Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[N:10]=[CH:9][C:8](Br)=[CH:7][N:6]=1)=[O:4].C1C=CC(P(C2C=CC3C(=CC=CC=3)C=2C2C3C(=CC=CC=3)C=CC=2P(C2C=CC=CC=2)C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C([O-])([O-])=O.[Cs+].[Cs+].[C:64](=[NH:77])([C:71]1[CH:76]=[CH:75][CH:74]=[CH:73][CH:72]=1)[C:65]1[CH:70]=[CH:69][CH:68]=[CH:67][CH:66]=1>CC([O-])=O.CC([O-])=O.[Pd+2].C1(C)C=CC=CC=1>[CH3:1][O:2][C:3]([C:5]1[N:10]=[CH:9][C:8]([N:77]=[C:64]([C:65]2[CH:70]=[CH:69][CH:68]=[CH:67][CH:66]=2)[C:71]2[CH:76]=[CH:75][CH:74]=[CH:73][CH:72]=2)=[CH:7][N:6]=1)=[O:4]
Reactant: N=C(c1ccccc1)c1ccccc1
Reactant: COC(=O)c1ncc(Br)cn1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: Cc1ccccc1
Product: COC(=O)c1ncc(N=C(c2ccccc2)c2ccccc2)cn1
Temperature: 105 °C
Reaction time: 17 h
Yield: 46.4 %

Procedure:
To a round bottom was added 5-bromo-pyrimidine-2-carboxylic acid methyl ester (14.50 g, 66.81 mmol), (+/−)-BINAP (4.16 g, 6.68 mmol), Pd(OAc)2 (750 mg, 3.34 mmol), and Cs2CO3 (26.1 g, 80.2 mmol). Toluene (100 mL) and benzophenone imine (12.3 mL, 73.5 mmol) were added and the mixture heated to 105° C. as an orange mixture. At 17 h, the reaction was cooled and partitioned between ethyl acetate and 1N NaOH. The aqueous layer was extracted with ethyl acetate and the combined organics dried over MgSO4. Purification by silica gel flash chromatography (ethyl acetate/heptane) gave 5-(benzhydrylidene-amino)-pyrimidine-2-carboxylic acid methyl ester (9.83 g, 46%) as a bright yellow solid. 1H NMR (400 MHz, DMSO-d6, δ): 8.42 (s, 2 H) 7.74 (d, J=6.8 Hz, 2 H) 7.61 (m, 1 H) 7.54 (m, 2 H) 7.38 (br. s., 3 H) 7.26 (br. s., 2 H) 3.83 (s, 3 H); MS (M+1): 318.2.
Reaction SMILES: [C:1]([O:5][C:6](=[O:22])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=2)=[CH:10][C:9]=1[NH2:21])([CH3:4])([CH3:3])[CH3:2].C([O:27][C:28](=O)[CH2:29][C:30]([C:32]1[N:33]=[C:34]([N:37]2[CH:41]=[CH:40][N:39]=[CH:38]2)[S:35][CH:36]=1)=[O:31])(C)(C)C>>[C:1]([O:5][C:6](=[O:22])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:15]=[CH:16][C:17]([F:20])=[CH:18][CH:19]=2)=[CH:10][C:9]=1[NH:21][C:28](=[O:27])[CH2:29][C:30]([C:32]1[N:33]=[C:34]([N:37]2[CH:41]=[CH:40][N:39]=[CH:38]2)[S:35][CH:36]=1)=[O:31])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)CC(=O)c1csc(-n2ccnc2)n1
Reactant: CC(C)(C)OC(=O)Nc1ccc(-c2ccc(F)cc2)cc1N
Product: CC(C)(C)OC(=O)Nc1ccc(-c2ccc(F)cc2)cc1NC(=O)CC(=O)c1csc(-n2ccnc2)n1
Yield: 62.1 %

Procedure:
Prepared from (3-amino-4′-fluoro-biphenyl-4-yl)-carbamic acid tert.-butyl ester (Example G39) (151 mg, 0.5 mmol) and 3-(2-imidazol-1-yl-thiazol-4-yl)-3-oxo-propionic acid tert.-butyl ester (Example H19) (235 mg, 0.8 mmol) according to the general procedure K. Obtained as an orange oil (162 mg).
Reaction SMILES: [OH-].[Na+].[N:3]#[C:4][NH2:5].C1C=CC=CC=1.Br[CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[CH2:26]Br>CCCCCCCC[N+](CCCCCCCC)(CCCCCCCC)C.[Cl-].C(Cl)Cl>[CH:16]1[C:15]2[C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[CH2:26][N:3]([C:4]#[N:5])[CH2:13][C:14]=2[CH:19]=[CH:18][CH:17]=1
Reactant: N#CN
Reactant: BrCc1ccccc1-c1ccccc1CBr
Agent: CCCCCCCC[N+](C)(CCCCCCCC)CCCCCCCC
Agent: [Cl-]
Agent: [Na+]
Solvent: c1ccccc1
Solvent: ClCCl
Product: N#CN1Cc2ccccc2-c2ccccc2C1
Reaction time: 6 h

