Azzindani/Open_Reaction_Data huggingface dataset:
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](O)=[N:22]3)=[CH:17][CH:16]=2)[CH:10]=1)(=[O:8])=[O:7])([CH3:4])([CH3:3])[CH3:2].[N:25]1[CH:30]=[CH:29][CH:28]=[C:27]([C:31]2[CH:36]=[CH:35][C:34]([NH2:37])=[CH:33][CH:32]=2)[CH:26]=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:37][C:34]4[CH:33]=[CH:32][C:31]([C:27]5[CH:26]=[N:25][CH:30]=[CH:29][CH:28]=5)=[CH:36][CH:35]=4)=[N:22]3)=[CH:17][CH:16]=2)[CH:10]=1)(=[O:8])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)NS(=O)(=O)c1cccc(-c2ccc3cnc(O)nn23)c1
Reactant: Nc1ccc(-c2cccnc2)cc1
Product: CC(C)(C)NS(=O)(=O)c1cccc(-c2ccc3cnc(Nc4ccc(-c5cccnc5)cc4)nn23)c1

Procedure:
N-tert-Butyl-3-[2-(4-pyridin-3-yl-phenylamino)-pyrrolo[2,1-f][1,2,4]triazin-7-yl]-benzenesulfonamide was prepared from N-tert-butyl-3-(2-hydroxy-pyrrolo[2,1-f][1,2,4]triazin-7-yl)-benzenesulfonamide and 4-pyridin-3-yl-phenylamine in an analogous manner to Example 1052a. Product isolated as a pale yellow solid (14 mg, 9%). m.p.=250-253° C.; LCMS (m/e) 499 (M+H); 1H-NMR (CDCl3, 400 MHz) δ 8.90 (s, 1H), 8.80 (s, 1H), 8.78 (s, 1H), 8.57 (s, 1H), 8.26 (d, 1H, J=7.8 Hz), 7.95 (d, 1H, J=7.9 Hz), 7.89 (d, 1H, J=7.9 Hz), 7.75 (d, 1H, J=8.5 Hz), 7.69 (d, 1H, J=8.5 Hz), 7.65-7.57 (m, 1H), 7.44-7.32 (m, 1H), 7.10 (d, 1H, J=4.7 Hz), 6.97 (s, 1H), 6.89 (d, 1H, J=4.7 Hz), 1.18 (s, 9H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:12])[C:7]=1[CH2:8][C:9]([OH:11])=O.C(N1C=CN=C1)(N1C=CN=C1)=O.[CH3:25][O:26][C:27]1[CH:28]=[C:29]([CH:33]([CH2:36][CH:37]([CH3:39])[CH3:38])[CH2:34][NH2:35])[CH:30]=[CH:31][CH:32]=1>C1COCC1>[Cl:12][C:6]1[CH:5]=[N:4][CH:3]=[C:2]([Cl:1])[C:7]=1[CH2:8][C:9]([NH:35][CH2:34][CH:33]([C:29]1[CH:30]=[CH:31][CH:32]=[C:27]([O:26][CH3:25])[CH:28]=1)[CH2:36][CH:37]([CH3:39])[CH3:38])=[O:11]
Reactant: COc1cccc(C(CN)CC(C)C)c1
Reactant: O=C(O)Cc1c(Cl)cncc1Cl
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Product: COc1cccc(C(CNC(=O)Cc2c(Cl)cncc2Cl)CC(C)C)c1
Yield: 97.4 %

Procedure:
By working in a way similar to that described in example 4 but using (3,5-dichloropyridin-4-yl)-acetic acid (2.06 g, 10 mmoles), carbonyldiimidazole (1.78 g, 11 mmoles), THF (30 ml) and 2-(3-methoxy-phenyl)-4-methyl-pentylamine (2.07 g, 10 mmoles), obtained as described in example 21, 3.85 g of the title compound were obtained (yield: 97.6%), m.p.: 98-99° C.
Reaction SMILES: [OH-].[Na+].[CH3:3][NH:4][C:5]([CH2:7][C:8]1[C:9]2[CH2:10][C:11]3[N:16]4[CH:17]=[C:18]([C:20]([O:22]CC)=[O:21])[N:19]=[C:15]4[C:14](=[O:25])[NH:13][C:12]=3[C:26]=2[CH:27]=[CH:28][CH:29]=1)=[O:6]>O1CCOCC1>[CH3:3][NH:4][C:5]([CH2:7][C:8]1[C:9]2[CH2:10][C:11]3[N:16]4[CH:17]=[C:18]([C:20]([OH:22])=[O:21])[N:19]=[C:15]4[C:14](=[O:25])[NH:13][C:12]=3[C:26]=2[CH:27]=[CH:28][CH:29]=1)=[O:6]
Reactant: CCOC(=O)c1cn2c3c([nH]c(=O)c2n1)-c1cccc(CC(=O)NC)c1C3
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Product: CNC(=O)Cc1cccc2c1Cc1c-2[nH]c(=O)c2nc(C(=O)O)cn12
Reaction time: 2 h

