Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1]N1C(=O)N(Cl)C(=O)N(Cl)C1=O.[CH:13]1([NH:16][C:17]2[N:22]=[C:21]([C:23]3[N:27]4[CH:28]=[CH:29][N:30]=[C:31]([CH3:32])[C:26]4=[N:25][C:24]=3[C:33]3[CH:38]=[CH:37][C:36]([F:39])=[CH:35][CH:34]=3)[CH:20]=[CH:19][N:18]=2)[CH2:15][CH2:14]1>C(Cl)(Cl)Cl.C(Cl)Cl>[Cl:1][C:20]1[C:21]([C:23]2[N:27]3[CH:28]=[CH:29][N:30]=[C:31]([CH3:32])[C:26]3=[N:25][C:24]=2[C:33]2[CH:34]=[CH:35][C:36]([F:39])=[CH:37][CH:38]=2)=[N:22][C:17]([NH:16][CH:13]2[CH2:15][CH2:14]2)=[N:18][CH:19]=1
Reactant: O=c1n(Cl)c(=O)n(Cl)c(=O)n1Cl
Reactant: Cc1nccn2c(-c3ccnc(NC4CC4)n3)c(-c3ccc(F)cc3)nc12
Solvent: ClCCl
Solvent: ClC(Cl)Cl
Product: Cc1nccn2c(-c3nc(NC4CC4)ncc3Cl)c(-c3ccc(F)cc3)nc12
Temperature: 25 °C
Yield: 95 %

Procedure:
Trichloroisocyanuric acid (0.001 g, 0.04 mmol) was added portion-wise to a refluxing mixture of cyclopropyl-4-[2-(4-fluorophenyl)-8-methylimidazo[1,2-a]pyrazin-3-yl]-pyrimidin-2-ylamine (Example #A.2.1, 0.050 g, 0.14 mmol) in CHCl3 (2.5 mL). The reaction mixture was refluxed for 3 h, cooled to room temperature, diluted with DCM and washed with a saturated aqueous solution of Na2CO3. The organic phase was dried over MgSO4, filtered, and evaporated. The resulting residue was purified by silica gel chromatography using a gradient of heptane/EtOAc (50:50 to 0:100) to afford 0.015 g (27%) of the title compound. LC/MS (Table 1, Method g) Rt=2.71 min; MS m/z: 393.2 (M+H)+.
Reaction SMILES: C[O:2][C:3]([C@H:5]1[CH2:10][CH2:9][C@H:8]([CH2:11][N:12]2[C:21](=[O:22])[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[NH:14][C:13]2=[O:23])[CH2:7][CH2:6]1)=[O:4].[H-].[Na+].[CH3:26]I.O>C1COCC1>[CH3:26][N:14]1[C:15]2[C:20](=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:21](=[O:22])[N:12]([CH2:11][C@H:8]2[CH2:7][CH2:6][C@H:5]([C:3]([OH:2])=[O:4])[CH2:10][CH2:9]2)[C:13]1=[O:23]
Reactant: CI
Reactant: COC(=O)[C@H]1CC[C@H](Cn2c(=O)[nH]c3ccccc3c2=O)CC1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: Cn1c(=O)n(C[C@H]2CC[C@H](C(=O)O)CC2)c(=O)c2ccccc21
Temperature: 25 °C
Reaction time: 24 h

Procedure:
trans-4-(2,4-Dioxo-1,4-dihydro-2H-quinazolin-3-ylmethyl)-cyclohexane carboxylic acid methyl ester (1.5 g, 4.7 mmol) was dissolved in dry THF (20 ml) under nitrogen atmosphere. NaH (0.125 g, 5.2 mmol 60% in mineral oil) was added at 0° C. The reaction mixture was allowed to reach ambient temperature and then CH3I (324 μL, 5.2 mmol) was added. The reaction mixture was left stirring at room temperature for 24 hours, few drops of water were added and the solvent was removed under reduced pressure. The residue was suspended in water and 112 mg of NaOH were added. The mixture was heated at 100° C. for 30 minutes. The solution was allowed to reach room temperature and acidified to pH 3 with HCl 6N with the formation of a white precipitate which was isolated by filtration. (1.0 g, yield 66%)
Reaction SMILES: CON(C)[C:4]([C:6]1[CH:7]=[N:8][N:9]2[C:14]([CH3:16])([CH3:15])[CH2:13][CH:12]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[N:11]([CH2:23][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[C:10]=12)=[O:5].[CH3:31][C:32]1[CH:40]=[CH:39][C:35]([CH2:36][Mg]Cl)=[CH:34][CH:33]=1>C1COCC1>[CH2:23]([N:11]1[CH:12]([C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH2:13][C:14]([CH3:16])([CH3:15])[N:9]2[N:8]=[CH:7][C:6]([C:4](=[O:5])[CH2:31][C:32]3[CH:40]=[CH:39][C:35]([CH3:36])=[CH:34][CH:33]=3)=[C:10]12)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: CON(C)C(=O)c1cnn2c1N(Cc1ccccc1)C(c1ccccc1)CC2(C)C
Reactant: Cc1ccc(C[Mg]Cl)cc1
Solvent: C1CCOC1
Product: Cc1ccc(CC(=O)c2cnn3c2N(Cc2ccccc2)C(c2ccccc2)CC3(C)C)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 89 %