Procedure:
180 ml of 50% sodium hydroxide solution are treated at about 60° C. in sequence with 7.7 g of cyanamide, 1.3 g of tricaprylmethylammonium chloride, 360 ml of benzene and 62 g of 2,2'-bis(bromomethyl)-biphenyl, and the mixture is stirred at 60°-70° C. for 6 hours. After cooling the reaction mixture this is transferred to a separating funnel and shaken with 50 ml of methylene chloride, whereby the separated product is taken up in the methylene chloride phase. The aqueous phase is back-extracted twice with methylene chloride. The combined extracts are subsequently washed with water, dried over anhydrous sodium sulphate and evaporated, and the residue is taken up in 100 ml of toluene and the solution is heated to reflux temperature, filtered and treated at about 50° C. with 200 ml of tert.-butyl methyl ether. Finally, the crystals which are precipitated by ice-cooling are filtered off under suction and dried. In this manner there is obtained pure 5,7-dihydro-6H-dibenz[c,e]azepine-6-carbonitrile, m.p. 121°-124° C.
Reaction SMILES: [CH3:1][C:2]1([CH3:25])[CH2:15][N:14]2[C:5](=[N:6][C:7]3[C:12]([C:13]2=[O:16])=[CH:11][CH:10]=[C:9]([C:17]#[C:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=2)[CH:8]=3)[NH:4][CH2:3]1.[H-].[Na+].[CH3:28]I>C1COCC1>[CH3:28][N:4]1[C:5]2=[N:6][C:7]3[C:12]([C:13](=[O:16])[N:14]2[CH2:15][C:2]([CH3:25])([CH3:1])[CH2:3]1)=[CH:11][CH:10]=[C:9]([C:17]#[C:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=1)[CH:8]=3
Reactant: CI
Reactant: CC1(C)CNc2nc3cc(C#Cc4ccccn4)ccc3c(=O)n2C1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CN1CC(C)(C)Cn2c1nc1cc(C#Cc3ccccn3)ccc1c2=O
Temperature: 25 °C
Reaction time: 24 h
Yield: 9.7 %

Procedure:
A mixture of 3,3-dimethyl-9-(pyridin-2-ylethynyl)-3,4-dihydro-1H-pyrimido[2,1-b]quinazolin-6(2H)-one (30 mg, 0.09 mmol), NaH (14 mg, 0.36 mmol) and MeI (28 mg, 0.2 mmol) in dry THF was stirred for 24 h at room temperature. Then the solvent was evaporated to give the crude product, which was purified by column chromatography to give 3 mg of the title compound. MS (ESI): 345 (MH+). 1H NMR (300 MHz, CDCl3) δ 8.66-8.65 (d, J=4.8 Hz, 1H), 8.08-8.05 (d, J=8.2 Hz, 1H), 7.75-7.69 (td, J=7.8, 1.8 Hz, 1H), 7.60-7.55 (m, 2H), 7.31-7.30 (m, 2H), 3.82 (s, 2H), 3.28 (s, 3H), 3.18 (s, 2H), 1.13 (s, 6H).
Reaction SMILES: Cl[C:2]1[C:11]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=2)=[N:10][C:9]2[C:4](=[CH:5][C:6]([Cl:19])=[C:7]([Cl:18])[CH:8]=2)[N:3]=1.[OH:20][CH2:21][CH2:22][N:23]([CH2:28][CH2:29][OH:30])[CH2:24][CH2:25][CH2:26][NH2:27]>C1(C)C=CC=CC=1>[Cl:18][C:7]1[CH:8]=[C:9]2[C:4](=[CH:5][C:6]=1[Cl:19])[N:3]=[C:2]([NH:27][CH2:26][CH2:25][CH2:24][N:23]([CH2:28][CH2:29][OH:30])[CH2:22][CH2:21][OH:20])[C:11]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=1)=[N:10]2
Reactant: NCCCN(CCO)CCO
Reactant: Clc1cc2nc(Cl)c(-c3ccccn3)nc2cc1Cl
Solvent: Cc1ccccc1
Product: OCCN(CCO)CCCNc1nc2cc(Cl)c(Cl)cc2nc1-c1ccccn1
Yield: 78.3 %