Procedure:
8.2 ml of 1N sodium hydroxide solution are added dropwise, under a stream of nitrogen and at a temperature in the region of 20° C., to a suspension of 1 g of ethyl 9-(N-methylaminocarbonylmethyl)-4,5-dihydro-4-oxo-10H-imidazo[1,2-a]indeno[1,2-e]pyrazin-2-carboxylate in a dioxane distilled water (100/27 by volume) mixture. The reaction is continued for 2 hours at the same temperature. The light-grey insoluble material is filtered, washed with acetone and then taken up in 15 ml of distilled water. This aqueous solution is filtered and then acidified to pH 1 with N hydrochloric acid. The precipitate formed is filtered and washed with water, with acetone and then with ethyl ether to result in 0.59 g of the trihydrate of 9-(N-methylaminocarbonylmethyl)-4,5-dihydro-4-oxo-10H-imidazo[1,2-a]indeno[1,2-e]pyrazin-2-carboxylic acid in the form of a white powder, the melting point of which is greater than 260° C. (Analysis C17H14N4O4.3H2O; % Calculated C: 60.35, H: 4.17, N: 16.56; % Found C: 60.0, H: 4.1, N: 16.3; 1H NMR spectrum in CD3CO2D, T=300 K, δ in ppm (300 MHz): 2.7 (3H, s, NCH3), 3.9 (2H, , CH2CO), 4.1 (2H, s, CH2), 7.2 (1H, d, J=8 Hz, arom. CH), 7.4 (1H, t, J=8 Hz, arom. CH), 7.7 (1H, d, J=8 Hz, arom. CH), 8.5 (1H, s, imidazole H)).
Reaction SMILES: Cl.Cl.[NH2:3][C:4]1[C:19]([Cl:20])=[CH:18][C:7]([C:8]([NH:10][CH2:11][CH:12]2[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]2)=[O:9])=[C:6]([O:21][CH3:22])[CH:5]=1.[CH2:23]([S:30]([CH2:33][CH2:34][CH2:35][CH2:36][CH2:37]Cl)(=[O:32])=[O:31])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>>[NH2:3][C:4]1[C:19]([Cl:20])=[CH:18][C:7]([C:8]([NH:10][CH2:11][CH:12]2[CH2:13][CH2:14][N:15]([CH2:37][CH2:36][CH2:35][CH2:34][CH2:33][S:30]([CH2:23][C:24]3[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=3)(=[O:31])=[O:32])[CH2:16][CH2:17]2)=[O:9])=[C:6]([O:21][CH3:22])[CH:5]=1
Reactant: O=S(=O)(CCCCCCl)Cc1ccccc1
Reactant: COc1cc(N)c(Cl)cc1C(=O)NCC1CCNCC1
Agent: Cl
Product: COc1cc(N)c(Cl)cc1C(=O)NCC1CCN(CCCCCS(=O)(=O)Cc2ccccc2)CC1

Procedure:
4-Amino-5-chloro-2-methoxy-N-(piperidin-4-ylmethyl)benzamide dihydrochloride and 5-benzylsulfonylpentyl chloride were reacted and treated in the same manner as in Example 199 to give 4-amino-5-chloro-2-methoxy-N-((1-(5-benzylsulfonylpentyl)piperidin-4-yl)methyl)-benzamide.
Reaction SMILES: [CH2:1]([N:8]1[CH2:12][C@H:11]([C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=2)[C@@H:10]([C@@H:20]([OH:22])[CH3:21])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].Cl[C:26]1[CH:33]=[CH:32][C:29]([C:30]#[N:31])=[CH:28][N:27]=1>CN(C=O)C>[CH2:1]([N:8]1[CH2:12][C@H:11]([C:13]2[CH:14]=[CH:15][C:16]([Cl:19])=[CH:17][CH:18]=2)[C@@H:10]([C@@H:20]([O:22][C:26]2[CH:33]=[CH:32][C:29]([C:30]#[N:31])=[CH:28][N:27]=2)[CH3:21])[CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: C[C@H](O)[C@H]1CN(Cc2ccccc2)C[C@@H]1c1ccc(Cl)cc1
Reactant: N#Cc1ccc(Cl)nc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: C[C@H](Oc1ccc(C#N)cn1)[C@H]1CN(Cc2ccccc2)C[C@@H]1c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 80.3 %