Procedure:
To 0.65 g (1.61 mmol) of 3 dissolved in 20 mL of THF was added 6.4 mL (3.2 mmol) of a 0.5 M solution of 4-methylbenzylmagnesium chloride in THF via syringe over 10 min. After stirring at room temperature for 1 h, the reaction was quenched by addition of approximately 2 mL of saturated aqueous ammonium chloride. The reaction was then diluted with AcOEt and dried over sodium sulfate. Filtering the solution through a short plug of silica gel and concentrating in vacuo provided the crude product as an oil. Purification of this oil by flash chromatography eluting with 75% hexanes/AcOEt gave 0.64 g (89%) of the title compound as a white foam. MS Calcd.: 449. Found: 450 (M+H).
Reaction SMILES: [F:1][C:2]1[C:20](F)=[CH:19][C:5]2=[N:6][C:7]3[N:8]([CH3:18])[CH:9]=[C:10]([C:15]([OH:17])=[O:16])[C:11](=[O:14])[C:12]=3[CH:13]=[C:4]2[CH:3]=1.CS(O)(=O)=O.CS(O)(=O)=O.[NH2:32][CH:33]1[CH2:36][NH:35][C:34]1([CH3:38])[CH3:37]>>[NH2:32][CH:33]1[CH2:36][N:35]([C:20]2[C:2]([F:1])=[CH:3][C:4]3[C:5]([CH:19]=2)=[N:6][C:7]2[N:8]([CH3:18])[CH:9]=[C:10]([C:15]([OH:17])=[O:16])[C:11](=[O:14])[C:12]=2[CH:13]=3)[C:34]1([CH3:38])[CH3:37]
Reactant: Cn1cc(C(=O)O)c(=O)c2cc3cc(F)c(F)cc3nc21
Reactant: CC1(C)NCC1N
Agent: CS(=O)(=O)O
Product: Cn1cc(C(=O)O)c(=O)c2cc3cc(F)c(N4CC(N)C4(C)C)cc3nc21
Temperature: 100 °C
Reaction time: 5 h
Yield: 32.4 %

