Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3](=[O:25])[CH2:4][N:5]1[C:11](=[O:12])[CH2:10][CH2:9][N:8]([C:13](=[O:24])/[CH:14]=[CH:15]/[C:16]2[CH:21]=[CH:20][C:19]([Cl:22])=[C:18]([Cl:23])[CH:17]=2)[CH2:7][CH2:6]1.Br[CH2:27][C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29].OS([O-])(=O)=O.[K+]>C1COCC1>[CH3:1][O:2][C:3](=[O:25])[CH:4]([N:5]1[C:11](=[O:12])[CH2:10][CH2:9][N:8]([C:13](=[O:24])/[CH:14]=[CH:15]/[C:16]2[CH:21]=[CH:20][C:19]([Cl:22])=[C:18]([Cl:23])[CH:17]=2)[CH2:7][CH2:6]1)[CH2:27][C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29]
Reactant: CC(C)(C)OC(=O)CBr
Reactant: COC(=O)CN1CCN(C(=O)/C=C/c2ccc(Cl)c(Cl)c2)CCC1=O
Agent: O=S(=O)([O-])O
Agent: [K+]
Solvent: C1CCOC1
Product: COC(=O)C(CC(=O)OC(C)(C)C)N1CCN(C(=O)/C=C/c2ccc(Cl)c(Cl)c2)CCC1=O
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 18 %

Procedure:
A solution of 0.50 g (1.30 mmol) of {4-[(E)-3-(3,4-dichloro-phenyl)-acryloyl]-7-oxo-[1,4]diazepan-1-yl}-acetic acid methyl ester in 25 ml of THF was treated slowly at −78° C. with 1.48 ml (1.48 mmol) of lithium hexamethyldisilylazide 1M in THF. After 30 min at −78° C., a solution of 0.67 ml (4.54 mmol) of tert-butyl bromoacetate in 2.5 ml of THF was added dropwise. The solution was stirred at −78° C. for 5 h, poured on cooled aqueous 10% KHSO4 solution and extracted with Et2O (3×). The organic phases were washed with aqueous 10% NaCl, dried (Na2SO4) and evaporated. The residue was purified on a SiO2-column (n-heptane/EtOAc 1:1 to 2:3) to afford the titled compound in 18% yield as light yellow foam. MS: 499.1 (MH+, 2Cl).
Reaction SMILES: [CH2:1]([O:8][CH2:9][C@@:10]1([N:43]2[CH:51]=[C:49]([CH3:50])[C:47](=[O:48])[NH:46][C:44]2=[O:45])[O:42][C@H:22]([CH2:23][O:24][Si](C(C)(C)C)(C2C=CC=CC=2)C2C=CC=CC=2)[C@@H:12]([O:13][C:14](=[O:21])[C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH2:11]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.N1C=CC=CC=1.F>C1COCC1.CCOC(C)=O>[CH2:1]([O:8][CH2:9][C@@:10]1([N:43]2[CH:51]=[C:49]([CH3:50])[C:47](=[O:48])[NH:46][C:44]2=[O:45])[O:42][C@H:22]([CH2:23][OH:24])[C@@H:12]([O:13][C:14](=[O:21])[C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH2:11]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cc1cn([C@@]2(COCc3ccccc3)C[C@H](OC(=O)c3ccccc3)[C@@H](CO[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)O2)c(=O)[nH]c1=O
Agent: F
Solvent: C1CCOC1
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Product: Cc1cn([C@@]2(COCc3ccccc3)C[C@H](OC(=O)c3ccccc3)[C@@H](CO)O2)c(=O)[nH]c1=O
Yield: 96.8 %