Procedure:
To a stirred solution of 250 mg (0.79 mmol) of (S)-1-[(3R,4S)-1-benzyl-4-(4-chloro-phenyl)-pyrrolidin-3-yl]-ethanol in DMF (10 mL) was added NaH (57 mg, 1.18 mmol). The reaction mixture was stirred at RT for 30 minutes, and then at 50° C. for 20 minutes. A solution of 6-chloro-nicotinonitrile (132 mg, 0.95 mmol) in DMF (2 mL) was added dropwise and stirring was continued 3 hours at 50° C. The reaction mixture was concentrated under vacuo. Extraction with EtOAc/H2O, followed by column chromatography (SiO2, EtOAc/H, 1:3) yielded 265 mg (80%) of the title compound as a colorless oil. ES-MS m/e: 418.3 (M+H+).
Reaction SMILES: O=P(Cl)(Cl)[Cl:3].CN(C)C1C=CC=CC=1.[CH2:15]([O:18][C:19]1[CH:20]=[C:21]2[C:26](=[CH:27][CH:28]=1)[NH:25][C:24]([C:29]1[CH:30]=[N:31][CH:32]=[CH:33][CH:34]=1)=[N:23][C:22]2=O)[CH2:16][CH3:17].CN(C)C1C=CC=CC=1>O=P(Cl)(Cl)Cl>[Cl:3][C:22]1[C:21]2[C:26](=[CH:27][CH:28]=[C:19]([O:18][CH2:15][CH2:16][CH3:17])[CH:20]=2)[N:25]=[C:24]([C:29]2[CH:30]=[N:31][CH:32]=[CH:33][CH:34]=2)[N:23]=1
Reactant: CCCOc1ccc2[nH]c(-c3cccnc3)nc(=O)c2c1
Reactant: O=P(Cl)(Cl)Cl
Solvent: CN(C)c1ccccc1
Product: CCCOc1ccc2nc(-c3cccnc3)nc(Cl)c2c1
Temperature: 120 °C
Reaction time: 2 h
Yield: 54.7 %

Procedure:
(This method is representative of method F1, F2, F3 and F4. These three methods can be implemented in a similar way except for substitution of the appropriate chlorinating reagent, solvent and temperature) To a mixture of 6-propoxy-2-pyridin-3-yl-1H-quinazolin-4-one (1.00 g, 3.56 mmol) in POCl3 (10 mL) was added N,N-dimethylaniline (0.1 mL). The resulting mixture was stirred at 120° C. for 2 h. After the reaction was completed, POCl3 was removed in vacuo, and the residue was added to ice-water slowly. The pH was adjusted to around 7 by slowly adding NaHCO3 (sat.) at 0 (C. The resultant solid was collected and purified by chromatography on silica gel eluted with petroleum ether/ethyl acetate (v/v=4:1 to 1:1) to give 580 mg of v-a as a pale yellow solid (54.7%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[C:4]([Cl:12])[C:3]=1[NH:13][N:14]=[C:15](Cl)[CH:16]([C:18]([F:21])([F:20])[F:19])[CH3:17].[CH2:23]([NH:25][C:26]#[N:27])[CH3:24].C(N(CC)CC)C>O1CCCC1>[Cl:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[C:4]([Cl:12])[C:3]=1[N:13]1[C:26]([NH:25][CH2:23][CH3:24])=[N:27][C:15]([CH:16]([C:18]([F:21])([F:20])[F:19])[CH3:17])=[N:14]1
Reactant: CCNC#N
Reactant: CC(C(Cl)=NNc1c(Cl)cc(C(F)(F)F)cc1Cl)C(F)(F)F
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCNc1nc(C(C)C(F)(F)F)nn1-c1c(Cl)cc(C(F)(F)F)cc1Cl
Reaction time: 3 h
Yield: 68.9 %