Procedure:
(RS)-8-(3-Amino-2,2-dimethyl-1-azetidinyl)-7-fluoro-1-methyl-4-oxo-1,4-dihydrobenzo[b][1,8]-naphthyridine-3-carboxylic acid was prepared under the conditions described in Example 15, but starting with 1.45 g of 7,8-difluoro-1-methyl-4-oxo-1,4-dihydrobenzo-[b][1,8]naphthyridine-3-carboxylic acid and 2.33 g of 3-amino-2,2-dimethylazetidine dimethanesulphonate. The reaction mixture is heated with stirring to approximately 100° C. for 5 hours. 0.6 g of (RS)-8-(3-amino-2,2-dimethyl-1-azetidinyl)-7-fluoro-1-methyl-4-oxo-1,4-dihydrobenzo[b][1,8]naphthyridine-3-carboxylic acid is obtained in the form of a yellow solid, which decomposes at 285° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[O:9][C:10]1[CH:15]=[C:14]([Cl:16])[CH:13]=[C:12]([Br:17])[CH:11]=1.C([N-]C(C)C)(C)C.[Li+].CN([CH:29]=[O:30])C>C1COCC1>[Br:17][C:12]1[CH:11]=[C:10]([CH:15]=[C:14]([Cl:16])[CH:13]=1)[O:9][C:3]1[C:2]([Cl:1])=[CH:7][CH:6]=[C:5]([F:8])[C:4]=1[CH:29]=[O:30]
Reactant: CN(C)C=O
Reactant: Fc1ccc(Cl)c(Oc2cc(Cl)cc(Br)c2)c1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: O=Cc1c(F)ccc(Cl)c1Oc1cc(Cl)cc(Br)c1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
To a solution of 3-bromo-5-chlorophenyl 2-chloro-5-fluorophenyl ether (100 g, 298 mmol) in THF (300 mL) cooled to −78° C. over a dry ice/acetone bath was added 1.8M lithium diisopropylamide in hexanes/THF/ethylbenzene (174 mL, 313 mmol) over 10 min. The resulting mixture was stirred for 20 minutes and then treated with DMF (46.1 mL, 595 mmol). The DMF-treated mixture was then removed from the cooling bath and allowed to warm to room temperature and then left at room temperature for 1 hour. The reaction mixture was then quenched with water (1000 mL) and extracted with EtOAc (3×500 mL). The combined extracts were washed with water (500 mL), dried over MgSO4, and concentrated in vacuo. This residue was purified on a silica gel column (0-40% CH2Cl2/hexanes) to give the title product. LRMS (M−18+1)=346.7
Reaction SMILES: [C:1]([C:3]1[C:8](=[O:9])[NH:7][C:6]([C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:5][C:4]=1[CH3:15])#[N:2].F[B-](F)(F)F.[CH3:21][O+](C)C.[OH-].[Na+]>C(Cl)Cl>[C:1]([C:3]1[C:4]([CH3:15])=[CH:5][C:6]([C:10]([O:12][CH2:13][CH3:14])=[O:11])=[N:7][C:8]=1[O:9][CH3:21])#[N:2]
Reactant: CCOC(=O)c1cc(C)c(C#N)c(=O)[nH]1
Reactant: C[O+](C)C
Agent: F[B-](F)(F)F
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Product: CCOC(=O)c1cc(C)c(C#N)c(OC)n1
Temperature: 25 °C
Reaction time: 24 h
Yield: 52.9 %

Procedure:
To a stirred suspension of ethyl 5-cyano-4-methyl-6-oxo-1,6-dihydropyridine-2-carboxylate (2.0 g, 9.70 mmol) in CH2Cl2 (25 mL) was added trimethyloxonium tetrafluoroborate (2.0 g, 13.52 mmol). The reaction was rinsed down with CH2Cl2 and stirred at RT for 24 h. (The reaction eventually cleared up.) To the reaction was added 1 N NaOH (75 mL). After stirring for 10 minutes the mixture was poured into a separatory funnel. The CH2Cl2 phase was removed, dried (Na2SO4), filtered and concentrated under vacuum. Purification by silica gel chromatography (Analogix SF25-40 g, 50 to 100% CH2Cl2 in hexanes) gave the product ethyl 5-cyano-6-methoxy-4-methylpicolinate (1.13 g, 5.13 mmol, 52.9% yield) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ 7.75 (s, 1H), 4.37 (q, J=7.1 Hz, 2H), 4.03 (s, 3H), 2.55 (s, 3H), 1.33 (t, J=7.2 Hz, 3H). MS (ES)+ m/e 221.2 [M+H]+.
Reaction SMILES: [CH3:1][CH:2]([C:22](=[O:25])[CH2:23][CH3:24])[C:3]([O:5][CH2:6][C:7]1[C:12]([CH:13]([CH3:15])[CH3:14])=[CH:11][C:10]([CH:16]([CH3:18])[CH3:17])=[CH:9][C:8]=1[CH:19]([CH3:21])[CH3:20])=[O:4].[B-](F)(F)(F)[F:27].[B-](F)(F)(F)F.C1[N+]2(CCl)CC[N+](F)(CC2)C1>O>[F:27][C:2]([CH3:1])([C:22](=[O:25])[CH2:23][CH3:24])[C:3]([O:5][CH2:6][C:7]1[C:12]([CH:13]([CH3:14])[CH3:15])=[CH:11][C:10]([CH:16]([CH3:17])[CH3:18])=[CH:9][C:8]=1[CH:19]([CH3:21])[CH3:20])=[O:4]
Reactant: CCC(=O)C(C)C(=O)OCc1c(C(C)C)cc(C(C)C)cc1C(C)C
Reactant: F[B-](F)(F)F
Agent: F[N+]12CC[N+](CCl)(CC1)CC2
Solvent: O
Product: CCC(=O)C(C)(F)C(=O)OCc1c(C(C)C)cc(C(C)C)cc1C(C)C
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 89.2 %