Procedure:
A solution of 2,6,7-trichloro-3-pyridin-2-yl-quinoxaline (0.50 g) and 3-[bis(2-hydroxy-ethyl)amino]-propylamine (0.51 g) in toluene (25 mL) was refluxed under nitrogen atmosphere for 16 hours. After refluxing, the reaction mixture was cooled, filtered, and concentrated under vacuum. The residue was purified by flash chromatography (silica gel, 1:9 methanol/dichloromethane) to give a yellow solid. Recrystallization from methanol and water gave the product as a yellow plate like crystals (0.55 g); mp 88-90° C.
Reaction SMILES: [CH:1]([NH:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)([CH3:3])[CH3:2].CCN(CC)CC.[Br:19][CH2:20][C:21](Br)=[O:22]>C(Cl)(Cl)Cl.C(Cl)Cl>[CH2:5]([N:4]([CH:1]([CH3:3])[CH3:2])[C:21](=[O:22])[CH2:20][Br:19])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: CC(C)NCc1ccccc1
Reactant: O=C(Br)CBr
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)N(Cc1ccccc1)C(=O)CBr
Temperature: 0 °C
Reaction time: 24 h
Yield: 80.5 %

Procedure:
To a solution of N-isopropylbenzylamine (40 mL, 240 mmol) in CHCl3 (300 mL) was added Et3N (36.8 mL). The reaction was cooled to 0° C. and bromoacetyl bromide (21.8 mL, 251 mmol) was added. The mixture was stirred at room temperature for 24 hours and was diluted with CH2Cl2. The organic solution was washed consecutively with 5% aqueous HCl (1×) and aqueous NaHCO3 (1×). The organic solution was dried (Na2SO4), filtered and concentrated. The residue was dissolved in 40% EtOAc in hexanes and was filtered through a silica gel pad to provide 52.2 g of N-benzyl-2-bromo-N-isopropyl-acetamide. 1H NMR (CD2Cl2) δ 7.20-7.40 (m, 5H), 4.53 (d, 2H), 4.22 (m) and 4.74 (m, total 1H), 4.01 (s, 1H), 3.72 (s, 1H), 1.20 (d, 3H), 1.12 (d, 3H).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([C:11](O)=[O:12])[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.CSC.B>C1COCC1>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2([CH2:11][OH:12])[CH2:9][CH2:10]2)=[CH:6][CH:7]=1
Reactant: O=C(O)C1(c2ccc(Br)cc2)CC1
Agent: B
Solvent: CSC
Solvent: C1CCOC1
Product: OCC1(c2ccc(Br)cc2)CC1
Reaction time: 4 h
Yield: 95.9 %

Procedure:
To a solution of 1-(4-bromophenyl)cyclopropane carboxylic acid (3.0 g, 12.4 mmol) in dry THF (40 mL) under nitrogen atmosphere, was added borane dimethyl sulphide (8.83 mL, 19.8 mmol, 2 M solution in DCM) at 0° C. The reaction mixture was stirred at r.t for 4 h. After the completion of reaction as confirmed by TLC, the reaction mixture was quenched by dropwise addition of methanol until effervescence stopped. Volatiles were evaporated in vacuo and the compound was diluted with ethyl acetate (80 mL). The organic layer was separated; washed with water (3×10 mL), dried over Na2SO4 and concentrated. The crude product obtained was purified by column chromatography (silica gel, 1:4 EtOAc:Pet Ether) to afford title compound (2.7 g, 96%) as a solid.
Reaction SMILES: [Cl:1][C:2]1[C:3]([N:17]([CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][C:24]([O:26]CC)=[O:25])[CH3:18])=[CH:4][C:5]([O:15][CH3:16])=[C:6]([CH:14]=1)[C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8].[OH-].[Na+].Cl.C(OCC)(=O)C>C(O)C>[C:10]([O:9][C:7]([C:6]1[C:5]([O:15][CH3:16])=[CH:4][C:3]([N:17]([CH3:18])[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][C:24]([OH:26])=[O:25])=[C:2]([Cl:1])[CH:14]=1)=[O:8])([CH3:13])([CH3:12])[CH3:11]
Reactant: CCOC(=O)CCCCCN(C)c1cc(OC)c(C(=O)OC(C)(C)C)cc1Cl
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: CCO
Product: COc1cc(N(C)CCCCCC(=O)O)c(Cl)cc1C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 2 h
Yield: 102 %