Procedure:
7.8 g (0.02 mol) of 2-trifluoromethylpropionyl chloride 2,6-dichloro-4-trifluoromethylphenylhydrazone and 1.5 g (0.022 mol) of ethyl cyanamide were dissolved in 50 ml of tetrahydrofuran, and 2.5 g (0.025 mol) of triethylamine was dropwise added thereto under stirring and cooling with ice. After completion of the dropwise addition, the stirring was continued at room temperature for 3 hours. The solvent was distilled off under reduced pressure. The residue was dissolved in hexane, and the organic layer was washed with water and dried over anhydrous magnesium sulfate. Then, hexane was distilled off under reduced pressure. Further, the residue was subjected to distillation under reduced pressure. The fraction having a boiling point of 110°-120° C./0.1-0.2 mmHg was subjected to recrystallization from hexane to obtain 5.8 g (yield: 69%) of the desired compound having a melting point of from 82° to 83° C. as slightly yellow prismatic crystals.
Reaction SMILES: [CH:1]1([NH:4][C:5](=[O:31])[C:6]2[CH:11]=[CH:10][C:9]([CH3:12])=[C:8]([N:13]3[CH:18]=[CH:17][N:16]=[C:15]([NH:19][C:20]([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=4[OH:29])([CH3:22])[CH3:21])[C:14]3=[O:30])[CH:7]=2)[CH2:3][CH2:2]1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:39][CH:40]1[CH2:45][CH2:44][N:43](C(OC(C)(C)C)=O)[CH2:42][CH2:41]1>C(#N)C>[CH:1]1([NH:4][C:5](=[O:31])[C:6]2[CH:11]=[CH:10][C:9]([CH3:12])=[C:8]([N:13]3[CH:18]=[CH:17][N:16]=[C:15]([NH:19][C:20]([CH3:22])([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=4[O:29][CH2:39][CH:40]4[CH2:45][CH2:44][NH:43][CH2:42][CH2:41]4)[CH3:21])[C:14]3=[O:30])[CH:7]=2)[CH2:3][CH2:2]1
Reactant: Cc1ccc(C(=O)NC2CC2)cc1-n1ccnc(NC(C)(C)c2ccccc2O)c1=O
Reactant: CC(C)(C)OC(=O)N1CCC(CBr)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: Cc1ccc(C(=O)NC2CC2)cc1-n1ccnc(NC(C)(C)c2ccccc2OCC2CCNCC2)c1=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 23.7 %

Procedure:
N-Cyclopropyl-3-(3-(2-(2-hydroxyphenyl)propan-2-ylamino)-2-oxopyrazin-1(2H)-yl)-4-methylbenzamide (Example 134, 0.172 g), potassium carbonate (0.114 g) and tert-butyl 4-(bromomethyl)piperidine-1-carboxylate (0.114 g) were stirred together in acetonitrile (10 mL) at reflux overnight. The cooled reaction mixture was evaporated to dryness and the residue partitioned between ethyl acetate (20 mL) and water (20 mL). The separated aqueous layer was further extracted into ethyl acetate (2×20 mL), the combined organics were dried (MgSO4) and evaporated. The residue was dissolved in dichloromethane (10 mL) and treated with trifluoroacetic acid (1 ml), after stirring at room temperature for 1 h, the solvent was evaporated to leave the crude product. Purification by preparative HPLC (Gemini column—acetonitrile/0.2% ammonia mobile phase) afforded the title compound as a solid (50 mg).
Reaction SMILES: [CH2:1]([C:3]1[NH:4][C:5]2[C:10]([C:11]=1[C:12](=[O:15])[CH2:13][CH3:14])=[CH:9][CH:8]=[C:7]([C:16]([O:18][CH3:19])=[O:17])[CH:6]=2)[CH3:2].[Cl:20][C:21]1[CH:28]=[CH:27][CH:26]=[CH:25][C:22]=1[CH2:23]Br>>[Cl:20][C:21]1[CH:28]=[CH:27][CH:26]=[CH:25][C:22]=1[CH2:23][N:4]1[C:5]2[C:10](=[CH:9][CH:8]=[C:7]([C:16]([O:18][CH3:19])=[O:17])[CH:6]=2)[C:11]([C:12](=[O:15])[CH2:13][CH3:14])=[C:3]1[CH2:1][CH3:2]
Reactant: CCC(=O)c1c(CC)[nH]c2cc(C(=O)OC)ccc12
Reactant: Clc1ccccc1CBr
Product: CCC(=O)c1c(CC)n(Cc2ccccc2Cl)c2cc(C(=O)OC)ccc12