Procedure:
At 0° C., 444 mg of 2,4,6-triisopropylbenzyl 2-methyl-3-oxopentanoate (1.28 mmol) are dissolved in 10 ml of F-TEDA (0.145 M in MeCN, 1.45 mmol). After equilibration for 10 minutes, 1.28 ml of catalyst C7 (0.05 M in MeCN, 0.064 mmol, 5 mol %) are added dropwise and the resulting cloudy, lemon-yellow solution is stirred at 0° C. for 25 h. The reaction mixture is taken up in water and TBME, and the organic phase is separated off, washed twice with saturated aqueous NaCl solution and concentrated in an RE. Purification of the crude product by liquid chromatography (TBME/hexane 1:25) affords 416 mg (89%) of 2,4,6-triisopropylbenzyl 2-fluoro-2-methyl-3-oxopentanoate as colourless oil with an ee of 85.6%.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([S:12]([N:15]([CH2:23][C:24]([O:26]C)=O)[C:16]2[CH:21]=[CH:20][C:19]([CH3:22])=[CH:18][CH:17]=2)(=[O:14])=[O:13])=[CH:8][CH:7]=1.O.[NH2:29][NH2:30]>CO>[NH:29]([C:24](=[O:26])[CH2:23][N:15]([C:16]1[CH:21]=[CH:20][C:19]([CH3:22])=[CH:18][CH:17]=1)[S:12]([C:9]1[CH:10]=[CH:11][C:6]([O:5][CH2:4][CH2:3][O:2][CH3:1])=[CH:7][CH:8]=1)(=[O:14])=[O:13])[NH2:30]
Reactant: NN
Reactant: COCCOc1ccc(S(=O)(=O)N(CC(=O)OC)c2ccc(C)cc2)cc1
Solvent: O
Solvent: CO
Product: COCCOc1ccc(S(=O)(=O)N(CC(=O)NN)c2ccc(C)cc2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
The crude carboxylic acid methyl ester resulting from the precedent step, e.g. methyl ({[4-(2-methoxyethoxy)phenyl]sulfonyl}-4-methylanilino)acetate (1 mmol), was dissolved in MeOH (3.5 mL). Hydrazine hydrate was added (0.385 mL). The reaction mixture was stirred overnight at room temperature. Solvents were evaporated. The crude product was dissolved in ethyl acetate (4 mL) and was washed with water (4 mL). Aqueous phase was extracted with ethyl acetate (3×2 mL) and with methylene chloride (2×2 mL). Combined organic phases were dried over magnesium sulfate, filtrated and solvents were evaporated. The desired product, e.g. N-(2-hydrazino-2-oxoethyl)-4-(2-methoxyethoxy)-N-(4-methylphenyl)benzenesulfonamide was isolated as a light yellow oil, in 86% purity by HPLC (MaxPlot detection between 230 and 400 m). This intermediate was used in the next step without further purification.
Reaction SMILES: [C:1]([CH:3]([C:9](=[O:27])[C:10]1[C:11]([NH:16][C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([C:23]([F:26])([F:25])[F:24])[CH:18]=2)=[N:12][CH:13]=[CH:14][CH:15]=1)C(OCC)=O)#[N:2].Cl.[OH-].[Na+]>C(O)(=O)C>[NH2:2][C:1]1[N:16]([C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([C:23]([F:26])([F:25])[F:24])[CH:18]=2)[C:11]2[C:10]([C:9](=[O:27])[CH:3]=1)=[CH:15][CH:14]=[CH:13][N:12]=2
Reactant: CCOC(=O)C(C#N)C(=O)c1cccnc1Nc1cccc(C(F)(F)F)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Product: Nc1cc(=O)c2cccnc2n1-c1cccc(C(F)(F)F)c1
Temperature: 25 °C
Yield: 54.4 %