Procedure:
The silyl ether 4 (96.0 g, 136.4 mmol) in THF (600 mL) was treated with hydrogen fluoride-pyridine (70% HF in pyridine, 30 mL) at 0° C. for 4 h under a N2 atmosphere. The resultant mixture was diluted with AcOEt (600 mL) and washed with H2O (2×300 mL). The organic layer was dried (MgSO4) and concentrated at reduced pressure. The residue was purified by silica gel column chromatography (CH2Cl2 /AcOEt 10:1) to give 61.6 g (97%) of 5 as a white solid. Rf (CH2Cl2 /AcOEt 10:1) 0.29. 1H-NMR (CDCl3 +D2O): 1.95 (s, 3H, 5-Me), 2.53 (m, 2H, 2'-H), 4.00 (m, 2H, 5'-H), 4.25 (m, 1H, 4'-H), 4.71 (s, 2H, O--CH2 --Ph), 5.51 (s, 2H, N--CH2 --O), 5.60 (m, 1H 3'-H), 6.36 (dd, 1H, J=7.6, 6.6 Hz, 1'-H), 7.25-7.66 (m, 9H, 6-H and aromatic-H), 8.05 (d, 2H, J=7.1 Hz, aromatic-H). 13C-NMR (CDCl3): 13.29 (-, 5-Me), 37.82 (+, 2'-C), 62.54 (+, 5'-C), 70.73 (+, O--C--Ph), 72.25 (+, N--C--O), 75.82 (-, 4'-C), 85.43 (-, 3'-C), 86.13 (-, 1'-C), 110.41 (+, 5-C), 127.65, 128.36, 128.59 (-, aromatic-C), 129.34 (+, aromatic-C), 129.69 (-, 6-C), 133.60, 135.40 (-, aromatic-C), 137.87 (+, aromatic-C), 151.18 (+, 2-C), 163.65 (+, 4-C), 166.11 (+, benzoyl C=O).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([C:8]2[S:12][C:11]([CH:13]([CH3:15])[CH3:14])=[N:10][C:9]=2[C:16]2[CH:17]=[C:18]([CH:20]=[CH:21][CH:22]=2)[NH2:19])[CH:5]=[CH:4][N:3]=1.[CH3:23][N:24]1[CH:28]=[C:27]([S:29](Cl)(=[O:31])=[O:30])[CH:26]=[N:25]1>>[Cl:1][C:2]1[N:7]=[C:6]([C:8]2[S:12][C:11]([CH:13]([CH3:15])[CH3:14])=[N:10][C:9]=2[C:16]2[CH:17]=[C:18]([NH:19][S:29]([C:27]3[CH:26]=[N:25][N:24]([CH3:23])[CH:28]=3)(=[O:31])=[O:30])[CH:20]=[CH:21][CH:22]=2)[CH:5]=[CH:4][N:3]=1
Reactant: Cn1cc(S(=O)(=O)Cl)cn1
Reactant: CC(C)c1nc(-c2cccc(N)c2)c(-c2ccnc(Cl)n2)s1
Product: CC(C)c1nc(-c2cccc(NS(=O)(=O)c3cnn(C)c3)c2)c(-c2ccnc(Cl)n2)s1
Yield: 58.6 %

Procedure:
Following a procedure analogous to the procedure described in Intermediate 14 using 3-[5-(2-chloro-4-pyrimidinyl)-2-(1-methylethyl)-1,3-thiazol-4-yl]aniline (600 mg, 1.8 mmol) and 1-methyl-1H-pyrazole-4-sulfonyl chloride (0.49 g, 2.7 mmol) the title compound was obtained (500 mg, 58.6% yield). 1H NMR (400 MHz, CDCl3) δ ppm 8.31 (d, J=5.3 Hz, 1H), 7.72 (d, J=0.9 Hz, 1H), 7.65 (d, J=0.9 Hz, 1H), 7.32-7.37 (m, 1H), 7.21-7.30 (m, 2H), 6.94 (S, 1H), 6.92 (d, J=5.3 Hz, 1H), 3.86 (S, 3H), 3.31-3.41 (m, 1H), 1.44 (d, J=6.8, 6H). MS (ES+): 475 [M+H]+.
Reaction SMILES: [CH2:1]([N:13]1[N:17]=[N:16][C:15]([NH:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[N:14]1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12]>[Ru].C(O)C>[CH:19]1([NH:18][C:15]2[N:16]=[N:17][N:13]([CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12])[N:14]=2)[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24]1
Reactant: CCCCCCCCCCCCn1nnc(Nc2ccccc2)n1
Agent: [Ru]
Solvent: CCO
Product: CCCCCCCCCCCCn1nnc(NC2CCCCC2)n1
Temperature: 25 °C