Procedure:
Methyl 1-(2-chlorobenzyl)-2-ethyl-3-propionylindole-6-carboxylate (278 mg) was prepared from methyl 2-ethyl-3-propionylindole-6-carboxylate (215 mg) and 2-chlorobenzyl bromide (0.24 ml) in a similar manner to that of Example 1.
Reaction SMILES: C1(C)C=CC(S(O)(=O)=O)=CC=1.[CH3:12][O:13][C:14]([C:16]1[CH:17]=[C:18]([CH3:41])[C:19]2[O:25][C:24]3[C:26]([Cl:37])=[CH:27][C:28]([N:30]([CH2:34][CH2:35][OH:36])[CH2:31][CH2:32]O)=[CH:29][C:23]=3[CH2:22][S:21](=[O:39])(=[O:38])[C:20]=2[CH:40]=1)=[O:15].C(=O)(O)[O-]>C1(C)C(C)=CC=CC=1.O>[CH3:12][O:13][C:14]([C:16]1[CH:17]=[C:18]([CH3:41])[C:19]2[O:25][C:24]3[C:26]([Cl:37])=[CH:27][C:28]([N:30]4[CH2:31][CH2:32][O:36][CH2:35][CH2:34]4)=[CH:29][C:23]=3[CH2:22][S:21](=[O:38])(=[O:39])[C:20]=2[CH:40]=1)=[O:15]
Reactant: COC(=O)c1cc(C)c2c(c1)S(=O)(=O)Cc1cc(N(CCO)CCO)cc(Cl)c1O2
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Solvent: Cc1ccccc1C
Solvent: O
Product: COC(=O)c1cc(C)c2c(c1)S(=O)(=O)Cc1cc(N3CCOCC3)cc(Cl)c1O2

Procedure:
Catalytic amount of p-toluene sulphonic acid (PTSA) was added to a stirred solution of compound of Example 13 (1 g, 2.19 mmol) in xylene (50 mL). Reaction mixture was refluxed in Dean-Stark apparatus for 6 h and xylene was removed by distillation. Reaction mixture was diluted with 50 mL water, neutralized using 10% sodim bicarbonate solution and extracted using ethyl acetate (3×50 mL), washed with brine (2×10 mL), dried on sodium sulphate. The crude product obtained was purified by column chromatography (silica gel, ethylacetate/pet. ether) to obtain the title compound. Yield: 0.32 g, (33%); mp: >320° C.; 1H NMR (DMSO-d6, 300 MHz): δ 2.68 (s, 3H, CH3), 3.15 (s, 4H, 2CH2), 3.74 (s, 4H, 2CH2), 3.90 (s, 3H, OCH3), 4.65 (s, 2H, CH2), 6.76 (s, 1H, Ar), 6.88 (s, 1H, Ar), 8.06 (s, 1H, Ar), 8.44 (s, 1H, Ar); MS: m/e (El) 437 (M+).
Reaction SMILES: [C:1]([O:4][CH2:5][C:6]1[CH2:13][S:12][CH:11]2[N:8]([C:9](=[O:26])[CH:10]2[NH:14][C:15](=[O:25])[CH2:16][C:17]2[CH:22]=[CH:21][C:20]([CH2:23]Cl)=[CH:19][CH:18]=2)[C:7]=1[C:27]([OH:29])=[O:28])(=[O:3])[CH3:2].[N-:30]=[N+:31]=[N-:32].[Na+]>CO>[C:1]([O:4][CH2:5][C:6]1[CH2:13][S:12][CH:11]2[N:8]([C:9](=[O:26])[CH:10]2[NH:14][C:15](=[O:25])[CH2:16][C:17]2[CH:22]=[CH:21][C:20]([CH2:23][N:30]=[N+:31]=[N-:32])=[CH:19][CH:18]=2)[C:7]=1[C:27]([OH:29])=[O:28])(=[O:3])[CH3:2]
Reactant: CC(=O)OCC1=C(C(=O)O)N2C(=O)C(NC(=O)Cc3ccc(CCl)cc3)C2SC1
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CO
Product: CC(=O)OCC1=C(C(=O)O)N2C(=O)C(NC(=O)Cc3ccc(CN=[N+]=[N-])cc3)C2SC1