Procedure:
Ethyl 2-cyano-3-oxo-3-(2-{[3-(trifluoromethyl)phenyl]amino}-3-pyridinyl)propanoate (2.0 g, 5.3 mmol) was heated to 120° C. in a mixture of conc. HCl (4 mL) and glacial acetic acid (2 mL) for 3 h. The reaction mixture was cooled to room temperature, and neutralized by slow addition of NaOH pellets. The mixture was extracted with CH2Cl2 (3×). The combined organic extracts were washed with saturated aqueous NaHCO3 (10 mL) and brine (10 mL), dried over MgSO4, and concentrated in vacuo. The residue was purified by prep-HPLC (YMC-Pack Pro C18 Column, 150×20 mm I.D.; 30–70% CH3CN in water, 20 min.) to afford 2-Amino-1-[3-(trifluoromethyl)phenyl]-1,8-naphthyridin-4(1H)-one (880 mg, 55%): LCMS RT: 2.03 min, MH+: 306.3.
Reaction SMILES: [CH2:1]([C@@H:8]([CH2:12][CH2:13][C@H:14]([CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)[C:15](=[O:32])[NH:16][C@H:17]1[CH2:23][CH2:22][CH2:21][CH2:20][N:19]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=2[CH3:30])[C:18]1=[O:31])[C:9](O)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:40][C@H:41]1[CH2:47][CH2:46][S:45][C@H:44]2[CH2:48][CH2:49][C@@H:50]([C:52]([F:55])([F:54])[F:53])[CH2:51][N:43]2[C:42]1=[O:56]>>[CH2:33]([C@@H:14]([CH2:13][CH2:12][C@H:8]([CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[C:9]([NH:40][C@H:41]1[CH2:47][CH2:46][S:45][C@H:44]2[CH2:48][CH2:49][C@@H:50]([C:52]([F:53])([F:55])[F:54])[CH2:51][N:43]2[C:42]1=[O:56])=[O:10])[C:15]([NH:16][C@H:17]1[CH2:23][CH2:22][CH2:21][CH2:20][N:19]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=2[CH3:30])[C:18]1=[O:31])=[O:32])[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1
Reactant: Cc1ccccc1N1CCCC[C@H](NC(=O)[C@H](CC[C@H](Cc2ccccc2)C(=O)O)Cc2ccccc2)C1=O
Reactant: N[C@H]1CCS[C@H]2CC[C@@H](C(F)(F)F)CN2C1=O
Product: Cc1ccccc1N1CCCC[C@H](NC(=O)[C@H](CC[C@H](Cc2ccccc2)C(=O)N[C@H]2CCS[C@H]3CC[C@@H](C(F)(F)F)CN3C2=O)Cc2ccccc2)C1=O

Procedure:
(2R,5R)-2,5-Dibenzyl-N1-((S)-2-oxo-1-o-tolylazepan-3-yl)-N6-((4S,8R,10aS)-5-oxo-8-(trifluoromethyl)octahydro-2H-pyrido[2,1-b][1,3]thiazepin-4-yl)hexanediamide was synthesized as described in General Procedure H using Intermediate 71 (12 mg, 0.022 mmol) and Intermediate 61 (5.0 mg, 0.019 mmol) to give a white solid (5.7 mg, 38% yield). Anal. Calcd. for C43H51F3N4O4S m/z 776.7. found: 777.6 (M+H)+; 1H NMR (400 MHz, CDCl3) δ ppm 7.34-7.03 (m, 11H), 7.04-6.89 (m, 3H), 5.12 (t, J=7.3 Hz, 1H), 4.85-4.67 (m, 2H), 4.35 (d, J=14.8 Hz, 1H), 3.98 and 3.80 (s, 3H), 3.97-3.82 (m, 1H), 3.49-3.08 (m, 8H), 2.93-2.52 (m, 6H), 2.51-2.26 (m, 2H), 2.26-2.13 (m, 1H), 2.05-1.53 (m, 9H), 1.54-1.16 (m, 3H).
Reaction SMILES: Cl[C:2]1[N:3]=[CH:4][C:5]2[N:11]([CH2:12][CH2:13][CH3:14])[C:10](=[O:15])[C:9]([F:17])([F:16])[CH2:8][N:7]([CH:18]3[CH2:22][CH2:21][CH2:20][CH2:19]3)[C:6]=2[N:23]=1.[NH2:24][C:25]1[CH:33]=[CH:32][C:28]([C:29]([OH:31])=[O:30])=[CH:27][CH:26]=1.Cl>C(O)C>[CH:18]1([N:7]2[CH2:8][C:9]([F:17])([F:16])[C:10](=[O:15])[N:11]([CH2:12][CH2:13][CH3:14])[C:5]3[CH:4]=[N:3][C:2]([NH:24][C:25]4[CH:33]=[CH:32][C:28]([C:29]([OH:31])=[O:30])=[CH:27][CH:26]=4)=[N:23][C:6]2=3)[CH2:22][CH2:21][CH2:20][CH2:19]1
Reactant: CCCN1C(=O)C(F)(F)CN(C2CCCC2)c2nc(Cl)ncc21
Reactant: Nc1ccc(C(=O)O)cc1
Agent: Cl
Solvent: CCO
Product: CCCN1C(=O)C(F)(F)CN(C2CCCC2)c2nc(Nc3ccc(C(=O)O)cc3)ncc21
Yield: 81.3 %

