccc2)n1

Procedure:
The reaction was carried out in analogy to reaction step 1.3 by reacting 2-hydroxy-4-(4-methoxyphenyl)-3-(2-(3-phenyl-1H-pyrazol-1-yl)nicotinamido)butanoic acid with O-methylhydroxylamine hydrochloride. ESI-MS [M+H]+: 502.2
Reaction SMILES: Cl.[F:2][C:3]1[CH:8]=[C:7]([S:9]([CH3:12])(=[O:11])=[O:10])[CH:6]=[CH:5][C:4]=1[N:13]1[C:17]2=[N:18][CH:19]=[N:20][C:21]([S:22][CH:23]3[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]3)=[C:16]2[CH:15]=[N:14]1.Cl[C:30]1[N:35]=[CH:34][C:33]([CH2:36][CH3:37])=[CH:32][N:31]=1.C(N(CC)CC)C>C(O)(C)C>[CH2:36]([C:33]1[CH:32]=[N:31][C:30]([N:26]2[CH2:25][CH2:24][CH:23]([S:22][C:21]3[N:20]=[CH:19][N:18]=[C:17]4[N:13]([C:4]5[CH:5]=[CH:6][C:7]([S:9]([CH3:12])(=[O:11])=[O:10])=[CH:8][C:3]=5[F:2])[N:14]=[CH:15][C:16]=34)[CH2:28][CH2:27]2)=[N:35][CH:34]=1)[CH3:37]
Reactant: CCc1cnc(Cl)nc1
Reactant: CS(=O)(=O)c1ccc(-n2ncc3c(SC4CCNCC4)ncnc32)c(F)c1
Agent: Cl
Solvent: CC(C)O
Solvent: CCN(CC)CC
Product: CCc1cnc(N2CCC(Sc3ncnc4c3cnn4-c3ccc(S(C)(=O)=O)cc3F)CC2)nc1
Temperature: 150 °C
Yield: 34.8 %

Procedure:
A mixture of 1-(2-fluoro-4-methanesulfonyl-phenyl)-4-(piperidin-4-ylsulfanyl)-1H-pyrazolo[3,4-d]pyrimidine hydrochloride (250 mg, 0.56 mmol), 2-chloro-5-ethyl-pyrimidine (680 μL, 5.6 mmol), and triethylamine (315 μL, 2.24 mmol) in isopropanol (4 mL) was heated under microwave irradiation for 15 min at 150° C. The crude mixture was concentrated in vacuo and purified by HPLC to provide Compound A237 as a white solid (100 mg, 35%). 1H NMR (CDCl3, 400MHz) δ 1.18 (t, 3H), 1.82-1.94 (m, 2H), 2.28-2.37 (m, 2H), 2.53 (q, 2M), 3.06 (s, 3H), 3.55-3.64 (m, 2H), 4.41-4.55 (m, 3H), 7.82 (m, 3H), 8.24 (s, 1H), 8.37 (s, 2H), 8.74 (s, 1H). Exact mass calculated for C23H24FN7O2S2 513.61, found 514.4 (MH+).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]2[CH2:8][C:9]3[C:21]4[NH:20][C:19]5[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=5)[C:13]=4[C:12]4[C:22](=[O:25])[NH:23][CH2:24][C:11]=4[C:10]=3[C:4]=2[CH:3]=1.C[Si]([C:30]#[CH:31])(C)C.C(N(CC)CC)C>CN(C=O)C.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>[C:30]([C:2]1[CH:7]=[CH:6][C:5]2[CH2:8][C:9]3[C:21]4[NH:20][C:19]5[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=5)[C:13]=4[C:12]4[C:22](=[O:25])[NH:23][CH2:24][C:11]=4[C:10]=3[C:4]=2[CH:3]=1)#[CH:31]
Reactant: C#C[Si](C)(C)C
Reactant: O=C1NCc2c3c(c4[nH]c5ccccc5c4c21)Cc1ccc(Br)cc1-3
Agent: Cl[Pd]Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: C#Cc1ccc2c(c1)-c1c3c(c4c([nH]c5ccccc54)c1C2)C(=O)NC3
Temperature: 25 °C
Reaction time: 24 h
Yield: 8.2 %