Procedure:
A warm solution of 1 g of 3-[(acetyloxy)methyl]-7-[[2-[4-(chloromethyl)phenyl]acetyl]amino]-8-oxo-5-thia-1-azabicyclo[4.2.0]-oct-2-ene-2-carboxylic acid and 2 g. of sodium azide in 80 ml of methanol was refluxed for 4 hours after which the solvent was removed under high vacuum at room temperature. The residue was triturated with 80 ml of benzeneacetone (2:1) to give 3-[(Acetyloxy)methyl]-7-[[2-[4-(azidomethyl)phenyl]acetyl]amino]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2carboxylic acid. M.P. 135°-136° C.
Reaction SMILES: [H-].[Na+].[CH2:3]([O:10][C:11]([N:13]([CH2:15][C:16]1[NH:17][C:18]2[C:23]([CH:24]=1)=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH3:14])=[O:12])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[CH2:25](I)[CH3:26]>CN(C=O)C.O>[CH2:3]([O:10][C:11]([N:13]([CH2:15][C:16]1[N:17]([CH2:25][CH3:26])[C:18]2[C:23]([CH:24]=1)=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH3:14])=[O:12])[C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: CN(Cc1cc2ccccc2[nH]1)C(=O)OCc1ccccc1
Reactant: CCI
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCn1c(CN(C)C(=O)OCc2ccccc2)cc2ccccc21
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 84.9 %

Procedure:
NaH (60% dispersion in mineral oil, 0.25 g, 7.1 mmole) was added portionwise, allowing for gas evolution, to a solution of 2-[N-(benzyloxycarbonyl)-N-methylaminomethyl]-1H-indole (1.40 g, 4.75 mmole) in DMF (35 mL) at 0° C. When the NaH addition was complete, ethyl iodide (0.42 mL, 5.2 mmole) was added at 0° C. The reaction was stirred at 0° C. for 15 minutes then at RT overnight. The reaction was diluted with water and extracted with ethyl acetate. The combined extracts were dried over K2CO3 and concentrated to afford the title compound (1.30 g, 87%) as an orange solid: MS (ES) m/e 323 (M+H)+.
Reaction SMILES: C([Li])CCC.[CH2:6]([O:8][C:9]([N:11]1[CH2:16][CH2:15][C:14](=[O:17])[CH2:13][CH2:12]1)=[O:10])[CH3:7].Cl.[CH2:19]([O:26][C:27]1[CH:32]=[C:31]([O:33][CH2:34][C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[CH:30]=[CH:29][C:28]=1Br)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>O1CCCC1.CCCCCC>[CH2:6]([O:8][C:9]([N:11]1[CH2:12][CH2:13][C:14]([C:30]2[CH:29]=[CH:28][C:27]([O:26][CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)=[CH:32][C:31]=2[O:33][CH2:34][C:35]2[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=2)([OH:17])[CH2:15][CH2:16]1)=[O:10])[CH3:7]
Reactant: Brc1ccc(OCc2ccccc2)cc1OCc1ccccc1
Reactant: CCOC(=O)N1CCC(=O)CC1
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CCOC(=O)N1CCC(O)(c2ccc(OCc3ccccc3)cc2OCc2ccccc2)CC1
Temperature: -70 °C
Reaction time: 1 h