Procedure:
A mixture of 0.20 g (0.58 mmole) of 2-chloro-9-cyclopentyl-7,7-difluoro-5-propyl-5,7,8,9-tetrahydro-pyrimido[4,5-b][1,4]diazepin-6-one (VII-144) and 0.12 g (0.87 mmole) of 4-aminobenzoic acid in a 1:4 mixture of 10 mL of ethanol and 1M hydrochloric acid was heated at 100 degrees for 18 hours. After cooling, the precipitate was collected by filtration, washed with water and dried to give 0.21 g of 4-(9-cyclopentyl-7,7-difluoro-6-oxo-5-propyl-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-benzoic acid (I-144).
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][N:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][C:6]([CH2:12][CH2:13][CH3:14])=[N:7]2.[CH3:15][C:16]1[CH:17]=[CH:18][C:19]([S:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[C:20]([NH2:22])[CH:21]=1>>[CH3:15][C:16]1[CH:17]=[CH:18][C:19]([S:23][C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=2)=[C:20]([NH:22][C:2]2[C:3]3[C:8](=[N:7][C:6]([CH2:12][CH2:13][CH3:14])=[CH:5][CH:4]=3)[N:9]=[CH:10][CH:11]=2)[CH:21]=1
Reactant: Cc1ccc(Sc2ccccc2)c(N)c1
Reactant: CCCc1ccc2c(Cl)ccnc2n1
Product: CCCc1ccc2c(Nc3cc(C)ccc3Sc3ccccc3)ccnc2n1

Procedure:
The product from Example 2g (65 mg, 0.3 μmol) was reacted with the product from Example 1f (68 mg, 0.31 mmol) for 24 h following the procedure from Example 1g giving the title compound as a hydrochloride salt as a solid which was triturated with ether giving (10 mg, 84%). 1H NMR (300 MHz, DMSO-d6) δ ppm: 0.97 (t, J=7.35 Hz, 3H) 2.38 (qnt, J=7.35 Hz, 2H) 2.99 (dd, J=7.35 Hz, J=7.72 Hz, 2H) 6.31 (d, J=7.35 Hz, 1H) 7.23 (s, 5H) 7.35 (m, 4H) 7.79 (d, J=8.46 Hz, 1H) 8.38 (d, J=6.98 Hz, 1H) 9.01 (d, J=8.46 Hz, 1H) 11.10 (s, 1H) 14.35 (br s , 1H); MS (ESI+) m/z 386 (M−Cl)+; (ESI−) m/z 384 (M−HCl)−.
Reaction SMILES: F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.C(N(C(C)C)CC)(C)C.[C:34]([O:38][C:39]([N:41]1[CH2:46][CH2:45][S:44][CH:43]([C:47]([OH:49])=O)[CH2:42]1)=[O:40])([CH3:37])([CH3:36])[CH3:35].[NH2:50][C:51]1[CH:52]=[C:53]2[C:57](=[CH:58][CH:59]=1)[NH:56][N:55]=[C:54]2[C:60]([O:62][CH3:63])=[O:61]>CN(C=O)C>[CH3:63][O:62][C:60]([C:54]1[C:53]2[C:57](=[CH:58][CH:59]=[C:51]([NH:50][C:47]([CH:43]3[S:44][CH2:45][CH2:46][N:41]([C:39]([O:38][C:34]([CH3:35])([CH3:36])[CH3:37])=[O:40])[CH2:42]3)=[O:49])[CH:52]=2)[NH:56][N:55]=1)=[O:61]
Reactant: CC(C)(C)OC(=O)N1CCSC(C(=O)O)C1
Reactant: COC(=O)c1n[nH]c2ccc(N)cc12
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)c1n[nH]c2ccc(NC(=O)C3CN(C(=O)OC(C)(C)C)CCS3)cc12
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
2-(7-Aza-1H-benzotriazole-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (HATU) (1.9 g, 5 mmol) and diisopropyl ethyl amine (DIEA) (2.7 mL) was added to a suspension of 4-(tert-butoxycarbonyl)thiomorpholine-2-carboxylic acid (1.3 g, 5 mmol) in DMF (10 mL) and was stirred at room temperature for 15 minutes. Methyl 5-amino-1H-indazole-3-carboxylate (0.95 g, 5 mmol)) was added to the reaction and was stirred at room temperature for an additional 30 minutes. The reaction was quenched with water (50 mL) and extracted with ethyl acetate (3×20 mL). The extracts were combined, dried using anhydrous sodium sulfate, filtered, and concentrated in vacuo. The crude product (2.1 g) was progressed to the next step without purification.
Reaction SMILES: [CH2:1]([O:5][C:6]1[CH:11]=[C:10]([NH:12][CH:13]([CH3:15])[CH3:14])[N:9]=[CH:8][N:7]=1)[C:2]#[C:3][CH3:4].Br[CH2:17][C:18]#[C:19][CH3:20].[H-].[Na+]>O1CCCC1>[CH2:1]([O:5][C:6]1[CH:11]=[C:10]([N:12]([CH2:17][C:18]#[C:19][CH3:20])[CH:13]([CH3:15])[CH3:14])[N:9]=[CH:8][N:7]=1)[C:2]#[C:3][CH3:4]
Reactant: CC#CCOc1cc(NC(C)C)ncn1
Reactant: CC#CCBr
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC#CCOc1cc(N(CC#CC)C(C)C)ncn1
Temperature: 25 °C
Reaction time: 6 h
Yield: 75.6 %