Procedure:
A mixture of 2-dodecyl-N-phenyl-2H-tetrazol-5-amine (1.54 g, 0.00467 mol) and absolute ethanol (100 mL) was hydrogenated over 10% ruthenium on carbon (0.5 g) at 1100 psi and 100° C. for 10 hours. The mixture was allowed to cool to room temperature, and the catalyst was filtered off and washed with additional ethanol (200 mL). The filtrate and washings were combined and rotoevaporated to a glaze. The glaze was triturated with diethyl ether. The organic triturate was rotoevaporated to a solid, and the solid chromatographed on silica gel (50 g, 70-230 mesh) using PET ether-acetone (10:1, 7×50 mL) as eluent. Fractions containing title compound were rotoevaporated from dichloromethane to a white solid. The solid was dried in vacuo (25° C.), yield 1.30 g (83%), mp=51°-53° C.
Reaction SMILES: [C:1](Cl)(=[O:17])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16].[NH:19]([CH2:23][CH2:24][OH:25])[CH2:20][CH2:21][OH:22]>C(OCC)C.CO>[OH:22][CH2:21][CH2:20][N:19]([CH2:23][CH2:24][OH:25])[C:1](=[O:17])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16]
Reactant: OCCNCCO
Reactant: CCCCCCCCCCCCCCCC(=O)Cl
Solvent: CO
Solvent: CCOCC
Product: CCCCCCCCCCCCCCCC(=O)N(CCO)CCO
Temperature: 0 °C

Procedure:
A solution of 2.75 g palmitoyl chloride (10 mmol) in 20 ml anhydrous ethylether is added drop by drop in 30 minutes to a solution of 2.2 g diethanolamine (21 mmol) in 50 ml methanol and 100 ml anhydrous ethyl ether under continuous stirring at 0° C.
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][N:5]1[CH2:10][CH2:9][NH:8][CH2:7][C:6]1=[O:11].[CH2:12]=O>C(O)=O>[OH:1][CH2:2][CH2:3][CH2:4][N:5]1[CH2:10][CH2:9][N:8]([CH3:12])[CH2:7][C:6]1=[O:11]
Reactant: O=C1CNCCN1CCCO
Reactant: C=O
Solvent: O=CO
Product: CN1CCN(CCCO)C(=O)C1
Temperature: 25 °C
Reaction time: 4.5 h
Yield: 93 %

Procedure:
1-(3-Hydroxypropyl)piperazin-2-one (700 mg, 4.43 mmol) in formic acid (10 ml) and 37/40% aqueous formaldehyde solution (5 ml) was stirred and heated at 95° for 2 hr then the resulting solution evaporated in vacuo. The residue was taken up in 5% methanol in dichloromethane (20 ml), basified with a 7N solution of ammonia in methanol and stirred 4.5 hr at room temperature. The mixture was filtered and the filtrate purified by column chromatography on silica using increasing concentrations of methanolic ammonia in dichloromethane as eluent to give 1-(3-hydroxypropyl)-4-methylpiperazin-2-one (710 mg, 93%) as a colourless oil; NMR Spectrum:(CDCl3) 1.73 (quintet, 2H), 2.34 (s, 3H), 2.66 (t, 2H), 3.13 (s, 2H), 3.33 (t, 2H), 3.53 (m, 4H), 3.80 (s(broad, 1H).
Reaction SMILES: B([O-])([O-])O[C:3]1[CH:8]=[CH:7][C:6]([O:9][CH3:10])=[CH:5][CH:4]=1.Br[C:14]1[CH:19]=[CH:18][C:17]([C:20]2[CH:25]=[CH:24][C:23]([C:26]#[N:27])=[CH:22][CH:21]=2)=[C:16]([F:28])[CH:15]=1.C1C=CC=CC=1.C(=O)([O-])[O-].[K+].[K+]>C(O)C.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[CH3:10][O:9][C:6]1[CH:7]=[CH:8][C:3]([C:18]2[C:17]([C:20]3[CH:21]=[CH:22][C:23]([C:26]#[N:27])=[CH:24][CH:25]=3)=[C:16]([F:28])[CH:15]=[CH:14][CH:19]=2)=[CH:4][CH:5]=1
Reactant: COc1ccc(OB([O-])[O-])cc1
Reactant: N#Cc1ccc(-c2ccc(Br)cc2F)cc1
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: c1ccccc1
Solvent: CCO
Product: COc1ccc(-c2cccc(F)c2-c2ccc(C#N)cc2)cc1
Temperature: 25 °C
Yield: 47.5 %