Procedure:
The compound (200 mg, 0.48 mmol) obtained in Example 99c was dissolved in ethanol (4 mL), a 1 N aqueous sodium hydroxide solution (1.00 mL, 1.00 mmol) was added, and the mixture was stirred at room temperature for 2 hours. After the reaction was completed, a 1 N aqueous hydrochloric acid solution (1.00 mL, 1.00 mmol) was added to the reaction mixture under ice cooling, and ethyl acetate was further added to separate the layers. The resulting organic layer was separated, washed with saturated sodium chloride solution, and then dried with anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure to give crude 6-{[4-(tert-butoxycarbonyl)-2-chloro-5-methoxyphenyl](methyl)amino}hexanoic acid (189 mg).
Reaction SMILES: [CH3:1][C:2]1[N:6]([CH2:7][C:8]2[CH:13]=[CH:12][C:11]([CH3:14])=[CH:10][CH:9]=2)[N:5]=[C:4]([C:15](OC)=[O:16])[CH:3]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-].O.[OH-].[Na+]>C1COCC1>[CH3:1][C:2]1[N:6]([CH2:7][C:8]2[CH:13]=[CH:12][C:11]([CH3:14])=[CH:10][CH:9]=2)[N:5]=[C:4]([CH2:15][OH:16])[CH:3]=1
Reactant: COC(=O)c1cc(C)n(Cc2ccc(C)cc2)n1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: Cc1ccc(Cn2nc(CO)cc2C)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 94.7 %

Procedure:
To a solution of methyl 5-methyl-1-(4-methylbenzyl)-1H-pyrazole-3-carboxylate (Intermediate A, 5.0 g, 20.5 mmol) in THF (100 mL) at 0° C. was added a solution of lithium aluminum hydride (15.4 mL, 30.7 mmol, 2.0 M in THF) dropwise. The mixture was stirred at rt for 1 h. Celite® (3 g) was added to the mixture, followed by water (5 mL) dropwise and sodium hydroxide (1.0 N, 5 mL). The mixture was filtered through a pad of Celite® washing throroughly with ethyl acetate. The combined organics were diluted with ethyl acetate, washed with water (1×150 mL) and brine (1×150 mL), dried over Na2SO4, filtered and concentrated to dryness to afford the title compound as a light yellow solid (4.2 g, 95%): 1H NMR (300 MHz, DMSO-d6) δ 7.10 (d, 2H), 6.96 (d, 2H), 5.98 (s, 1H), 5.14 (s, 2H), 4.89 (t, 1H), 4.29 (d, 2H), 2.24 (s, 3H), 2.14 (s, 3H); ES-MS m/z 217.03, HPLC RT (Method A) 2.96 min.
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[CH:6][C:5]([C:9]2[CH:14]=[CH:13][N:12]=[CH:11][C:10]=2[NH:15][CH2:16][C:17]([F:20])([F:19])[F:18])=[C:4]([O:21][CH3:22])[CH:3]=1.[CH3:23][S:24]([C:27]1[CH:28]=[C:29]([CH:33]=[C:34]([C:36]([F:39])([F:38])[F:37])[CH:35]=1)[C:30](O)=[O:31])(=[O:26])=[O:25]>>[F:1][C:2]1[C:7]([F:8])=[CH:6][C:5]([C:9]2[CH:14]=[CH:13][N:12]=[CH:11][C:10]=2[N:15]([CH2:16][C:17]([F:18])([F:19])[F:20])[C:30](=[O:31])[C:29]2[CH:33]=[C:34]([C:36]([F:39])([F:37])[F:38])[CH:35]=[C:27]([S:24]([CH3:23])(=[O:26])=[O:25])[CH:28]=2)=[C:4]([O:21][CH3:22])[CH:3]=1
Reactant: COc1cc(F)c(F)cc1-c1ccncc1NCC(F)(F)F
Reactant: CS(=O)(=O)c1cc(C(=O)O)cc(C(F)(F)F)c1
Product: COc1cc(F)c(F)cc1-c1ccncc1N(CC(F)(F)F)C(=O)c1cc(C(F)(F)F)cc(S(C)(=O)=O)c1