Procedure:
In 5 ml of tetrahydrofuran were dissolved 164 mg of 4-(2-butynyloxy)-6-(isopropylamino)pyrimidine and 106 mg of 1-bromo-2-butyne, to which 40 mg of sodium hydride (60% in oil) was added, followed by stirring at room temperature for 6 hours. Then, ice water was added to the reaction mixture, which was extracted with ethyl acetate. The organic layer was washed with an aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and then concentrated. The residue was subjected to preparative silica gel thin layer chromatography to give 155 mg of 4-(2-butynyloxy)-6-(N-(2-butynyl)-N-isopropylamino)pyrimidine (the present compound (107)).
Reaction SMILES: Cl.[CH:2]1([CH2:5][O:6][C:7]2[CH:12]=[C:11]([F:13])[C:10]([CH3:14])=[CH:9][C:8]=2[C:15]2[C:16]3[NH:23][C:22]([CH3:24])=[C:21]([C:25]([NH:27][CH:28]4[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]4)=[O:26])[C:17]=3[N:18]=[CH:19][N:20]=2)[CH2:4][CH2:3]1.[C:34](Cl)(=[O:37])[CH2:35][CH3:36]>>[CH:2]1([CH2:5][O:6][C:7]2[CH:12]=[C:11]([F:13])[C:10]([CH3:14])=[CH:9][C:8]=2[C:15]2[C:16]3[NH:23][C:22]([CH3:24])=[C:21]([C:25]([NH:27][CH:28]4[CH2:29][CH2:30][N:31]([C:34](=[O:37])[CH2:35][CH3:36])[CH2:32][CH2:33]4)=[O:26])[C:17]=3[N:18]=[CH:19][N:20]=2)[CH2:4][CH2:3]1
Reactant: CCC(=O)Cl
Reactant: Cc1cc(-c2ncnc3c(C(=O)NC4CCNCC4)c(C)[nH]c23)c(OCC2CC2)cc1F
Agent: Cl
Product: CCC(=O)N1CCC(NC(=O)c2c(C)[nH]c3c(-c4cc(C)c(F)cc4OCC4CC4)ncnc23)CC1

Procedure:
Starting from 4-[2-(cyclopropylmethoxy)-4-fluoro-5-methylphenyl]-6-methyl-N-(piperidin-4-yl)-5H-pyrrolo[3,2-d]pyrimidine-7-carboxamide hydrochloride (example D.f40) and commercially available propionyl chloride the title compound is obtained as colorless solid.
Reaction SMILES: F[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[N+:12]([O-:14])=[O:13])[NH:8][C:7](=[O:15])[N:6]([NH:16][S:17]([CH3:20])(=[O:19])=[O:18])[C:5]2=[O:21].[C:22]1([N:28]2[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]2)[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>>[N+:12]([C:11]1[CH:10]=[C:9]2[C:4]([C:5](=[O:21])[N:6]([NH:16][S:17]([CH3:20])(=[O:19])=[O:18])[C:7](=[O:15])[NH:8]2)=[CH:3][C:2]=1[N:31]1[CH2:32][CH2:33][N:28]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH2:29][CH2:30]1)([O-:14])=[O:13]
Reactant: CS(=O)(=O)Nn1c(=O)[nH]c2cc([N+](=O)[O-])c(F)cc2c1=O
Reactant: c1ccc(N2CCNCC2)cc1
Product: CS(=O)(=O)Nn1c(=O)[nH]c2cc([N+](=O)[O-])c(N3CCN(c4ccccc4)CC3)cc2c1=O
Yield: 66 %