Procedure:
A solution of 7.6 g of 4-methoxyphenyl borate dissolved in 60 ml of ethanol was dropped at room temperature into a mixture containing 13 g of 4-bromo-2-fluoro-4'-cyanobiphenyl, 0.5 g of tetrakis (triphenylphosphine) palladium, 90 ml benzene and 70 ml of a 2M potassium carbonate aqueous solution. This was then refluxed for five hours and cooled to room temperature, the reaction liquid was extracted with chloroform and washed three times with water, and the chloroform was removed. The residue that was obtained underwent vacuum distillation, and then was recrystallized from acetone to yield 6.6 g of 4-methoxy-3'-fluoro-4"-cyanoterphenyl. This compound exhibited a nematic liquid crystal phase, with a C-N point of 126° C. and an N-I point of 247.3° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:9][CH2:10][CH2:11]Cl)=[CH:4][CH:3]=1.[CH3:13][CH:14]([CH3:30])[C:15]([NH:17][C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([CH:24]2[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]2)[CH:19]=1)=[O:16]>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:9][CH2:10][CH2:11][N:27]2[CH2:28][CH2:29][CH:24]([C:20]3[CH:19]=[C:18]([NH:17][C:15](=[O:16])[CH:14]([CH3:13])[CH3:30])[CH:23]=[CH:22][CH:21]=3)[CH2:25][CH2:26]2)=[CH:4][CH:3]=1
Reactant: ClCCCOc1ccc(Cl)cc1
Reactant: CC(C)C(=O)Nc1cccc(C2CCNCC2)c1
Product: CC(C)C(=O)Nc1cccc(C2CCN(CCCOc3ccc(Cl)cc3)CC2)c1

Procedure:
Prepared by Procedure G and Scheme B1 using 1-chloro-4-(3-chloropropoxy)benzene and 2-methyl-N-[3-(4-piperidinyl)phenyl]propanamide: 1H NMR (400 MHz, CDCl3) δ 7.71 (dd, 1H, J=3.2, 5.7 Hz), 7.53 (dd, 1H, J=3.2, 5.7 Hz), 7.50 (m, 1H), 7.31 (m, 1H), 7.24-7.20 (m, 2H), 6.94 (d, 1H, J=7.9 Hz), 6.85-6.82 (m, 2H), 4.00 (t, 2H, J=6.1 Hz), 3.07 (d, 2H, J=10.9 Hz), 2.55 (m, 3H), 2.50 (sept, 1H, J=6.2 Hz), 2.08 (dt, 2H, J=3.1, 10.9 Hz), 2.00 (m, 2H), 1.83 (m, 3H), 1.69 (qt, 1H, J=6.2 Hz), 1.24 (d, 6H, J=6.8 Hz); Anal. Calcd for C24H31ClN2O2+HCl: C, 63.8; H, 7.09; N, 6.21. Found: C, 63.3; H, 7.04; N, 6.27; ESMS m/e: 415.2 (M+H)+.
Reaction SMILES: Br[C:2]1[S:3][C:4]([NH:32]C(=O)OC(C)(C)C)=[C:5]([C:7](=[O:31])[NH:8][C:9]2[CH:10]=[N:11][N:12]([CH3:30])[C:13]=2[C@@H:14]2[CH2:20][CH2:19][C@@H:18]([NH:21]C(OC(C)(C)C)=O)[C@@H:17]([F:29])[CH2:16][O:15]2)[N:6]=1.[F:40][C:41]1[C:42]([C:50]([F:53])([F:52])[F:51])=[C:43](B(O)O)[CH:44]=[CH:45][CH:46]=1>>[NH2:32][C:4]1[S:3][C:2]([C:43]2[CH:44]=[CH:45][CH:46]=[C:41]([F:40])[C:42]=2[C:50]([F:51])([F:53])[F:52])=[N:6][C:5]=1[C:7]([NH:8][C:9]1[CH:10]=[N:11][N:12]([CH3:30])[C:13]=1[C@@H:14]1[CH2:20][CH2:19][C@@H:18]([NH2:21])[C@@H:17]([F:29])[CH2:16][O:15]1)=[O:31]
Reactant: Cn1ncc(NC(=O)c2nc(Br)sc2NC(=O)OC(C)(C)C)c1[C@@H]1CC[C@@H](NC(=O)OC(C)(C)C)[C@@H](F)CO1
Reactant: OB(O)c1cccc(F)c1C(F)(F)F
Product: Cn1ncc(NC(=O)c2nc(-c3cccc(F)c3C(F)(F)F)sc2N)c1[C@@H]1CC[C@@H](N)[C@@H](F)CO1