Procedure:
The title compound was prepared in analogy to example 90, from [4-(4,5-difluoro-2-methoxy-phenyl)-pyridin-3-yl]-(2,2,2-trifluoro-ethyl)-amine (example 132, intermediate a) and 3-methanesulfonyl-5-trifluoromethyl-benzoic acid (example 114, intermediate a) after a reaction time of 72 hours. The compound was purified by silica gel chromatography using a MPLC system (CombiFlash Companion, Isco Inc.) eluting with a gradient of CH2Cl2: EtOAc (100:0 to 85:15). Light brown foam (21%). MS (ESI): m/z=569.077 [M+H]+.
Reaction SMILES: [C:1]([O:5][C:6](=[O:48])[NH:7][CH:8]([C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1)[C:9](N1CCCCC1C(=O)NC1C=CC(C#CC2C(C3C=C(C)C=CC=3O)=NN(C)C=2)=CC=1)=[O:10])([CH3:4])([CH3:3])[CH3:2].[Cl:49][C:50]1[CH:51]=[CH:52][C:53]([OH:79])=[C:54]([C:56]2[C:60]([C:61]#[C:62][C:63]3[CH:68]=[CH:67][C:66]([NH:69][C:70]([CH:72]4[CH2:77][O:76][CH2:75][CH2:74][NH:73]4)=[O:71])=[CH:65][CH:64]=3)=[CH:59][N:58]([CH3:78])[N:57]=2)[CH:55]=1.N(C(OC(C)(C)C)=O)[C@@H](C(O)=O)C1C=CC=CC=1>>[C:1]([O:5][C:6](=[O:48])[NH:7][CH:8]([C:42]1[CH:43]=[CH:44][CH:45]=[CH:46][CH:47]=1)[C:9]([N:73]1[CH2:74][CH2:75][O:76][CH2:77][CH:72]1[C:70](=[O:71])[NH:69][C:66]1[CH:65]=[CH:64][C:63]([C:62]#[C:61][C:60]2[C:56]([C:54]3[CH:55]=[C:50]([Cl:49])[CH:51]=[CH:52][C:53]=3[OH:79])=[N:57][N:58]([CH3:78])[CH:59]=2)=[CH:68][CH:67]=1)=[O:10])([CH3:4])([CH3:2])[CH3:3]
Reactant: Cn1cc(C#Cc2ccc(NC(=O)C3COCCN3)cc2)c(-c2cc(Cl)ccc2O)n1
Reactant: Cc1ccc(O)c(-c2nn(C)cc2C#Cc2ccc(NC(=O)C3CCCCN3C(=O)C(NC(=O)OC(C)(C)C)c3ccccc3)cc2)c1
Agent: CC(C)(C)OC(=O)N[C@@H](C(=O)O)c1ccccc1
Product: Cn1cc(C#Cc2ccc(NC(=O)C3COCCN3C(=O)C(NC(=O)OC(C)(C)C)c3ccccc3)cc2)c(-c2cc(Cl)ccc2O)n1

Procedure:
Using the same procedure for the preparation of 3D, reaction of compound 7D with BOC-D-Phg-OH (2D) afforded the title compound 8D, which was purified by silica column chromatography eluting with dichloromethane/EtOAc (9/1, 8/1, 7/1) to give pure 8D as white powder in similar yield. 1H NMR (CDCl3, 500 MHz) δ 10.68 (s, 1H), 8.72 (s, 1H), 8.61 (s, 1H), 7.92 (d, 2H, J=7.0 Hz), 7.63 (s, 1H), 7.57 (d, 2H, J=8.0 Hz), 7.43 (m, 5H), 7.20 (d, 1H, J=8.5 Hz), 6.97 (dd, 1H, J=9.0, 1.0 Hz), 5.48 (d, 1H, J=6.0 Hz), 5.40 (d, 1H, J=5.5 Hz), 5.29 (s, 1H), 4.82 (d, 1H, J=12.0 Hz), 3.96 (s, 3H), 3.78 (d, 1H, J=10.5 Hz), 3.65 (t, 1H, J=12.5 Hz), 3.60 (t, 1H, J=10.0 Hz), 3.43 (dd, 1H, J=11.5, 2.0 Hz), 3.07 (t, 1H, J=11.5 Hz), 1.45 (s, 9H). LCMS (ESI) m/z 692.34 (MNa+), 670.33 (MH+), 614.24 (100), 570.23. HPLC: tR=5.35 min.
Reaction SMILES: [CH3:1][C:2]1([CH3:8])[O:7][CH2:6][CH2:5][NH:4][CH2:3]1.[Cl:9][C:10]1[CH:15]=[C:14](Cl)[N:13]=[C:12]([N:17]2[CH2:22][CH2:21][O:20][CH2:19][CH2:18]2)[N:11]=1.C(N(CC)CC)C>CCO>[Cl:9][C:10]1[N:11]=[C:12]([N:17]2[CH2:22][CH2:21][O:20][CH2:19][CH2:18]2)[N:13]=[C:14]([N:4]2[CH2:5][CH2:6][O:7][C:2]([CH3:8])([CH3:1])[CH2:3]2)[CH:15]=1
Reactant: Clc1cc(Cl)nc(N2CCOCC2)n1
Reactant: CC1(C)CNCCO1
Solvent: CCN(CC)CC
Solvent: CCO
Product: CC1(C)CN(c2cc(Cl)nc(N3CCOCC3)n2)CCO1
Temperature: 110 °C