Procedure:
To a solution of 3-bromo-5H,6H,12H,13H-indeno[2,3-a]pyrrolo[3,4-c]carbazole-7(7H)one (Compound I-9) (435 mg, 1.1 mmol), trimethylsilylacetylene (0.47 ml, 3.3 mmol) and triethylamine (1.0 mL) in DMF (11 mL) was added bis(triphenylphosphine)palladium(II)chloride (17 mg). The solution was heated in a sealed reaction tube at 100°-110° C. for 24 h. The mixture was cooled to ambient temperature, filtered through a pad of celite then the solvent concentrated at reduced pressure. The product was dissolved in DMF (8 mL), MeOH (8 mL) cesium fluroide (370 mg, 2.4 mmol) added and the mixture stirred at ambient temperature 24 h. The solvent was concentrated at reduced pressure to give a dark solid. Purification by column chromatography (silica gel, EtOAc:MeOH; 10:1, Rf =0.53) give 30 mg of a tan solid. The compound was further purified by preparative TLC (silica gel, EtOAc:hexane; 3:1) to give Compound I-36 as a tan solid, mp>300° C. 1H NMR (DMSO-d6, 300 MHz): d 4.2 (s, 2H), 5.0 (s, 2H), 7.38-7.46 (m, 3H), 7.58-7.75 (m,4H), 8.15 (s, 1H), 9.42 (d, 1H, J=9 Hz), 12.19 (s, 1H; MS m/e=335 (m+).
Reaction SMILES: C([Mg]Cl)(C)C.Br[C:7]1[CH:8]=[C:9]([C:13]#[N:14])[S:10][C:11]=1[Cl:12].C[O:16][S:17]([C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([Br:25])[CH:20]=1)=O.[Cl-].[NH4+]>C1COCC1.C(OCC)(=O)C>[Br:25][C:21]1[CH:20]=[C:19]([S:17]([C:7]2[CH:8]=[C:9]([C:13]#[N:14])[S:10][C:11]=2[Cl:12])=[O:16])[CH:24]=[CH:23][CH:22]=1
Reactant: N#Cc1cc(Br)c(Cl)s1
Reactant: COS(=O)c1cccc(Br)c1
Agent: CC(C)[Mg]Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: N#Cc1cc(S(=O)c2cccc(Br)c2)c(Cl)s1
Temperature: 25 °C
Reaction time: 8 h
Yield: 85.5 %

Procedure:
Isopropyl magnesium chloride solution (Aldrich, 2.0 M in THF, 2.92 mL, 5.84 mmol) was added dropwise over 1.5 hours to a −78° C. suspension of 4-bromo-5-chloro-thiophene-2-carbonitrile (Example 24: step b, 1 g, 4.49 mmol) in THF (anhydrous, 20 mL) under argon. The reaction mixture was treated with 3-bromo-benzenesulfinic acid methyl ester solution (Example 24: step d, 1 g, 4.49 mmol, 10 mL of THF) in one portion at −78° C. and then stirred overnight at room temperature. Saturated ammonium chloride solution was added to the mixture and stirred for 30 minutes at room temperature. The reaction mixture was diluted with ethyl acetate and washed with water and brine. The organic layer was dried over magnesium sulfate, filtered, concentrated in vacuo, and purified by column chromatography (silica gel, 15-25% ethyl acetate/hexanes) to afford the title compound as a light yellow solid (1.33 g, 85% yield). 1H-NMR (CDCl3): δ 7.86-7.88 (m, 1H), 7.69 (dm, 1H, J=7.9 Hz), 7.64 (dm, 1H, J=7.9 Hz), 7.62 (s, 1H), 7.42 (t, 1H, J=7.9 Hz).