Procedure:
Following the procedure for Example 101 starting from tert-butyl N-[2-bromo-4-[[5-[(2S,5R,6R)-5-(tert-butoxycarbonylamino)-6-fluoro-oxepan-2-yl]-1-methyl-pyrazol-4-yl]carbamoyl]thiazol-5-yl]carbamate (Intermediate 88), and replacing 3,6-dihydro-2H-pyran-4-boronic acid pinacol ester with (3-fluoro-2-(trifluoromethyl)phenyl)boronic acid gave 267. 1H NMR (400 MHz, DMSO-d6) δ 9.25 (s, 1H), 7.87-7.76 (m, 2H), 7.66-7.50 (m, 2H), 7.44 (s, 2H), 4.90 (dd, J=7.6, 3.8 Hz, 1H), 4.82-4.50 (m, 1H), 3.95-3.75 (m, 2H), 3.70 (s, 3H), 3.13 (dd, J=21.1, 8.4 Hz, 1H), 2.22-2.11 (m, 1H), 1.79-1.51 (m, 5H). LCMS (ES+) m/z 517 (M+1).
Reaction SMILES: [N:1]1([C:7]2[CH:14]=[CH:13][CH:12]=[CH:11][C:8]=2[C:9]#[N:10])[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.C(=O)([O-])[O-].[K+].[K+].[I-].[K+].Br[CH2:24][CH2:25][CH:26]=[C:27]1[C:33]2[CH:34]=[CH:35][CH:36]=[CH:37][C:32]=2[CH2:31][CH2:30][C:29]2[CH:38]=[CH:39][CH:40]=[CH:41][C:28]1=2>C(C(C)=O)C.C(OCC)(=O)C>[CH:38]1[C:29]2[CH2:30][CH2:31][C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=3[C:27](=[CH:26][CH2:25][CH2:24][N:4]3[CH2:5][CH2:6][N:1]([C:7]4[CH:14]=[CH:13][CH:12]=[CH:11][C:8]=4[C:9]#[N:10])[CH2:2][CH2:3]3)[C:28]=2[CH:41]=[CH:40][CH:39]=1
Reactant: N#Cc1ccccc1N1CCNCC1
Reactant: BrCCC=C1c2ccccc2CCc2ccccc21
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CCC(C)=O
Solvent: CCOC(C)=O
Product: N#Cc1ccccc1N1CCN(CCC=C2c3ccccc3CCc3ccccc32)CC1
Temperature: 25 °C

Procedure:
The above benzonitrile (4.89 g, 26 mmol) was dissolved in methyl ethyl ketone (100 ml), and potassium carbonate (21.7 g, 157 mmol), potassium iodide (3.45 g, 52 mmol), and 5-(3-bromo-1-propylidene)-10,11-dihydro-5H-dibenzo[a,d]cycloheptene (8.18 g, 26 mmol), were added. The resulting mixture was stirred at reflux temperature for 18 h. After cooling to room temperature, ethyl acetate (200 ml) was added and the mixture was washed with water (2×150 ml), dried (MgSO4) and concentrated in vacuo. The residue was purified by flash chromatography on silica gel eluting first with a mixture of ethyl acetate and heptane (1:4), and then with a mixture of ethyl acetate and heptane (1:2). This afforded 5.60 g of the title compound as a solid.
Reaction SMILES: [CH2:1]([S:8]([N:11]([CH2:35][C:36]([F:39])([F:38])[F:37])[C@H:12]1[CH2:17][CH2:16][C@H:15]([C:18]([O:27][Si](CC)(CC)CC)([C:23]([F:26])([F:25])[F:24])[C:19]([F:22])([F:21])[F:20])[CH2:14][CH2:13]1)(=[O:10])=[O:9])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C[Si]([N-][Si](C)(C)C)(C)C.[Li+].[CH2:50](Br)[C:51]1[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=1.Cl>C1COCC1.CCOCC>[F:39][C:36]([F:37])([F:38])[CH2:35][N:11]([C@H:12]1[CH2:17][CH2:16][C@H:15]([C:18]([OH:27])([C:19]([F:22])([F:20])[F:21])[C:23]([F:24])([F:25])[F:26])[CH2:14][CH2:13]1)[S:8]([CH:1]([C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[CH2:50][C:51]1[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=1)(=[O:10])=[O:9]
Reactant: BrCc1ccccc1
Reactant: CC[Si](CC)(CC)OC([C@H]1CC[C@H](N(CC(F)(F)F)S(=O)(=O)Cc2ccccc2)CC1)(C(F)(F)F)C(F)(F)F
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: Cl
Agent: [Li+]
Solvent: CCOCC
Solvent: C1CCOC1
Product: O=S(=O)(C(Cc1ccccc1)c1ccccc1)N(CC(F)(F)F)[C@H]1CC[C@H](C(O)(C(F)(F)F)C(F)(F)F)CC1
Reaction time: 0.5 h