Procedure:
A mixture of 2,2-dimethylmorpholine (2.0 equiv.), 4-(4,6-dichloropyrimidin-2-yl)morpholine (1 equiv.) and triethylamine (6 equiv.) in EtOH (0.2 M) were heated to 110° C. for 25 min in the microwave. The reaction mixture was partitioned between EtOAc and water. The organic phase was dried over sodium sulfate. The resulting solution was concentrated and dried under vacuo to give 4-(6-chloro-2-morpholinopyrimidin-4-yl)-2,2-dimethylmorpholine and was used in the next step without further purification. LCMS (m/z) (M+H)=313.2, Rt=0.86 min.
Reaction SMILES: C(=O)=O.CO.[OH:6][CH:7]([CH2:21][OH:22])[CH2:8][CH2:9][NH:10][C:11](=[O:20])[O:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>>[CH2:13]([O:12][C:11](=[O:20])[NH:10][CH2:9][CH2:8][C@H:7]([OH:6])[CH2:21][OH:22])[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: O=C(NCCC(O)CO)OCc1ccccc1
Agent: O=C=O
Solvent: CO
Product: O=C(NCC[C@H](O)CO)OCc1ccccc1

Procedure:
The title compound was prepared by chiral separation (Preparative chiral SFC, ChiralPak® AD-H, 250×50 mm, mobile phase: CO2/MeOH (3:2), flow rate: 110 mL/min, back pressure: 100 bar, column temperature: 38° C., wavelength: 210 nm, cycletime: ˜4.0 min) of a racemic mixture of benzyl (3,4-dihydroxybutyl)carbamate (Prepared accordingly to WO2011107608), faster eluting isomer (Peak 1). Analytical chiral SFC (ChiralPak AD-3, 150×4.6 mm, eluent: CO2/MeOH+0.05% DEA (75:35), flow rate: 2.5 mL/min, back pressure: 100 bar, temperature: 35° C., 210 nm): tR=2.22 min.
Reaction SMILES: [Cl:1][C:2]1[C:10]([F:11])=[C:9]2[C:5]([C:6]([S:26][C:27]3[CH:32]=[CH:31][CH:30]=[C:29]([C:33]([O:35][CH2:36][CH3:37])=[O:34])[C:28]=3[F:38])=[C:7](C3CC3)[N:8]2[C:12]2[CH:13]=N[N:15]([CH2:17][CH2:18]CC(O)=O)[CH:16]=2)=[CH:4][CH:3]=1.C1C(=O)N([Br:46])C(=O)C1>C(Cl)Cl.O>[Br:46][C:7]1[N:8]([C:12]2[CH:16]=[N:15][CH:17]=[CH:18][CH:13]=2)[C:9]2[C:5]([C:6]=1[S:26][C:27]1[C:28]([F:38])=[C:29]([CH:30]=[CH:31][CH:32]=1)[C:33]([O:35][CH2:36][CH3:37])=[O:34])=[CH:4][CH:3]=[C:2]([Cl:1])[C:10]=2[F:11]
Reactant: O=C1CCC(=O)N1Br
Reactant: CCOC(=O)c1cccc(Sc2c(C3CC3)n(-c3cnn(CCCC(=O)O)c3)c3c(F)c(Cl)ccc23)c1F
Solvent: O
Solvent: ClCCl
Product: CCOC(=O)c1cccc(Sc2c(Br)n(-c3cccnc3)c3c(F)c(Cl)ccc23)c1F
Reaction time: 16 h
Yield: 51.4 %