Procedure:
In a 500 ml three-necked flask, 20 g of 2,4-bis(benzyloxy)-1-bromobenzene are dissolved in 240 ml of tetrahydrofuran. The mixture is cooled to −70° C. and then 26 ml of 2.5M n-butyllithium in hexane are added. The reaction medium is stirred at −70° C. for 1 hour, and then 11.1 g of 4-oxo-piperidine-1-carboxylic acid ethyl ester are added dropwise. The reaction medium is stirred at −70° C. for 2 hours and then left at ambient temperature overnight. The reaction medium is poured into 100 ml of a 2M solution of hydrochloric acid and then extracted with 400 ml of ethyl acetate. The organic phases are combined, washed with 150 ml of water and then dried over magnesium sulphate and evaporated.
Reaction SMILES: [Cl:1][C:2]1[C:11]([O:12][CH2:13][C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=2)=[C:10]([O:22][CH2:23][C:24]2[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[CH:26][CH:25]=2)[CH:9]=[C:8]2[C:3]=1[C:4](=[O:47])[C:5]([C:35]([O:37]CC1C=CC(OC)=CC=1)=[O:36])=[CH:6][N:7]2[CH:32]1[CH2:34][CH2:33]1.[OH-].[K+]>CO.O>[Cl:1][C:2]1[C:11]([O:12][CH2:13][C:14]2[CH:15]=[CH:16][C:17]([O:20][CH3:21])=[CH:18][CH:19]=2)=[C:10]([O:22][CH2:23][C:24]2[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[CH:26][CH:25]=2)[CH:9]=[C:8]2[C:3]=1[C:4](=[O:47])[C:5]([C:35]([OH:37])=[O:36])=[CH:6][N:7]2[CH:32]1[CH2:33][CH2:34]1
Reactant: COc1ccc(COC(=O)c2cn(C3CC3)c3cc(OCc4ccc(OC)cc4)c(OCc4ccc(OC)cc4)c(Cl)c3c2=O)cc1
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: COc1ccc(COc2cc3c(c(Cl)c2OCc2ccc(OC)cc2)c(=O)c(C(=O)O)cn3C2CC2)cc1
Temperature: 90 °C
Reaction time: 3 h
Yield: 85.8 %

Procedure:
To a suspension of 4-methoxybenzyl 5-chloro-1-cyclopropyl-6,7-bis((4-methoxy benzyl)oxy)-4-oxo-1,4-dihydroquinoline-3-carboxylate (18 g, 27.4 mmol) in a mixture of Methanol (120 mL) and Water (60.0 mL) was added potassium hydroxide (3.08 g, 54.9 mmol) portionwise. The resulting mixture was stirred at 90° C. for 3 h. LCMS indicated completion of the reaction. The reaction mixture was cooled down to r.t. and concentrated, and was then diluted with water and adjusted pH to 1 using 2 N HCl (aq.). The precipitates were collected by filtration and dried to afford 5-chloro-1-cyclopropyl-6,7-bis((4-methoxybenzyl)oxy)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (12.6 g, 23.51 mmol, 86% yield) as pale yellow solid. LCMS: [M+H]+: 536.3.
Reaction SMILES: [CH:1]1([S:4]([NH2:7])(=[O:6])=[O:5])[CH2:3][CH2:2]1.[H-].[Na+].[CH3:10][C:11]1([CH3:42])[C:20]2[C:15](=[C:16]([C:21](O)=[O:22])[CH:17]=[CH:18][CH:19]=2)[NH:14][CH:13]([C:24]2[CH:29]=[CH:28][CH:27]=[C:26]([N:30]3[CH2:35][CH2:34][N:33]([C:36]4[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=4)[CH2:32][CH2:31]3)[CH:25]=2)[CH2:12]1.C(N1C=CN=C1)(N1C=CN=C1)=O>CN(C)C=O.O>[CH3:10][C:11]1([CH3:42])[C:20]2[C:15](=[C:16]([C:21]([NH:7][S:4]([CH:1]3[CH2:3][CH2:2]3)(=[O:6])=[O:5])=[O:22])[CH:17]=[CH:18][CH:19]=2)[NH:14][CH:13]([C:24]2[CH:29]=[CH:28][CH:27]=[C:26]([N:30]3[CH2:31][CH2:32][N:33]([C:36]4[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=4)[CH2:34][CH2:35]3)[CH:25]=2)[CH2:12]1
Reactant: NS(=O)(=O)C1CC1
Reactant: CC1(C)CC(c2cccc(N3CCN(c4ccccc4)CC3)c2)Nc2c(C(=O)O)cccc21
Agent: O=C(n1ccnc1)n1ccnc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CC1(C)CC(c2cccc(N3CCN(c4ccccc4)CC3)c2)Nc2c(C(=O)NS(=O)(=O)C3CC3)cccc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 25 %