Procedure:
A solution of 50 mg (0.08 mmol) of trans benzyl-N-(2,2,2-trifluoro-ethyl)-N-[4-(2,2,2-trifluoro-1-triethylsilanyloxy-1-trifluoromethyl-ethyl)-cyclohexyl]-sulfonamide (example 30.1) in 0.5 mL of THF was cooled to −78° C. and treated with 0.11 mL of a 1M solution lithium bis(trimethylsilyl)amide in THF. The mixture was allowed to reach ca −5° C. within 30 min and treated with 0.11 mL (0.1 mmol) of benzylbromide. The mixture was stirred overnight and distributed between diluted aqueous solution of HCl and Et2O. The combined organic phases were dried over Na2SO4 and the solvent was evaporated. The residue was redissolved in MeOH and treated with 0.5 mL of a 2M solution of NaOMe in MeOH. Distribution of this solution between a saturated aqueous solution of NH4Cl and Et2O, drying of the combined organic phases over Na2SO4, evaporation and column chromatography on silica gel with heptane/EtOAc 4:1 gave 50 mg (76%) of (rac) trans 1,2-diphenyl-ethanesulfonic acid (2,2,2-trifluoro-ethyl)-[4-(2,2,2-trifluoro-1-hydroxy-1-trifluoromethyl-ethyl)-cyclohexyl]-amide as a colorless foam, MS: 590 (M−H)−.
Reaction SMILES: [ClH:1].O1CCOCC1.C(OC([N:15]1[CH2:20][CH2:19][C:18]([NH:31]C(OC(C)(C)C)=O)([CH2:21][O:22][CH2:23][C:24]2[CH:29]=[CH:28][C:27]([Cl:30])=[CH:26][CH:25]=2)[CH2:17][CH2:16]1)=O)(C)(C)C>CO>[ClH:30].[ClH:1].[Cl:30][C:27]1[CH:26]=[CH:25][C:24]([CH2:23][O:22][CH2:21][C:18]2([NH2:31])[CH2:19][CH2:20][NH:15][CH2:16][CH2:17]2)=[CH:29][CH:28]=1
Reactant: CC(C)(C)OC(=O)NC1(COCc2ccc(Cl)cc2)CCN(C(=O)OC(C)(C)C)CC1
Agent: Cl
Solvent: CO
Solvent: C1COCCO1
Product: NC1(COCc2ccc(Cl)cc2)CCNCC1
Temperature: 25 °C
Reaction time: 17 h
Yield: 100 %

Procedure:
A 4M solution of HCl in dioxane (0.68 ml, 2.7 mmol) was added dropwise to a solution of 4-tert-butoxycarbonylamino-4-(4-chloro-benzyloxymethyl)-piperidine-1-carboxylic acid tert-butyl ester (12 mg, 0.028 mmol) in methanol (1 mL). The solution was stirred at rt for 17 h. The solvents were removed by evaporation to give 4-(4-chloro-benzyloxymethyl)-piperidin-4-ylamine dihydrochloride (9.2 mg, 0.028 mmol, 100%) that was used in the next step without further purification.
Reaction SMILES: FC(F)(F)C([O-])=O.[F:8][C:9]1[CH:14]=[CH:13][C:12]([CH:15]([C:20]2[C:28]3[C:23](=[CH:24][C:25]([O:29][CH2:30][CH2:31][CH2:32][N:33]([C:41]4[CH:46]=[CH:45][CH:44]=[CH:43][NH+:42]=4)CC4C=CC=CC=4)=[CH:26][CH:27]=3)[NH:22][CH:21]=2)[CH2:16][C:17]([OH:19])=[O:18])=[CH:11][CH:10]=1.C(=O)([O-])O.[Na+]>CC(C)=O.[Pd]>[F:8][C:9]1[CH:10]=[CH:11][C:12]([CH:15]([C:20]2[C:28]3[C:23](=[CH:24][C:25]([O:29][CH2:30][CH2:31][CH2:32][NH:33][C:41]4[CH:46]=[CH:45][CH:44]=[CH:43][N:42]=4)=[CH:26][CH:27]=3)[NH:22][CH:21]=2)[CH2:16][C:17]([OH:19])=[O:18])=[CH:13][CH:14]=1
Reactant: O=C(O)CC(c1ccc(F)cc1)c1c[nH]c2cc(OCCCN(Cc3ccccc3)c3cccc[nH+]3)ccc12
Agent: [Pd]
Agent: O=C([O-])C(F)(F)F
Agent: O=C([O-])O
Solvent: CC(C)=O
Product: O=C(O)CC(c1ccc(F)cc1)c1c[nH]c2cc(OCCCNc3ccccn3)ccc12
Reaction time: 10 h