Procedure:
N-(6-Fluoro-7-nitro-2,4-dioxo-1,4-dihydro-2H-quinazolin-3-yl)-methanesulfonamide (30 mg, 0.0943 mmol) is reacted with 1-phenyl-piperazine according to the GPA affording 28.6 mg (66%) of an orange powder. Rt=4.49 min.
Reaction SMILES: Cl.[CH3:2][C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][CH:11]=1)[C:6]([NH2:8])=[NH:7].[Cl:12][C:13]1[CH:17]=[CH:16][S:15][C:14]=1[C:18]([NH:20]N)=O>>[Cl:12][C:13]1[CH:17]=[CH:16][S:15][C:14]=1[C:18]1[NH:20][N:8]=[C:6]([C:5]2[CH:9]=[CH:10][CH:11]=[C:3]([CH3:2])[CH:4]=2)[N:7]=1
Reactant: NNC(=O)c1sccc1Cl
Reactant: Cc1cccc(C(=N)N)c1
Agent: Cl
Product: Cc1cccc(-c2n[nH]c(-c3sccc3Cl)n2)c1

Procedure:
The title compound was prepared from 3-methyl-benzamidine hydrochloride and 3-chloro-thiophene-2-carboxylic acid hydrazide by a procedure similar to Example 88b as a yellow solid (0.013 g, 5.6%). 1H NMR (CD3OD): 7.75 (s, 1H), 7.69 (d, J=5.7 Hz, 1H), 7.4 (d, J=5.7 Hz, 1H), 7.24 (m, 2H), 6.97 (d, J=6.3 Hz, 1H), 3.10 (s, 3H).
Reaction SMILES: [CH3:1][C:2]1([CH3:33])[C:6]2[C:7]([O:12][C:13]3[N:18]=[CH:17][C:16]([NH:19][C:20]([C@H:22]([NH:25][C:26](=[O:32])OC(C)(C)C)[CH2:23][CH3:24])=[O:21])=[CH:15][N:14]=3)=[CH:8][CH:9]=[C:10]([CH3:11])[C:5]=2[O:4][CH2:3]1.ClC(Cl)(OC(=O)OC(Cl)(Cl)Cl)Cl>Cl.C(O)(C)C.C(OCC)(=O)C>[CH2:23]([C@H:22]1[NH:25][C:26](=[O:32])[N:19]([C:16]2[CH:15]=[N:14][C:13]([O:12][C:7]3[C:6]4[C:2]([CH3:33])([CH3:1])[CH2:3][O:4][C:5]=4[C:10]([CH3:11])=[CH:9][CH:8]=3)=[N:18][CH:17]=2)[C:20]1=[O:21])[CH3:24]
Reactant: CC[C@@H](NC(=O)OC(C)(C)C)C(=O)Nc1cnc(Oc2ccc(C)c3c2C(C)(C)CO3)nc1
Agent: Cl
Agent: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Solvent: CC(C)O
Solvent: CCOC(C)=O
Product: CC[C@H]1NC(=O)N(c2cnc(Oc3ccc(C)c4c3C(C)(C)CO4)nc2)C1=O
Temperature: 35 °C
Yield: 89.6 %

Procedure:
1,1-dimethylethyl {(1R)-1-[({2-[(3,3,7-trimethyl-2,3-dihydro-1-benzofuran-4-yl)oxy]-5-pyrimidinyl}amino)carbonyl]propyl}carbamate (Intermediate 34, 213 mg, 0.47 mmol) was dissolved in HCl 5-6 N in isopropanol (1 mL) and the resulting solution was heated to 35° C. for 30 minutes. The reaction mixture was then concentrated under vacuum, the residue diluted with ethyl acetate (50 mL) and an aqueous 5% solution of K2CO3 (30 mL). Two phases were separated and the organic layer was washed with an aqueous saturated solution of ammonium chloride (30 mL), dried over Na2SO4 and concentrated under vacuum. The resulting crude was dissolved in ethyl acetate (10 mL) and triethylamine was added (0.23 mL, 1.64 mmol). The reaction mixture was cooled to 0-5° C. and a solution of triphosgene (55 mg, 0.185 mmol) in ethyl acetate (5 mL) was added drop wise in 10 minutes. The reaction was quenched with water (50 mL) and extracted with ethyl acetate (50 mL). The organic layer was washed with brine dried over Na2SO4 and concentrated under vacuum. The residue was purified purified by flash chromatography on silica gel using cyclohexane/ethyl acetate 50:50 as eluent affording the title compound (161 mg) as a white solid.