Procedure:
To a stirred solution of indole 1 (Example 22, Step 2; 60 mg, 0.13 mmol) in CH2Cl2 (5 mL) under inert atmosphere was added NBS (60 mg, 0.33 mmol) at RT and stirred for 16 h. The mixture was diluted with water (10 mL) and extracted with CH2Cl2 (2×25 mL). The combined organic extracts were washed with brine (10 mL), dried (Na2SO4), filtered and concentrated under reduced pressure to obtain the crude. This was purified (silica gel; 10% EtOAc/hexanes) to afford compound 2 (35 mg, 50%) as a pale brown solid. 1H NMR (500 MHz, DMSO-d6): δ 8.91 (s, 1H), 8.81-8.80 (m, 1H), 8.20 (d, J=8.5 Hz, 1H), 7.70-7.66 (m, 2H), 7.40-7.37 (m, 2H), 7.18 (t, J=8.0 Hz, 1H), 7.16-7.13 (m, 1H), 4.33 (q, 2H), 1.32 (t, J=7.5 Hz, 3H); MS: m/z 525.3 (M++2).
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6](B(O)O)[CH:7]=[CH:8][CH:9]=1)(=[O:3])[CH3:2].Br[C:14]1[CH:15]=[C:16]2[C:20](=[CH:21][CH:22]=1)[C:19](=[O:23])[CH2:18][CH2:17]2>>[C:1]([C:4]1[CH:5]=[C:6]([C:14]2[CH:15]=[C:16]3[C:20](=[CH:21][CH:22]=2)[C:19](=[O:23])[CH2:18][CH2:17]3)[CH:7]=[CH:8][CH:9]=1)(=[O:3])[CH3:2]
Reactant: O=C1CCc2cc(Br)ccc21
Reactant: CC(=O)c1cccc(B(O)O)c1
Product: CC(=O)c1cccc(-c2ccc3c(c2)CCC3=O)c1

Procedure:
The title compound was prepared from 3-acetylphenyl boronic acid and 5-bromo-1-indanone according to the coupling procedure as described in example 6. MS (ESI) m/z 251; HRMS: calcd for C17H14O2+H+, 251.10666; found (ESI, [M+H]+), 251.1077.
Reaction SMILES: [CH2:1]([O:13][C:14]1[CH:22]=[CH:21][C:17]([C:18](O)=O)=[CH:16][CH:15]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].[H-].[H-].[H-].[H-].[Li+].[Al+3].C(OC1C=CC(CO)=CC=1)CCCCCCCCCCC.P(Br)(Br)[Br:51]>>[CH2:1]([O:13][C:14]1[CH:22]=[CH:21][C:17]([CH2:18][Br:51])=[CH:16][CH:15]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12]
Reactant: BrP(Br)Br
Reactant: CCCCCCCCCCCCOc1ccc(C(=O)O)cc1
Agent: CCCCCCCCCCCCOc1ccc(CO)cc1
Agent: [Al+3]
Agent: [H-]
Product: CCCCCCCCCCCCOc1ccc(CBr)cc1

Procedure:
According to customary procedures, 4-dodecyloxybenzoic acid was reduced with LiAlH4 and the formed 4-dodecyloxybenzyl alcohol was brominated with phosphorus tribromide to obtain 4-dodecyloxybenzyl bromide. Then, 2.0 g of the so-obtained compound was reacted with 1.0 g of p-acetoxyphenol in the presence of NaH in dimethylformamide to obtain 1.2 g of 4-dodecyloxybenzyl(4-acetoxyphenyl) ether. The so-obtained compounds was dissolved in a liquid mixture of tetrahydrofuran and an equimolar amount of 1N LiOH was added to the solution to remove the acetyl group, and post treatments were carried out according to customary procedures to obtain 1.0 g of 4-dodecyloxybenzyl(4-hydroxyphenyl) ether.
Reaction SMILES: [CH3:1][C:2]1[C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:8]=2[C:9]2[CH:10]=[CH:11][C:12]3[CH:16]=[C:15](C(OCC)=O)[S:14][C:13]=3[C:22]=2[CH:23]=1>CCO>[CH3:1][C:2]1[C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:8]=2[C:9]2[CH:10]=[CH:11][C:12]3[CH:16]=[CH:15][S:14][C:13]=3[C:22]=2[CH:23]=1
Reactant: CCOC(=O)c1cc2ccc3c4ccccc4c(C)cc3c2s1
Solvent: CCO
Product: Cc1cc2c(ccc3ccsc32)c2ccccc12
Yield: 82.3 %