Procedure:
60 mg (94 μmol) of 26 are dissolved in 5 ml of acetone and hydrogenated for 10 hours at RT and atmospheric pressure in the presence of 40 mg (0.48 mmol) of sodium hydrogen carbonate and 20 mg of palladium/activated carbon (10%). Removal of the catalyst by filtration and evaporation of the solution gives 3-(4-fluorophenyl)-3-{6-[3-(pyridin-2-ylamino)propoxy]indol-3-yl}propionic acid. Preparative HPLC on RP-18 gives 3-(4-fluorophenyl)-3-{6-[3-(pyridin-2-ylamino)propoxy]indol-3-yl}propionic acid trifluoroacetate.
Reaction SMILES: [CH3:1][C:2](=[CH:5][CH:6]([CH3:9])[CH2:7][CH3:8])[CH2:3][CH3:4].[Cl:10][SiH:11]([Cl:13])[Cl:12].N(C1(C#N)CCCCC1)=NC1(C#N)CCCCC1>>[CH3:1][CH:2]([CH:5]([Si:11]([Cl:13])([Cl:12])[Cl:10])[CH:6]([CH3:9])[CH2:7][CH3:8])[CH2:3][CH3:4]
Reactant: CCC(C)=CC(C)CC
Reactant: Cl[SiH](Cl)Cl
Agent: N#CC1(N=NC2(C#N)CCCCC2)CCCCC1
Product: CCC(C)C(C(C)CC)[Si](Cl)(Cl)Cl
Yield: 58.3 %

Procedure:
A one-liter autoclave equipped with a stirrer was charged in a nitrogen atmosphere with 76 grams (0.60 mol) of 3,5-dimethyl-3-heptene, 161 grams (1.2 mol) of trichlorosilane and 29 grams (0.12 mol) of 1,1'-azobis(cyclohexane-1-carbonitrile) and the mixture was reacted at a temperature of 130° C. for 5 days. The resulting reaction mixture was purified by distillation thereby obtaining 92 grams (0.35 mol) of 3,5-dimethyl-4-trichlorosilylheptane. The structure of the resulting product was identified by 1H-NMR.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:7]=[CH:8][C:9]2[NH:14][C:13](=[O:15])[O:12][CH:11]([CH:16]([CH3:18])[CH3:17])[C:10]=2[CH:19]=1.[Cl:20][C:21]1[CH:22]=[C:23]([SH:28])[CH:24]=[CH:25][C:26]=1[Cl:27]>>[Cl:20][C:21]1[CH:22]=[C:23]([S:28][CH2:2][CH2:3][CH2:4][O:5][C:6]2[CH:7]=[CH:8][C:9]3[NH:14][C:13](=[O:15])[O:12][CH:11]([CH:16]([CH3:18])[CH3:17])[C:10]=3[CH:19]=2)[CH:24]=[CH:25][C:26]=1[Cl:27]
Reactant: CC(C)C1OC(=O)Nc2ccc(OCCCCl)cc21
Reactant: Sc1ccc(Cl)c(Cl)c1
Product: CC(C)C1OC(=O)Nc2ccc(OCCCSc3ccc(Cl)c(Cl)c3)cc21

Procedure:
Prepared analogously to Example 1 from 6-(3-chloropropoxy)-4-isopropyl-4H-3,1-benzoxazin-2-one and 3,4-dichloro-thiophenol.
Reaction SMILES: [O:1]=[C:2]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[CH2:3][C:4]#[N:5].[N-:12]=[N+:13]=[N-:14].[Na+].[Cl-].C([NH+](CC)CC)C>C1(C)C=CC=CC=1>[C:6]1([C:2](=[O:1])[CH2:3][C:4]2[N:5]=[N:12][NH:13][N:14]=2)[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: N#CCC(=O)c1ccccc1
Reactant: [N-]=[N+]=[N-]
Agent: CC[NH+](CC)CC
Agent: [Cl-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: O=C(Cc1nn[nH]n1)c1ccccc1
Yield: 74 %