Procedure:
To a suspension of cyclopropanesulfonic acid amide (96 mg, 0.8 mmol) in N,N-dimethylformamide (1.5 mL) was added sodium hydride (32 mg, 0.8 mmol). The resulting mixture was stirred at 25° C. for 1 h to afford Solution A76. A solution of 4,4-dimethyl-2-[3-(4-phenyl-piperazin-1-yl)-phenyl]-1,2,3,4-tetrahydro-quinoline-8-carboxylic acid (50 mg, 0.11 mmol) and 1,1′-carbonyldiimidazole (37 mg, 0.23 mmol) in N,N-dimethylformamide (2 mL) was stirred at 70° C. for 1 h and cooled to room temperature to afford Solution B76. Solution B76 was added to Solution A76 and the resulting mixture was stirred at 25° C. for 1 h. To the reaction mixture was added water (0.5 mL). The mixture was filtered to remove the insoluble solid, and the filtrate was purified by Waters automated flash system (column: Xterra 30 mm×100 mm, sample manager 2767, pump 2525, detector: ZQ mass and UV 2487, solvent system: acetonitrile and 0.1% ammonium hydroxide in water) afforded cyclopropanesulfonic acid {4,4-dimethyl-2-[3-(4-phenyl-piperazin-1-yl)-phenyl]-1,2,3,4-tetrahydro-quinoline-8-carbonyl}-amide (15 mg, 24%) as a white solid: MS (ESI) M+1=545.2.
Reaction SMILES: [F:1][C:2]1([F:26])[C:8]([CH3:10])([CH3:9])[O:7][CH2:6][C:5](=O)[NH:4][C@@:3]1([C:13]1[CH:18]=[C:17]([C:19]2[N:20]([CH3:24])[N:21]=[CH:22][CH:23]=2)[CH:16]=[CH:15][C:14]=1[F:25])[CH3:12].COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:36])=CC=1>O1CCOCC1>[F:1][C:2]1([F:26])[C:8]([CH3:10])([CH3:9])[O:7][CH2:6][C:5](=[S:36])[NH:4][C@@:3]1([C:13]1[CH:18]=[C:17]([C:19]2[N:20]([CH3:24])[N:21]=[CH:22][CH:23]=2)[CH:16]=[CH:15][C:14]=1[F:25])[CH3:12]
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: Cn1nccc1-c1ccc(F)c([C@@]2(C)NC(=O)COC(C)(C)C2(F)F)c1
Solvent: C1COCCO1
Product: Cn1nccc1-c1ccc(F)c([C@@]2(C)NC(=S)COC(C)(C)C2(F)F)c1
Yield: 122.4 %

Procedure:
The reaction of (R)-6,6-difluoro-5-[2-fluoro-5-(2-methyl-2H-pyrazol-3-yl)-phenyl]-5,7,7-trimethyl-[1,4]oxazepan-3-one (133 mg, 364 μmol) with Lawesson's reagent (120 mg, 292 μmol) in 1,4-dioxane (12 ml) yielded the (R)-6,6-difluoro-5-[2-fluoro-5-(2-methyl-2H-pyrazol-3-yl)-phenyl]-5,7,7-trimethyl-[1,4]oxazepan-3-thione (137 mg, 98% yield) as a colorless oil. MS (ISP): m/z=384.2 [M+H]+.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:10][CH:9]=2)[CH:5]=[CH:4][N:3]=1.[IH:18]>ClCCl>[I:18][C:2]1[N:7]=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:10][CH:9]=2)[CH:5]=[CH:4][N:3]=1
Reactant: I
Reactant: FC(F)(F)c1ccc(-c2ccnc(Cl)n2)cc1
Solvent: ClCCl
Product: FC(F)(F)c1ccc(-c2ccnc(I)n2)cc1
Reaction time: 0.67 h
Yield: 94.9 %

Procedure:
2-Chloro-4-[4-(trifluoromethyl)phenyl]pyrimidine (which may be prepared as described in Description 5) (1.22 g, 4.72 mmol) was added portionwise to HI (57% in water) (4.98 mL, 37.74 mmol) at 0° C. and the dark mixture was stirred for 40 mins. Dichloromethane (5 mL) was added and the resultant light brown mixture was stirred at 0° C. for 18.25 hrs. Additional dichloromethane (5 mL) was added followed by HI (57% in water) (1.87 mL, 14.15 mmol) and vigorous stirring was continued at 0° C. for a further 18 hrs. The mixture was quenched by the addition of satd. aq. K2CO3 (care: gas evolved). After basification, satd. sodium metabisulphite was added and stirring was continued for 5 mins. The mixture was diluted with further DCM and the phases were separated. The organic layer was dried (Na2SO4) and the solvent evaporated to afford the 2-iodo-4-[4-(trifluoromethyl)phenyl]pyrimidine (D6) (1.57 g, 4.48 mmol, 95.1% yield) as a yellow solid.