Procedure:
Ethyl 5-methylphenanthro[1,2-b]thiophene-2-carboxylate (H. G. Pars Pharmaceutical Laboratories, Inc.) was hydrolyzed and decarboyxlated according to the procedure outlined in Example 15B to give an 82.3% yield of 5-methylphenanthro[1,2-b]thiophene, mp 129.5°-131°, (EtOH), (C,N,S).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][N:11]=1)[N:8]([CH2:12][C@H:13]1[CH2:17][CH2:16][NH:15][CH2:14]1)[CH:7]=[C:6]([C:18]([O:20][CH2:21][CH3:22])=[O:19])[C:5]2=[O:23].I[CH2:25][CH2:26][CH3:27].C(=O)([O-])[O-].[K+].[K+]>C(#N)C.CN(C=O)C>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][N:11]=1)[N:8]([CH2:12][C@H:13]1[CH2:17][CH2:16][N:15]([CH2:25][CH2:26][CH3:27])[CH2:14]1)[CH:7]=[C:6]([C:18]([O:20][CH2:21][CH3:22])=[O:19])[C:5]2=[O:23]
Reactant: CCOC(=O)c1cn(C[C@H]2CCNC2)c2cnc(Br)cc2c1=O
Reactant: CCCI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: CN(C)C=O
Product: CCCN1CC[C@H](Cn2cc(C(=O)OCC)c(=O)c3cc(Br)ncc32)C1
Temperature: 60 °C
Reaction time: 48 h
Yield: 38 %

Procedure:
To a solution of (5)-ethyl 6-bromo-4-oxo-1-(pyrrolidin-3-ylmethyl)-1,4-dihydro-1,7-naphthyridine-3-carboxylate Intermediate 94 (511.5 mg, 1.2 mmol, 1 equiv.) in acetonitrile (3 mL) and DMF (1 mL) was added iodopropane (0.234 mL, 2.4 mmol, 2 equiv.) followed by potassium carbonate (663 mg, 4.8 mmol, 4 equiv.). The reaction was stirred at 60° C. for 2 days. The reaction was cooled to 23° C. and concentrated. The residue was re-suspended and partitioned between ethyl acetate (10 mL) and water (10 mL). The aqueous layer was extracted with ethyl acetate (2×10 mL), and the organics were dried and concentrated to afford (S)-ethyl 6-bromo-4-oxo-1-((1-propylpyrrolidin-3-yl)methyl)-1,4-dihydro-1,7-naphthyridine-3-carboxylate (211 mg, 38%). Calcd for C19H24BrN3O3 [M+H]+: 424.0.
Reaction SMILES: FC(F)(F)C(O)=O.[CH:8]12[NH:15][CH:12]([CH2:13][CH2:14]1)[CH2:11][N:10]([C:16](=[O:21])[C:17]([F:20])([F:19])[F:18])[CH2:9]2.C(N(CC)CC)C.Br[CH2:30][C:31]1[S:39][C:38]2[C:37]([N:40]3[CH2:45][CH2:44][O:43][CH2:42][CH2:41]3)=[N:36][C:35]([Cl:46])=[N:34][C:33]=2[CH:32]=1>C1COCC1>[Cl:46][C:35]1[N:36]=[C:37]([N:40]2[CH2:41][CH2:42][O:43][CH2:44][CH2:45]2)[C:38]2[S:39][C:31]([CH2:30][N:15]3[CH:8]4[CH2:14][CH2:13][CH:12]3[CH2:11][N:10]([C:16](=[O:21])[C:17]([F:18])([F:19])[F:20])[CH2:9]4)=[CH:32][C:33]=2[N:34]=1
Reactant: O=C(N1CC2CCC(C1)N2)C(F)(F)F
Reactant: Clc1nc(N2CCOCC2)c2sc(CBr)cc2n1
Solvent: O=C(O)C(F)(F)F
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: O=C(N1CC2CCC(C1)N2Cc1cc2nc(Cl)nc(N3CCOCC3)c2s1)C(F)(F)F
Temperature: 25 °C
Reaction time: 17 h
Yield: 71 %

Procedure:
To a solution of 1-(3,8-diaza-bicyclo[3.2.1]oct-3-yl)-2,2,2-trifluoro-ethanone trifluoroacetic acid salt (106 mg, 0.33 mmol) in THF (5 mL) were added triethylamine (161 μL, 1.16 mmol) and 6-bromomethyl-2-chloro-4-morpholin-4-yl-thieno[3,2-d]pyrimidine (100 mg, 0.29 mmol). The reaction mixture was stirred at RT for 17 h, then concentrated in vacuo. The resultant residue was purified by column chromatography to give the title compound as a white solid (98 mg, 71%).