Procedure:
3-Oxo-3-phenyl-propionitrile (6.5 g, 45 mmol), sodium azide (3.3 g, 50 mmol) and triethylammonium chloride (6.7 g, 50 mmol) were stirred in dry toluene (100 mL) under argon at 90° C. for 18 h. A two-phase system was formed. The reaction mixture was cooled and extracted with NaOH (2M, 2×50 mL). The aqueous solution was poured into hydrochloric acid (4M, 200 mL) and the crude product precipitated and was filtered off and recrystalliced from acetonitrile. Yield: 74%.
Reaction SMILES: [C:1]([Si:5]([CH3:12])([CH3:11])[O:6][C@@H:7]([CH3:10])[CH2:8][OH:9])([CH3:4])([CH3:3])[CH3:2].O[N:14]1[C:18](=[O:19])[C:17]2=[CH:20][CH:21]=[CH:22][CH:23]=[C:16]2[C:15]1=[O:24].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>C1COCC1>[C:1]([Si:5]([CH3:12])([CH3:11])[O:6][C@@H:7]([CH3:10])[CH2:8][O:9][N:14]1[C:18](=[O:19])[C:17]2[C:16](=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:15]1=[O:24])([CH3:3])([CH3:4])[CH3:2]
Reactant: O=C1c2ccccc2C(=O)N1O
Reactant: C[C@@H](CO)O[Si](C)(C)C(C)(C)C
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: C[C@@H](CON1C(=O)c2ccccc2C1=O)O[Si](C)(C)C(C)(C)C
Temperature: 25 °C

Procedure:
To a suspension of (S)-2-(tert-butyl-dimethyl-silanyloxy)-propan-1-ol (53.0 g, 0.28 mol), N-hydroxyphthalimide (47.0 g, 0.29 mol) and triphenylphosphine (77.9 g, 0.30 mol) in THF (200 ml) at 0° C. was added dropwise DIAD (56.8 ml, 0.29 mol). During the addition the reagents dissolved and the solution turned a dark red colour before fading to pale yellow colour on completion of the addition. The reaction mixture was stirred and allowed to warm to room temperature overnight. The reaction mixture was concentrated in vacuo and the resultant residue re-dissolved in diethyl ether. The suspension was filtered and the filtrate was concentrated in vacuo to yield the crude title compound as a pale yellow oil. The material was used without further purification in the subsequent step.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([F:23])[CH:18]=2)=[C:5]([C:7]([N:9]2[C@H:14]([CH2:15][NH2:16])[CH2:13][C@H:12]3[C@@H:10]2[CH2:11]3)=[O:8])[N:6]=1.[CH3:24][N:25]1[C:33]([C:34](O)=[O:35])=[C:32]2[C:27]([CH:28]=[CH:29][CH:30]=[CH:31]2)=[N:26]1>>[NH2:1][C:2]1[S:3][C:4]([C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([F:23])[CH:18]=2)=[C:5]([C:7]([N:9]2[C@H:14]([CH2:15][NH:16][C:34]([C:33]3[N:25]([CH3:24])[N:26]=[C:27]4[C:32]=3[CH:31]=[CH:30][CH:29]=[CH:28]4)=[O:35])[CH2:13][C@H:12]3[C@@H:10]2[CH2:11]3)=[O:8])[N:6]=1
Reactant: Cn1nc2ccccc2c1C(=O)O
Reactant: NC[C@@H]1C[C@@H]2C[C@@H]2N1C(=O)c1nc(N)sc1-c1cccc(F)c1
Product: Cn1nc2ccccc2c1C(=O)NC[C@@H]1C[C@@H]2C[C@@H]2N1C(=O)c1nc(N)sc1-c1cccc(F)c1

Procedure:
prepared by reaction of [2-amino-5-(3-fluoro-phenyl)-thiazol-4-yl]-((1S,3S,5S)-3-aminomethyl-2-aza-bicyclo[3.1.0]hex-2-yl)-methanone with 2-methyl-2H-indazole-3-carboxylic acid. LC-MS (basic): tR=0.80 min; [M+H]+=491.0.
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:9]([OH:11])=O)=[CH:4][C:5]([F:8])=[N:6][CH:7]=1.[CH:12]([NH2:14])=O>>[F:8][C:5]1[N:6]=[CH:7][C:2]2[N:1]=[CH:12][NH:14][C:9](=[O:11])[C:3]=2[CH:4]=1
Reactant: Nc1cnc(F)cc1C(=O)O
Reactant: NC=O
Product: O=c1[nH]cnc2cnc(F)cc12
Yield: 20 %

Procedure:
Reaction of 5-amino-2-fluoropyridine-4-carboxylic acid with formamide at 140° C. as above gave 6-fluoro-3H-pyrido[3,4-d]pyrimidin-4-one (˜20%). 1H NMR (DMSO) δ 12.48 (1H, m), 8.74 (1H, s), 8.16 (1H, s), 7.63 (1H, d, J=3 Hz).